- Email: [email protected]
Presynaptic K+ channels: electrifying regulators of synaptic terminal excitability
Review
TRENDS in Neurosciences Vol.27 No.4 April 2004
Presynaptic K1 channels: electrifying regulators of synaptic terminal excitability Paul D. Dodson and Ian D. Forsythe Department of Cell Physiology and Pharmacology, University of Leicester, PO Box 138, Leicester LE1 9HN, UK
Potassium channels are crucial regulators of neuronal excitability, setting resting membrane potentials and firing thresholds, repolarizing action potentials and limiting excitability. Although most of our understanding of K1 channels is based on somatic recordings, there is good evidence that these channels are present in synaptic terminals. In recent years the improved access to presynaptic compartments afforded by direct recording techniques has indicated diverse roles for native K1 channels, from suppression of aberrant firing to action potential repolarization and activity-dependent modulation of synaptic activity. This article reviews the growing evidence for multiple roles and discrete localization of distinct K1 channels at presynaptic terminals. From the ionic basis of action potential generation [1] to the recent structural elucidation of the Kþ channel pore [2], insights into voltage-dependent activation have revolutionized our understanding of neuronal excitability, channel gating and permeation [3]. Over the past 15 years, . 70 different Kþ channel subunits have been identified and their molecular structure and diversity investigated
(Box 1). However, from a post-genomic perspective this extraordinary molecular diversity makes the task of understanding the function of native channels all the more challenging. Recent data from direct presynaptic recordings raise interesting questions about the identity, composition and precise roles of presynaptic voltage-gated Kþ channels in the regulation of synaptic transmission. It is increasingly clear that neuronal function is affected not only by ion channel properties but also by ion channel location, in focal ‘hot-spots’ around release sites [4] or as density gradients along neuronal dendrites [5], and by expression gradients across neuronal populations within a given nucleus [6,7]. In myelinated axons, compartmentalization at nodes of Ranvier is a key element of saltatory conduction – indeed, mammalian peripheral axons have few voltage-gated Kþ channels at the node [8]. In simple functional terms, a myelinated axon can be considered as three compartments (Figure 1): an initial segment, where somatic inputs summate and initiate an action potential; a variable-length myelinated axon, which must reliably transmit the information as trains of action potentials; and a final segment, beyond which the synaptic terminal
Low-voltage-activated (e.g. Kv1) High-voltage-activated (e.g. Kv3) A-type (e.g. Kv4 or Kv1.4)
Somatodendritic
Axonal
Terminal TRENDS in Neurosciences
Figure 1. Kþ channel localization. Low-voltage-activated Kþ channels (purple; e.g. Kv1) are prevalent in the initial axonal segment and terminal segment, in addition to juxtaparanodal location at nodes of Ranvier. High-voltage-activated Kþ channels (dark blue; e.g. Kv3) are localized to somatodendritic regions, sometimes as density gradients. They are also localized to synaptic terminals and nodes of Ranvier in some CNS myelinated fibres (although not at peripheral nodes). Inactivating A-type channels (orange; e.g. Kv4 or Kv1.4) are broadly expressed, contributing to activity-dependent effects on neuronal firing. They can also be localized to synaptic terminals.
Corresponding author: Ian D. Forsythe ([email protected]). www.sciencedirect.com 0166-2236/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tins.2004.02.012
Review
TRENDS in Neurosciences Vol.27 No.4 April 2004
211
Box 1. K1 channel diversity More than 70 channel subunits have been identified that possess a conserved pore architecture and are permeable to Kþ. Voltagedependent Kþ channels form as tetramers of four Kv a-subunits, each with six transmembrane domains (S1 –S6); S1 – S4 form the voltagesensing region, S5 and S6 from each a-subunit line the central pore, and the S5– S6 linker (or P region), which contains the Kþ-selective GYG motif, forms the selectivity filter [3]. Following the cloning of the four Drosophila voltage-gated Kþ channel genes Shaker, Shab, Shal and Shaw [77], 29 members of related voltage-gated Kþ channel families have been identified in mammals and divided into eight gene families [named KCNA (Kv1.1–Kv1.8), KCNB (Kv2.1 and Kv2.2), KCNC (Kv3.1– Kv3.4), KCND (Kv4.1–Kv4.3), KCNF (Kv5.1), KCNG (Kv6.1 –Kv6.4), KCNS (Kv9.1 –Kv9.3) and KCNV (Kv8.1–Kv8.3)]. The Kv1, Kv2, Kv3 and Kv4 families can form homomeric or heteromeric channels with other
expands. There are parallels between the initial and terminal segments of the axon (Figure 1) in having an associated capacitive load (those of the soma and terminal membranes, respectively) and being adjacent to regions of low action potential threshold [9]; hence, regulation of excitability will be crucial to avoid corruption of information by aberrant action potential generation. The aim of this article is to review the evidence for presynaptic localization of voltage-gated Kþ channels in the mammal, and to discuss the physiological roles of these channels in regulating action potential duration and excitability in this rather inaccessible neuronal compartment. Functional diversity of K1 channels Potassium channel diversity is created by the expression of a large number of genes, the presence of various spliced variants and the formation of heteromeric channels (Box 1). Further diversity arises through association with chaperone and scaffolding molecules regulating subcellular location. In this way, channels can perform different functions by virtue of their location (and density) in specific neuronal compartments. For instance, several types of voltage-gated Kþ channel are localized to somatodendritic regions of neurons (Figure 1), where they serve to integrate synaptic inputs and regulate action potential firing (Box 2). In myelinated axons, Kþ channels containing Kv1.1 and Kv1.2 subunits are clustered at juxtaparanodal regions (Figure 1) in both the central and peripheral nervous system [8]. By contrast, unmyelinated axons express Kv1.4 channels [10] in a much more uniform fashion. Although recordings from peripheral nodes of Ranvier indicate little outward current in mammals [11], recent evidence demonstrates that high-voltage-activated channels (containing Kv3.1b) are present at some CNS nodes [12], supporting higher frequency transmission of shorter action potentials. Relatively little is known about voltage-gated Kþ channels at or around the presynaptic terminal: to what extent does the terminal need different Kþ channels from a myelinated axon or soma, and how might they influence synaptic transmission? Presynaptic K1 channels Studies of invertebrate nerve terminals show that presynaptic voltage-gated Kþ channels are involved in action potential repolarization [13–15] and early studies confirmed www.sciencedirect.com
subunits from within their own family [78]. The remaining ‘electrically silent’ families (Kv5, Kv6, Kv8 and Kv9) are unable to form functional homomeric channels but instead form heteromers with certain members of the Kv1 –Kv4 families. Other non-pore-forming b-subunits influence channel properties, localization and trafficking [79]. This molecular variety allows considerable functional diversity but makes elucidation of native channel composition and use of transgenic knockouts difficult (because removal of one subunit might be compensated by inclusion of other subunits, generating subtle phenotypes). However, although these permutations provide a wealth of possible combinations, only a minority have been detected in the brain. For instance, only a small fraction of the possible Kv1 family combinations have been detected by immunoprecipitation from brain tissue [80 –82].
that outward Kþ currents were present in mammalian synaptic terminals [16– 18]. Although the focus here is on voltage-gated Kþ channels, presynaptic terminals possess many other channels [19] that influence presynaptic conductance and directly or indirectly regulate transmitter release. Besides Naþ and Ca2þ channels, there is good evidence for Ca2þ-activated Kþ (BK) and IH channels in nerve terminals [4,14,20 – 27]. Electrotonic synapses mediated by gap junctions [28] are important components of transmission at some synapses (e.g. chick ciliary ganglion [29] and Mauthner cell [30]) but there is no evidence for electronic transmission at mammalian CNS synapses from which direct recordings have been made (the calyx of Held, cerebellar basket cell terminals and hippocampal mossy fibres). Functionally, voltage-gated Kþ channels can be broadly divided into three groups on the basis of their sensitivity to depolarization and their propensity to inactivate (Box 2). Low-voltage-activated currents (mediated by Kv1 channels) start to activate on modest depolarizations from resting membrane potentials, whereas high-voltage-activated currents (mediated by Kv3 channels, for example) require substantial depolarization (to , 0 mV) to achieve significant activation and hence participate only in action potential repolarization. The third type of Kþ current, generally referred to as A-currents, activates on depolarization and then rapidly undergoes voltage-dependent inactivation. Sustained voltage changes and/or repetitive activation (e.g. during trains of action potentials) allow accumulation of inactivation and so produce activitydependent changes. Recent evidence shows that lowthreshold currents oppose aberrant presynaptic firing [31,32], whereas high-voltage-activated Kþ channels are involved in presynaptic action potential repolarization [22,33] and presynaptic A-currents generate activitydependent changes [16,34]. So what is the evidence for the presence of these diverse Kþ conductances in presynaptic compartments? Low-voltage-activated K1 channels dampen presynaptic excitability Low-voltage-activated channels activate at around the threshold for regenerative action potentials. Somatic recordings show that postsynaptic Kv1 conductances play important roles in regulating neuronal firing pattern
212
Review
TRENDS in Neurosciences Vol.27 No.4 April 2004
Box 2. The role of voltage-gated K1 channels Voltage-gated Kþ channels play many important roles in the nervous system, in action potential repolarization [1,68], control of postsynaptic excitability [40,44,83] and regulation of oscillatory firing and interspike interval [84,85]. The diversity of voltage-gated Kþ channel genes allows formation of a multitude of ‘delayed rectifier’ channels with a broad spectrum of physiological properties. They are closed at resting membrane potentials; on activation by depolarization they directly hyperpolarize the membrane potential and indirectly influence membrane time-constant and synaptic conductances by a shunt mechanism. Voltage-clamp is a powerful means of exploring the full activation range of a conductance but it is important to appreciate that a physiological response need trigger only a small proportion of the full conductance. From a functional perspective, three broad subdivisions of voltagegated Kþ conductances are relevant. (i) Low-voltage-activated channels (Figure Ic) produce sustained outward currents in response to small depolarizations from rest to , 2 60 mV (straddling the threshold for action potential generation) and are half-activated at , –50 mV. Although Kv1 channels will start to activate during the first action potential, their slightly slower activation and deactivation (compared with high-voltage-activated Kþ currents) mean that they will have only a minor impact on the first action potential but instead raise the threshold for generation of subsequent action potentials. (ii) High voltage-activated currents require substantial depolarization for activation (Figure Ic); consequently, these currents contribute principally to action potential repolarization. Kv3 conductances are typical high-voltage-activated currents; in postsynaptic neurons, expression of non-inactivating Kv3 conductances has been clearly linked to generation of short-duration action potentials [68] in cortical interneurons [86 –91] and fast spiking neurons in the auditory pathway [69,83]. (iii) Transient outward Kþ currents (also termed A-currents) form a third functional subdivision of outward Kþ currents. Both low-voltageand high-voltage-activated channels can exhibit inactivation, dependent on incorporation of specific subunits. Their activation upon depolarization is followed by inactivation, generating a transient conductance change (Figure Id) owing to ‘ball and chain’ N-terminal mechanisms or slower C-type inactivation [3] (e.g. Kv1.4 and Kv1 channels possessing a Kvb1 subunit [79]). These inactivating channels therefore make a significant contribution to outward currents only transiently after large depolarizations, because inactivation renders the conductance of little significance at later times. However, in the classic A-currents (e.g. Kv4) the channels are often partially inactivated at resting membrane potentials (not shown), so small changes in voltage can strongly affect this baseline level of inactivation (the so-called ‘steady-state inactivation’). A-current activation is therefore enhanced by hyperpolarization, so permitting synaptic activity to modulate intrinsic excitability. A-currents can transiently slow the latency to the first few spikes and/or change interspike interval during a train. Inactivating currents might also play a role in synaptic integration by rapidly inactivating during an initial excitatory postsynaptic potential (EPSP) and reducing the threshold on summation with a second coincident EPSP to trigger an action potential [92].
in the auditory pathway [35– 39], neocortical pyramidal neurons [40], vestibular neurons [41,42], nodose ganglia [43,44], superior cervical ganglia [45], some cells of the dorsal root ganglia [46] and hippocampal pyramidal neurons [47]. Low-voltage-activated Kþ channels might also have a role in coincidence detection by enhancing rapid decay of excitatory postsynaptic potentials, decreasing the membrane time-constant [48]. A striking early indication that low-voltage-activated Kþ channels are located in nerve terminals came from immunohistochemical labelling of Kv1.1 and Kv1.2 (Figure 2a) in cerebellar basket cells [49 –52]. These specialized terminals provide an inhibitory input to www.sciencedirect.com
(a)
50 ms 10 mV –50 mV –100 mV
(b)
(c)
(d)
Low-voltageactivated (e.g. Kv1.1)
High-voltageactivated (e.g. Kv3.1)
A-current (e.g. Kv4.1 or Kv1.4)
TRENDS in Neurosciences
Figure I. Functional classification of voltage-gated Kþ channels. (a) Voltage protocol for the stylized outward Kþ current traces (b –d); each trace is a nominal 50 ms duration and generated by depolarizations from 2100 mV. Voltage steps to 2 50 mV and þ10 mV are shown superimposed. As a broad generalization, the response of Kv channels to depolarization can be divided into three groups. (b) Low-voltage-activated channels activate upon depolarization to voltages around the threshold for action potential generation. The majority activate rapidly and some can partially or completely inactivate (d). (c) High-voltage-activated channels activate little until the membrane potential is raised substantially above threshold, so little response is observed on voltage steps to 250 mV but large currents are evoked at þ10 mV. Consequently, these channels contribute predominantly to action potential repolarization. (d) A transient outward Kþ current is shown activating on voltage steps from a potential of 2100 mV (hence no steady-state inactivation is present). Following rapid activation giving a peak outward current, the channels inactivate and the current declines despite the fact that the depolarization is maintained.
Purkinje neurons via a ‘basket’ of terminals around the soma and endings (called pinceau) on the axon hillock. Using direct presynaptic recordings, Southan and Robertson [53] demonstrated that the basket cell terminals possess lowvoltage-activated Kv1 currents. Blockade or deletion of these channels increased spontaneous inhibitory postsynaptic current (sIPSC) frequency and amplitude in Purkinje neurons [32,54– 56], suggesting that the physiological function of these presynaptic Kv1 channels is to suppress hyper-excitability and reduce aberrant action potential generation. In phrenic nerve terminals, Kv1.1 is localized to the transition zone between the myelinated nerve and
Review
terminal region (Figure 2d) and is absent from the terminal. Repetitive discharges are generated on channel block [57] or on cooling in Kv1.1-deficient mice [58]. In several CNS nerve terminals, Kv1 channels are also found at the end of the axon within the transition zone (or ‘neck’) between the axon and the synaptic terminal. For example, in the middle molecular layer of the hippocampus, immunoreactivity for an inactivating Kþ channel subunit (Kv1.4) has been detected in the ‘necks’ of presynaptic terminals of perforant path axons [59]. Kv1.1 and Kv1.2 subunits are similarly localized in the last portion of the presynaptic axon at the calyx of Held (Figure 2c) and direct recordings from the calyx [18] show that it possesses substantial non-inactivating Kþ currents. Blockade of these presynaptic Kv1 channels results in additional
(a)
213
TRENDS in Neurosciences Vol.27 No.4 April 2004
Kv1.1
action potentials being fired (Figure 3a) in the hyperexcitable period during the depolarizing after-potential (DAP) that follows each orthodromic action potential [60,61]. Kv1 channels at internodal regions [62] and axon terminals [31] reduce the DAP amplitude, raising action potential threshold and preventing aberrant firing, but without contributing to the action potential waveform. A physiological consequence of this phenomenon is to minimize ‘reflection’ [63] of action potentials at axon terminals. This occurs because the DAP time-course is long enough to outlast the orthodromic action potential absolute refractory period – hence, the DAP can trigger an action potential that propagates in the antidromic direction (and collides with the next orthodromic spike, so further corrupting the firing pattern). Given the importance of timing for coincidence detection in binaural auditory pathways, one might predict early maturation
Kv1.2 (a)
Block of low-voltageactivated currents
40 mV 10 ms (b)
MAP2
+ Biocytin + Kv1.2 (b) Block of high-voltageactivated currents
(c)
(d)
40 mV 1 ms
α-BTX
(c)
Kv3.1
Cumulative inactivation of transient currents
∗ 1st Kv1.2
Kv1.1
Figure 2. Presynaptic localization of Kþ channel subunits in different terminals. (a) Basket cell terminals. Immunolocalization of Kv1.1 (blue) and Kv1.2 (green) subunits to basket cell terminals (arrows) surrounding cerebellar Purkinje cells. Reproduced, with permission, from Ref. [52] q (1997) by the Society for Neuroscience. (b) Vestibular primary afferent terminals. The spoon terminals of primary vestibular fibres (labelled blue with biocytin) synapse onto principal cells of the tangential nucleus [labelled green with microtubule-associated protein 2 (MAP2)]. Labelling with antibodies to Kv1.2 (red) shows that Kv1.2 is localized presynaptically. Reproduced, with permission, from Ref. [65] q (2003) Wiley-Liss, Inc and John Wiley and Sons, Inc. (c) Calyx of Held. Antibody labelling of Kv1.2 (green) is concentrated at the transition zone between the axon and presynaptic terminal, whereas the highvoltage-activated channel subunit Kv3.1b (red) is localized in the terminal itself. Reproduced, with permission, from Ref. [31] q (2003) Blackwell Publishing. (d) Phrenic neuromuscular junction. Labelling with antibodies to Kv1.1 (green) reveals juxtaparanodal location (asterisk indicates node) in fibre bundles but shows that Kv1.1 is not present at the endplate (nicotinic ACh receptors are labelled red with a-bungarotoxin). Reproduced, with permission, from Ref. [93] q (1998) by the Society for Neuroscience. Scale bar in (b), ,20 mm in (a,b,d); Scale bar in (c), 20 mm. www.sciencedirect.com
100th 40 mV 1 ms
Figure 3. The role of presynaptic Kþ channels in regulating action potential firing. (a) Low-voltage-activated currents prevent hyperexcitability at the calyx of Held. Blocking Kv1 channels results in the generation of an aberrant action potential (red trace) during the depolarizing after-potential that follows the orthodromic action potential (first spike, black). Arrow indicates stimulation of the presynaptic axon. Reproduced, with permission, from Ref. [31] q (2003) Blackwell Publishing. (b) High-voltage-activated currents ensure rapid repolarization of the presynaptic action potential at the calyx of Held. Blocking Kv3 channels with 1 mM tetraethylammonium results in presynaptic action potential broadening (red trace), potentiating transmitter release. Reproduced, with permission, from Ref. [33] q (1998) Macmillan Magazines Limited. (c) Transient currents contribute to activity-dependent plasticity in mossy fibre boutons. Cumulative inactivation of the transient current during a 50 Hz train results in broadening of the action potential (1st, 25th, 50th and 100th action potentials are shown), increasing transmitter release. Reproduced, with permission, from Ref. [34].
214
Review
TRENDS in Neurosciences Vol.27 No.4 April 2004
of presynaptic Kv1; there is certainly little change in the magnitude of Kv1 currents observed at the calyx of Held [31] between postnatal-days 9 – 14. However, Kv1.1deficient mice show a peak in spontaneous backfiring of phrenic axons at postnatal-day 17 that declines in adults [58], consistent with further developmental refinement. Modelling suggested a morphological explanation, but redistribution of Kv1 channels [64] or their interaction with other conductances are possible and deserve further enquiry. Other evidence points to presynaptic channels containing Kv1.2 subunit (Figure 2c). Immunoreactivity for Kv1.2, but not Kv1.1 [65], has been detected in the terminal region of vestibular ‘spoon’ terminals (Figure 2b). Kv1.2 is also important in preventing hyperexcitability in thalamocortical axon terminals, because blockade of Kv1.2 channels increased spontaneous excitatory postsynaptic current frequency in layer 5 pyramidal neurons of the prefrontal cortex. Interestingly, blocking Kv1.2 channels occludes the increase in excitability observed upon application of 5-HT, suggesting that 5-HT acts via modulation of these Kþ channels [66]. Similarly, blocking presynaptic Kv1.2-containing channels increased the frequency and amplitude of sIPSCs in the entorhinal cortex, [67]. All these data support a common role for presynaptic low-voltage-activated Kþ currents in preventing hyperexcitability in both central and peripheral nerve terminals. Action potential repolarization by presynaptic highvoltage-activated channels High-voltage-activated currents generally activate during the depolarizing phase of the action potential and therefore play important roles in repolarization and in facilitating high-frequency firing at somatic sites (Box 2) with little impact on firing threshold. Expression of Kv3 channels is clearly linked to fast-spiking interneuron phenotypes [68] and underlies the short action potentials in neurons of the auditory pathway [69]. Immunoreactivity for Kv3 channel subunits has been detected at several synaptic terminals, including the calyx of Held [22,31,70] (Figure 2c) and the terminals of hippocampal interneurons [71]. At the calyx of Held, these channels ensure extremely rapid repolarization, producing action potentials that last , 260 ms at 36 8C [60]. Intriguingly, the location of presynaptic Kv3.1 appears not to overlap with presynaptic Kv1.2 located in the last axonal segment [31], the presynaptic Kv3 channels being located only on the non-release face [70] of the terminal. The significance of this observation needs further investigation but even if propagation of the action potential into the terminal were passive, then a Kv3 current would be ideally localized close to the Ca2þ channels to shunt the action potential waveform and minimize action potential duration. Indeed, blocking the high-voltage-activated currents results in a considerable broadening of the presynaptic action potential (Figure 3b) and potentiation of neurotransmitter release. Such brief action potentials limit transmitter release and thus help to maintain reliable high-frequency firing at the synapse [33]. Similar highwww.sciencedirect.com
voltage-activated currents have also been observed in cerebellar basket cell terminals [53], suggesting similar roles at other synapses. Inactivating currents mediate activity-dependent changes in transmitter release Inactivating Kþ conductances add a further dimension to presynaptic control by introducing short-term activitydependent changes to the net outward current responsible for action potential repolarization. A-currents are not present in all presynaptic terminals and can activate at either low or high voltages, thus permitting short-term modulation of action potential thresholds or spike waveform. They clearly play a role in action potential repolarization, particularly when there are modest densities of non-inactivating Kþ currents. Cumulative inactivation during action potential trains leads to activitydependent changes in action potential duration and, hence, in neurotransmitter release. For example, at neurohypophysial presynaptic terminals, inactivation of the transient current during trains of stimuli results in broadening of the action potential waveform by 37% [16], augmenting Ca2þ entry and potentiating neuropeptide release. The pharmacology of the transient current in these terminals suggests that it might be mediated by Kv1.4-containing channels or members of the Kv4 family [17]. In the hippocampus, axonal swellings of mossy fibre axons (mossy fibre boutons), which form en passant synapses with CA3 pyramidal neurons, also exhibit activity-dependent changes. Geiger and Jonas [34] were able to make direct electrophysiological recordings from mossy fibre boutons, demonstrating that these too possess a fast inactivating current that is likely to be mediated by Kv1.1 –Kv1.4 heteromers. As in pituitary terminals, trains of stimuli resulted in cumulative inactivation of the transient current, causing broadening of the action potential waveform (Figure 3c) and potentiating transmitter release. This activity-dependent broadening could contribute to induction of long-term potentiation (LTP) during theta burst activity; intriguingly, antisense knockdown of Kv1.4 eliminated early-phase and late-phase LTP in hippocampal CA1 pyramidal neurons [72], suggesting that channels containing Kv1.4 might play important roles in other presynaptic terminals in the hippocampus. Modulation of K1 currents shapes neurotransmitter release Presynaptic Kþ currents play diverse roles in the regulation of action potential firing, and modulation of these channels can influence neurotransmitter release dramatically. In neurohypophysial nerve terminals, psychotropic drugs acting at sigma receptors modulate Kþ channels through direct protein – protein interactions [73], inhibiting the presynaptic transient current [74] and potentiating release. Similarly, application of 5-HT causes local spiking in thalamocortical terminals, mimicking the effect of blocking presynaptic Kv1.2-containing channels [66]. Intriguingly, activation of protein kinase C (PKC) had no effect on presynaptic Kv3 currents at the calyx of Held [75], despite the fact that PKC activation resulted in significant inhibition of postsynaptic Kv3 currents [76].
Review
TRENDS in Neurosciences Vol.27 No.4 April 2004
Conclusion and future directions The synaptic terminal is not merely an electrically passive extension of the axon – it possesses many presynaptic Kþ channels which serve to fine-tune excitability, maintain fidelity and modulate transmitter release. Localization of Kv1 channels in the last axonal segment is analogous to that observed at the initial segment and is associated with similar functions in regulating excitability. At some presynaptic terminals, repolarization is dominated by high-voltage-activated currents (e.g. that of Kv3) that, like similar somatic conductances, minimize action potential half-width and raise maximal firing rates. Other terminals express transient presynaptic Kþ currents, which allow short-term changes in presynaptic activity to influence release probability. Future work should examine how the Kv conductances integrate with other low-threshold conductances (e.g. BK, IH and KCNQ) and explore developmental changes. Further development of subunit-specific toxins, pharmacology and labelling will enable comparison of presynaptic and postsynaptic channel composition. Insights into location with respect to voltage-gated Naþ and Ca2þ channels and modelling of axon terminal excitability could then further our understanding of physiological function. Other interesting questions concern the intracellular signalling mechanisms that mediate competition between the factors enhancing and depressing excitability [10], including the mechanisms regulating channel insertion, clustering and localization. Acknowledgements We thank Helen Brew for comments on the manuscript and the Wellcome Trust and the UK Medical Research Council for research support. Paul D. Dodson’s present address is the Department of Neurobiology and Brain Research Institute, University of California at Los Angeles School of Medicine, Los Angeles, CA 90095, USA.
References 1 Hodgkin, A.L. and Huxley, A.F. (1952) A quantitative description of membrane current and its application to conduction and excitation in nerve. J. Physiol. 117, 500 – 544 2 Doyle, D.A. et al. (1998) The structure of the potassium channel: molecular basis of Kþ conduction and selectivity. Science 280, 69 – 77 3 Yellen, G. (2002) The voltage-gated potassium channels and their relatives. Nature 419, 35 – 42 4 Robitaille, R. et al. (1993) Functional colocalization of calcium and calcium-gated potassium channels in control of transmitter release. Neuron 11, 645– 655 5 Frick, A. et al. (2003) Normalization of Ca2þ signals by small oblique dendrites of CA1 pyramidal neurons. J. Neurosci. 23, 3243– 3250 6 Barnes-Davies, M. et al. (2004) Kv1 currents mediate a gradient of principal neuron excitability across the tonotopic axis in the rat lateral superior olive. Eur. J. Neurosci. 19, 325 – 333 7 Parameshwaran, S. et al. (2001) Expression of the Kv3.1 potassium channel in the avian auditory brainstem. J. Neurosci. 21, 485 – 494 8 Rasband, M.N. and Shrager, P. (2000) Ion channel sequestration in central nervous system axons. J. Physiol. 525, 63 – 73 9 Colbert, C.M. and Johnston, D. (1996) Axonal action-potential initiation and Naþ channel densities in the soma and axon initial segment of subicular pyramidal neurons. J. Neurosci. 16, 6676 – 6686 10 Rasband, M.N. et al. (2001) Distinct potassium channels on painsensing neurons. Proc. Natl. Acad. Sci. U. S. A. 98, 13373 – 13378 11 Chiu, S.Y. and Ritchie, J.M. (1980) Potassium channels in nodal and internodal axonal membrane of mammalian myelinated fibres. Nature 284, 170 – 171 www.sciencedirect.com
215
12 Devaux, J. et al. (2003) Kv3.1b is a novel component of CNS nodes. J. Neurosci. 23, 4509– 4518 13 Augustine, G.J. (1990) Regulation of transmitter release at the squid giant synapse by presynaptic delayed rectifier potassium current. J. Physiol. 431, 343 – 364 14 Sivaramakrishnan, S. et al. (1991) Calcium-activated potassium conductance in presynaptic terminals at the crayfish neuromuscular junction. J. Gen. Physiol. 98, 1161– 1179 15 Klein, M. et al. (1982) Serotonin modulates a specific potassium current in the sensory neurons that show presynaptic facilitation in Aplysia. Proc. Natl. Acad. Sci. U. S. A. 79, 5713 – 5717 16 Jackson, M. et al. (1991) Action potential broadening and frequencydependent facilitation of calcium signals in pituitary nerve terminals. Proc. Natl. Acad. Sci. U. S. A. 88, 380 – 384 17 Thorn, P.J. et al. (1991) A fast, transient Kþ current in neurohypophysial nerve terminals of the rat. J. Physiol. 432, 313 – 326 18 Forsythe, I.D. (1994) Direct patch recording from identified presynaptic terminals mediating glutamatergic EPSCs in the rat CNS, in vitro. J. Physiol. 479, 381 – 387 19 Meir, A. et al. (1999) Ion channels in presynaptic nerve terminals and control of transmitter release. Physiol. Rev. 79, 1019– 1088 20 Bielefeldt, K. et al. (1992) Three potassium channels in rat posterior pituitary nerve terminals. J. Physiol. 458, 41 – 67 21 Hu, H. et al. (2001) Presynaptic Ca2þ-activated Kþ channels in glutamatergic hippocampal terminals and their role in spike repolarization and regulation of transmitter release. J. Neurosci. 21, 9585– 9597 22 Ishikawa, T. et al. (2003) Distinct roles of Kv1 and Kv3 potassium channels at the calyx of Held presynaptic terminal. J. Neurosci. 23, 10445 – 10453 23 Sun, X-P. et al. (1999) Single-channel properties of BK-type calciumactivated potassium channels at a cholinergic presynaptic nerve terminal. J. Physiol. 518, 639 – 651 24 Augustine, G.J. et al. (1988) Role of calcium-activated potassium channels in transmitter release at the squid giant synapse. J. Physiol. 398, 149 – 164 25 Cuttle, M.F. et al. (2001) Modulation of a presynaptic hyperpolarization-activated cationic current IH at an excitatory synaptic terminal in the rat auditory brainstem. J. Physiol. 534, 733 – 744 26 Southan, A.P. et al. (2000) Hyperpolarization-activated currents in presynaptic terminals of mouse cerebellar basket cells. J. Physiol. 526, 91 – 97 27 Beaumont, V. and Zucker, R.S. (2000) Enhancement of synaptic transmission by cAMP modulation of presynaptic IH channels. Nat. Neurosci. 3, 133 – 141 28 LeBeau, F.E. et al. (2003) The role of electrical signaling via gap junctions in the generation of fast network oscillations. Brain Res. Bull. 62, 3 – 13 29 Dryer, S.E. and Chiappinelli, V.A. (1985) Properties of choroid and ciliary neurons in the avian ciliary ganglion and evidence for substance P as a neurotransmitter. J. Neurosci. 5, 2654 – 2661 30 Pereda, A. et al. (2003) Connexin35 mediates electrical transmission at mixed synapses on Mauthner cells. J. Neurosci. 23, 7489 – 7503 31 Dodson, P.D. et al. (2003) Presynaptic Kv1.2 channels suppress synaptic terminal hyperexcitability following action potential invasion. J. Physiol. 550, 27– 33 32 Southan, A.P. and Robertson, B. (1998) Patch-clamp recordings from cerebellar basket cell bodies and their presynaptic terminals reveal an asymmetric distribution of voltage-gated potassium channels. J. Neurosci. 18, 948 – 955 33 Wang, L.Y. and Kaczmarek, L.K. (1998) High-frequency firing helps replenish the readily releasable pool of synaptic vesicles. Nature 394, 384– 388 34 Geiger, J.R. and Jonas, P. (2000) Dynamic control of presynaptic Ca2þ inflow by fast-inactivating Kþ channels in hippocampal mossy fiber boutons. Neuron 28, 927 – 939 35 Manis, P.B. and Marx, S.O. (1991) Outward currents in isolated ventral cochlear nucleus neurons. J. Neurosci. 11, 2865– 2880 36 Rathouz, M. and Trussell, L. (1998) Characterization of outward currents in neurons of the avian nucleus magnocellularis. J. Neurophysiol. 80, 2824 – 2835 37 Mo, Z.L. et al. (2002) Dendrotoxin-sensitive Kþ currents contribute to
Review
216
38
39
40
41
42
43
44
45
46
47
48
49
50 51
52
53
54
55
56
57
58 59
60
TRENDS in Neurosciences Vol.27 No.4 April 2004
accommodation in murine spiral ganglion neurons. J. Physiol. 542, 763 – 778 Dodson, P.D. et al. (2002) Two heteromeric Kv1 potassium channels differentially regulate action potential firing. J. Neurosci. 22, 6953 – 6961 Brew, H.M. et al. (2003) Hyperexcitability and reduced low threshold potassium currents in auditory neurons of mice lacking the channel subunit Kv1.1. J. Physiol. 548, 1 – 20 Bekkers, J.M. and Delaney, A.J. (2001) Modulation of excitability by a-dendrotoxin-sensitive potassium channels in neocortical pyramidal neurons. J. Neurosci. 21, 6553– 6560 Gamkrelidze, G. et al. (1998) The differential expression of lowthreshold sustained potassium current contributes to the distinct firing patterns in embryonic central vestibular neurons. J. Neurosci. 18, 1449 – 1464 Chabbert, C. et al. (2001) Three types of depolarization-activated potassium currents in acutely isolated mouse vestibular neurons. J. Neurophysiol. 85, 1017– 1026 Glazebrook, P.A. et al. (2002) Potassium channels Kv1.1, Kv1.2 and Kv1.6 influence excitability of rat visceral sensory neurons. J. Physiol. 541, 467 – 482 Stansfeld, C.E. et al. (1986) 4-Aminopyridine and dendrotoxin induce repetitive firing in rat visceral sensory neurones by blocking a slowly inactivating outward current. Neurosci. Lett. 64, 299 – 304 Wang, H.S. and McKinnon, D. (1995) Potassium currents in rat prevertebral and paravertebral sympathetic neurones: control of firing properties. J. Physiol. 485, 319 – 335 Everill, B. et al. (1998) Morphologically identified cutaneous afferent DRG neurons express three different potassium currents in varying proportions. J. Neurophysiol. 79, 1814 – 1824 Wu, R.L. and Barish, M.E. (1992) Two pharmacologically and kinetically distinct transient potassium currents in cultured embryonic mouse hippocampal neurons. J. Neurosci. 12, 2235– 2246 Rothman, J.S. and Manis, P.B. (2003) The roles potassium currents play in regulating the electrical activity of ventral cochlear nucleus neurons. J. Neurophysiol. 89, 3097 – 3113 Veh, R.W. et al. (1995) Immunohistochemical localization of five members of the Kv1 channel subunits: contrasting subcellular locations and neuron-specific co-localizations in rat brain. Eur. J. Neurosci. 7, 2189 – 2205 Wang, H. et al. (1993) Heteromultimeric Kþ channels in terminal and juxtaparanodal regions of neurons. Nature 365, 75 – 79 Wang, H. et al. (1994) Localization of Kv1.1 and Kv1.2, Kþ channel proteins, to synaptic terminals, somata and dendrites in the mouse brain. J. Neurosci. 14, 4588– 4599 Rhodes, K.J. et al. (1997) Association and colocalization of the Kvb1 and Kvb2 b-subunits with Kv1 a-subunits in mammalian brain Kþ channel complexes. J. Neurosci. 17, 8246 – 8258 Southan, A.P. and Robertson, B. (2000) Electrophysiological characterization of voltage-gated Kþ currents in cerebellar basket and Purkinje cells: Kv1 and Kv3 channel subfamilies are present in basket cell nerve terminals. J. Neurosci. 20, 114– 122 Southan, A.P. and Robertson, B. (1998) Modulation of inhibitory postsynaptic currents (IPSCs) in mouse cerebellar Purkinje and basket cells by snake and scorpion toxin Kþ channel blockers. Br. J. Pharmacol. 125, 1375– 1381 Tan, Y.P. and Llano, I. (1999) Modulation by Kþ channels of action potential-evoked intracellular Ca2þ concentration rises in rat cerebellar basket cell axons. J. Physiol. 520, 65– 78 Zhang, C-L. et al. (1999) Specific alteration of spontaneous GABAergic inhibition in cerebellar Purkinje cells in mice lacking the potassium channel Kv1.1. J. Neurosci. 19, 2852 – 2864 Vatanpour, H. and Harvey, A.L. (1995) Modulation of acetylcholine release at mouse neuromuscular junctions by interaction of three homologous scorpion toxins with Kþ channels. Br. J. Pharmacol. 114, 1502–1506 Zhou, L. et al. (1999) Determinants of excitability at transition zones in Kv1.1-deficient myelinated nerves. J. Neurosci. 19, 5768 – 5781 Cooper, E.C. et al. (1998) Presynaptic localization of Kv1.4-containing A-type potassium channels near excitatory synapses in the hippocampus. J. Neurosci. 18, 965– 974 Borst, J.G. et al. (1995) Pre- and postsynaptic whole-cell recordings in the medial nucleus of the trapezoid body of the rat. J. Physiol. 489, 825 – 840
www.sciencedirect.com
61 Barrett, E.F. and Barrett, J.N. (1982) Intracellular recording from vertebrate myelinated axons: mechanism of the depolarizing afterpotential. J. Physiol. 323, 117 – 144 62 David, G. et al. (1995) Electrical and morphological factors influencing the depolarizing after-potential in rat and lizard myelinated axons. J. Physiol. 489, 141 – 157 63 Luscher, H.R. and Shiner, J.S. (1990) Computation of action potential propagation and presynaptic bouton activation in terminal arborizations of different geometries. Biophys. J. 58, 1377 – 1388 64 Vabnick, I. et al. (1999) Dynamic potassium channel distributions during axonal development prevent aberrant firing patterns. J. Neurosci. 19, 747 – 758 65 Popratiloff, A. et al. (2003) Developmental change in expression and subcellular localization of two Shaker-related potassium channel proteins (Kv1.1 and Kv1.2) in the chick tangential vestibular nucleus. J. Comp. Neurol. 461, 466 – 482 66 Lambe, E.K. and Aghajanian, G.K. (2001) The role of Kv1.2-containing potassium channels in serotonin-induced glutamate release from thalamocortical terminals in rat frontal cortex. J. Neurosci. 21, 9955– 9963 67 Cunningham, M.O. and Jones, R.S. (2001) Dendrotoxin sensitive potassium channels modulate GABA but not glutamate release in the rat entorhinal cortex in vitro. Neuroscience 107, 395 – 404 68 Rudy, B. and McBain, C.J. (2001) Kv3 channels: voltage-gated Kþ channels designed for high-frequency repetitive firing. Trends Neurosci. 24, 517 – 526 69 Wang, L.Y. et al. (1998) Contribution of the Kv3.1 potassium channel to high-frequency firing in mouse auditory neurones. J. Physiol. 509, 183– 194 70 Elezgarai, I. et al. (2003) Subcellular localization of the voltagedependent potassium channel Kv3.1b in postnatal and adult rat medial nucleus of the trapezoid body. Neuroscience 118, 889– 898 71 Sekirnjak, C. et al. (1997) Subcellular localization of the Kþ channel subunit Kv3.1b in selected rat CNS neurons. Brain Res. 766, 173 – 187 72 Meiri, N. et al. (1998) Memory and long-term potentiation (LTP) dissociated: Normal spatial memory despite CA1 LTP elimination with Kv1.4 antisense. Proc. Natl. Acad. Sci. U. S. A. 95, 15037 – 15042 73 Aydar, E. et al. (2002) The sigma receptor as a ligand-regulated auxiliary potassium channel subunit. Neuron 34, 399 – 410 74 Lupardus, P.J. et al. (2000) Membrane-delimited coupling between sigma receptors and Kþ channels in rat neurohypophysial terminals requires neither G-protein nor ATP. J. Physiol. 526, 527 – 539 75 Hori, T. et al. (1999) Presynaptic mechanism for phorbol ester-induced synaptic potentiation. J. Neurosci. 19, 7262 – 7267 76 Macica, C.M. et al. (2003) Modulation of the Kv3.1b potassium channel isoform adjusts the fidelity of the firing pattern of auditory neurons. J. Neurosci. 23, 1133 – 1141 77 Papazian, D.M. et al. (1987) Cloning of genomic and complementary DNA from shaker, a putative potassium channel gene from Drosophila. Science 237, 749– 753 78 Coetzee, W.A. et al. (1999) Molecular diversity of Kþ channels. Ann. N Y Acad. Sci. 868, 233 – 285 79 Robertson, B. (1997) The real life of voltage-gated Kþ channels: more than model behaviour. Trends Pharmacol. Sci. 18, 474 – 483 80 Wang, F.C. et al. (1999) Alpha subunit compositions of Kv1.1containing Kþ channel subtypes fractionated from rat brain using dendrotoxins. Eur. J. Biochem. 263, 230 – 237 81 Shamotienko, O.G. et al. (1997) Subunit combinations defined for Kþ channel Kv1 subtypes in synaptic membranes from bovine brain. Biochemistry 36, 8195 – 8201 82 Coleman, S.K. et al. (1999) Subunit composition of Kv1 channels in human CNS. J. Neurochem. 73, 849 – 858 83 Brew, H.M. and Forsythe, I.D. (1995) Two voltage-dependent Kþ conductances with complementary functions in postsynaptic integration at a central auditory synapse. J. Neurosci. 15, 8011 – 8022 84 Nisenbaum, E.S. et al. (1994) Contribution of a slowly inactivating potassium current to the transition to firing of neostriatal spiny projection neurons. J. Neurophysiol. 71, 1174– 1189 85 Connor, J.A. and Stevens, C.F. (1971) Prediction of repetitive firing behaviour from voltage clamp data on an isolated neurone soma. J. Physiol. 213, 31 – 53 86 Du, J. et al. (1996) Developmental expression and functional characterization of the potassium-channel subunit Kv3.1b in
Review
TRENDS in Neurosciences Vol.27 No.4 April 2004
parvalbumin-containing interneurons of the rat hippocampus. J. Neurosci. 16, 506 – 518 87 Erisir, A. et al. (1999) Function of specific Kþ channels in sustained high-frequency firing of fast-spiking neocortical interneurons. J. Neurophysiol. 82, 2476– 2489 88 Martina, M. et al. (1998) Functional and molecular differences between voltage-gated Kþ channels of fast-spiking interneurons and pyramidal neurons of rat hippocampus. J. Neurosci. 18, 8111 – 8125 89 Lien, C.C. and Jonas, P. (2003) Kv3 potassium conductance is necessary and kinetically optimized for high-frequency action potential generation in hippocampal interneurons. J. Neurosci. 23, 2058 – 2068
90 Lau, D. et al. (2000) Impaired fast-spiking, suppressed cortical inhibition and increased susceptibility to seizures in mice lacking Kv3.2 Kþ channel proteins. J. Neurosci. 20, 9071 – 9085 91 Baranauskas, G. et al. (1999) Delayed rectifier currents in rat globus pallidus neurons are attributable to Kv2.1 and Kv3.1/3.2 Kþ channels. J. Neurosci. 19, 6394– 6404 92 Pongs, O. (1999) Voltage-gated potassium channels: from hyperexcitability to excitement. FEBS Lett. 452, 31– 35 93 Zhou, L. et al. (1998) Temperature-sensitive neuromuscular transmission in Kv1.1 null mice: role of potassium channels under the myelin sheath in young nerves. J. Neurosci. 18, 7200 – 7215
Articles of interest in other Trends journals Vertebrate floor-plate specification: variations on common themes Uwe Stra¨ hle et al. Trends in Genetics 10.1016/j.tig.2004.01.002 Developmental cognitive neuroscience: progress and potential Yuko Munakata, B. J. Casey and Adele Diamond Trends in Cognitive Sciences 10.1016/j.tics.2004.01.005 Thinking the voice: neural correlates of voice perception Pascal Belin, Shirley Fecteau and Catherine Be´ dard Trends in Cognitive Sciences 10.1016/j.tics.2004.01.008 Cortical midline structures and the self Georg Northoff and Felix Bermpohl Trends in Cognitive Sciences 10.1016/j.tics.2004.01.004 Can language restructure cognition? The case for space Asifa Majid et al. Trends in Cognitive Sciences 10.1016/j.tics.2004.01.003 Do pediatric drugs cause developing neurons to commit suicide? John W. Olney et al. Trends in Pharmacological Sciences 10.1016/j.tips.2004.01.002 Virus-induced neurobehavioral disorders: mechanisms and implications, Keizo Tomonaga Trends in Molecular Medicine (February 2004) 10, 71–77 Huntingtin-protein interactions and the pathogenesis of Huntington’s disease Shi-Hua Li and Xiao-Jiang Li Trends in Genetics 10.1016/j.tig.2004.01.008 The CD4–Th1 model for multiple sclerosis: a crucial re-appraisal Hans Lassmann and Richard M. Ransohoff Trends in Immunology 10.1016/j.it.2004.01.007 Parkinson’s disease, pesticides and individual vulnerability Moreno Paolini, Andrea Sapone and Frank J. Gonzalez Trends in Pharmacological Sciences 10.1016/j.tips.2004.01.007 Antidepressant effects of inhibitors of cAMP phosphodiesterase (PDE4) James M. O’Donnell and Han-Ting Zhang Trends in Pharmacological Sciences 10.1016/j.tips.2004.01.003 Non-invasive measurement of brain damage in a primate model of multiple sclerosis Bert A. ’t Hart et al. Trends in Molecular Medicine (February 2004) 10, 85–91 Immunomodulatory and neuroprotective effects of inosine Gyo¨ rgy Hasko´ , Michail V. Sitkovsky and Csaba Szabo´ Trends in Pharmacological Sciences 10.1016/j.tips.2004.01.006 www.sciencedirect.com
217
TRENDS in Neurosciences Vol.27 No.4 April 2004
Presynaptic K1 channels: electrifying regulators of synaptic terminal excitability Paul D. Dodson and Ian D. Forsythe Department of Cell Physiology and Pharmacology, University of Leicester, PO Box 138, Leicester LE1 9HN, UK
Potassium channels are crucial regulators of neuronal excitability, setting resting membrane potentials and firing thresholds, repolarizing action potentials and limiting excitability. Although most of our understanding of K1 channels is based on somatic recordings, there is good evidence that these channels are present in synaptic terminals. In recent years the improved access to presynaptic compartments afforded by direct recording techniques has indicated diverse roles for native K1 channels, from suppression of aberrant firing to action potential repolarization and activity-dependent modulation of synaptic activity. This article reviews the growing evidence for multiple roles and discrete localization of distinct K1 channels at presynaptic terminals. From the ionic basis of action potential generation [1] to the recent structural elucidation of the Kþ channel pore [2], insights into voltage-dependent activation have revolutionized our understanding of neuronal excitability, channel gating and permeation [3]. Over the past 15 years, . 70 different Kþ channel subunits have been identified and their molecular structure and diversity investigated
(Box 1). However, from a post-genomic perspective this extraordinary molecular diversity makes the task of understanding the function of native channels all the more challenging. Recent data from direct presynaptic recordings raise interesting questions about the identity, composition and precise roles of presynaptic voltage-gated Kþ channels in the regulation of synaptic transmission. It is increasingly clear that neuronal function is affected not only by ion channel properties but also by ion channel location, in focal ‘hot-spots’ around release sites [4] or as density gradients along neuronal dendrites [5], and by expression gradients across neuronal populations within a given nucleus [6,7]. In myelinated axons, compartmentalization at nodes of Ranvier is a key element of saltatory conduction – indeed, mammalian peripheral axons have few voltage-gated Kþ channels at the node [8]. In simple functional terms, a myelinated axon can be considered as three compartments (Figure 1): an initial segment, where somatic inputs summate and initiate an action potential; a variable-length myelinated axon, which must reliably transmit the information as trains of action potentials; and a final segment, beyond which the synaptic terminal
Low-voltage-activated (e.g. Kv1) High-voltage-activated (e.g. Kv3) A-type (e.g. Kv4 or Kv1.4)
Somatodendritic
Axonal
Terminal TRENDS in Neurosciences
Figure 1. Kþ channel localization. Low-voltage-activated Kþ channels (purple; e.g. Kv1) are prevalent in the initial axonal segment and terminal segment, in addition to juxtaparanodal location at nodes of Ranvier. High-voltage-activated Kþ channels (dark blue; e.g. Kv3) are localized to somatodendritic regions, sometimes as density gradients. They are also localized to synaptic terminals and nodes of Ranvier in some CNS myelinated fibres (although not at peripheral nodes). Inactivating A-type channels (orange; e.g. Kv4 or Kv1.4) are broadly expressed, contributing to activity-dependent effects on neuronal firing. They can also be localized to synaptic terminals.
Corresponding author: Ian D. Forsythe ([email protected]). www.sciencedirect.com 0166-2236/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tins.2004.02.012
Review
TRENDS in Neurosciences Vol.27 No.4 April 2004
211
Box 1. K1 channel diversity More than 70 channel subunits have been identified that possess a conserved pore architecture and are permeable to Kþ. Voltagedependent Kþ channels form as tetramers of four Kv a-subunits, each with six transmembrane domains (S1 –S6); S1 – S4 form the voltagesensing region, S5 and S6 from each a-subunit line the central pore, and the S5– S6 linker (or P region), which contains the Kþ-selective GYG motif, forms the selectivity filter [3]. Following the cloning of the four Drosophila voltage-gated Kþ channel genes Shaker, Shab, Shal and Shaw [77], 29 members of related voltage-gated Kþ channel families have been identified in mammals and divided into eight gene families [named KCNA (Kv1.1–Kv1.8), KCNB (Kv2.1 and Kv2.2), KCNC (Kv3.1– Kv3.4), KCND (Kv4.1–Kv4.3), KCNF (Kv5.1), KCNG (Kv6.1 –Kv6.4), KCNS (Kv9.1 –Kv9.3) and KCNV (Kv8.1–Kv8.3)]. The Kv1, Kv2, Kv3 and Kv4 families can form homomeric or heteromeric channels with other
expands. There are parallels between the initial and terminal segments of the axon (Figure 1) in having an associated capacitive load (those of the soma and terminal membranes, respectively) and being adjacent to regions of low action potential threshold [9]; hence, regulation of excitability will be crucial to avoid corruption of information by aberrant action potential generation. The aim of this article is to review the evidence for presynaptic localization of voltage-gated Kþ channels in the mammal, and to discuss the physiological roles of these channels in regulating action potential duration and excitability in this rather inaccessible neuronal compartment. Functional diversity of K1 channels Potassium channel diversity is created by the expression of a large number of genes, the presence of various spliced variants and the formation of heteromeric channels (Box 1). Further diversity arises through association with chaperone and scaffolding molecules regulating subcellular location. In this way, channels can perform different functions by virtue of their location (and density) in specific neuronal compartments. For instance, several types of voltage-gated Kþ channel are localized to somatodendritic regions of neurons (Figure 1), where they serve to integrate synaptic inputs and regulate action potential firing (Box 2). In myelinated axons, Kþ channels containing Kv1.1 and Kv1.2 subunits are clustered at juxtaparanodal regions (Figure 1) in both the central and peripheral nervous system [8]. By contrast, unmyelinated axons express Kv1.4 channels [10] in a much more uniform fashion. Although recordings from peripheral nodes of Ranvier indicate little outward current in mammals [11], recent evidence demonstrates that high-voltage-activated channels (containing Kv3.1b) are present at some CNS nodes [12], supporting higher frequency transmission of shorter action potentials. Relatively little is known about voltage-gated Kþ channels at or around the presynaptic terminal: to what extent does the terminal need different Kþ channels from a myelinated axon or soma, and how might they influence synaptic transmission? Presynaptic K1 channels Studies of invertebrate nerve terminals show that presynaptic voltage-gated Kþ channels are involved in action potential repolarization [13–15] and early studies confirmed www.sciencedirect.com
subunits from within their own family [78]. The remaining ‘electrically silent’ families (Kv5, Kv6, Kv8 and Kv9) are unable to form functional homomeric channels but instead form heteromers with certain members of the Kv1 –Kv4 families. Other non-pore-forming b-subunits influence channel properties, localization and trafficking [79]. This molecular variety allows considerable functional diversity but makes elucidation of native channel composition and use of transgenic knockouts difficult (because removal of one subunit might be compensated by inclusion of other subunits, generating subtle phenotypes). However, although these permutations provide a wealth of possible combinations, only a minority have been detected in the brain. For instance, only a small fraction of the possible Kv1 family combinations have been detected by immunoprecipitation from brain tissue [80 –82].
that outward Kþ currents were present in mammalian synaptic terminals [16– 18]. Although the focus here is on voltage-gated Kþ channels, presynaptic terminals possess many other channels [19] that influence presynaptic conductance and directly or indirectly regulate transmitter release. Besides Naþ and Ca2þ channels, there is good evidence for Ca2þ-activated Kþ (BK) and IH channels in nerve terminals [4,14,20 – 27]. Electrotonic synapses mediated by gap junctions [28] are important components of transmission at some synapses (e.g. chick ciliary ganglion [29] and Mauthner cell [30]) but there is no evidence for electronic transmission at mammalian CNS synapses from which direct recordings have been made (the calyx of Held, cerebellar basket cell terminals and hippocampal mossy fibres). Functionally, voltage-gated Kþ channels can be broadly divided into three groups on the basis of their sensitivity to depolarization and their propensity to inactivate (Box 2). Low-voltage-activated currents (mediated by Kv1 channels) start to activate on modest depolarizations from resting membrane potentials, whereas high-voltage-activated currents (mediated by Kv3 channels, for example) require substantial depolarization (to , 0 mV) to achieve significant activation and hence participate only in action potential repolarization. The third type of Kþ current, generally referred to as A-currents, activates on depolarization and then rapidly undergoes voltage-dependent inactivation. Sustained voltage changes and/or repetitive activation (e.g. during trains of action potentials) allow accumulation of inactivation and so produce activitydependent changes. Recent evidence shows that lowthreshold currents oppose aberrant presynaptic firing [31,32], whereas high-voltage-activated Kþ channels are involved in presynaptic action potential repolarization [22,33] and presynaptic A-currents generate activitydependent changes [16,34]. So what is the evidence for the presence of these diverse Kþ conductances in presynaptic compartments? Low-voltage-activated K1 channels dampen presynaptic excitability Low-voltage-activated channels activate at around the threshold for regenerative action potentials. Somatic recordings show that postsynaptic Kv1 conductances play important roles in regulating neuronal firing pattern
212
Review
TRENDS in Neurosciences Vol.27 No.4 April 2004
Box 2. The role of voltage-gated K1 channels Voltage-gated Kþ channels play many important roles in the nervous system, in action potential repolarization [1,68], control of postsynaptic excitability [40,44,83] and regulation of oscillatory firing and interspike interval [84,85]. The diversity of voltage-gated Kþ channel genes allows formation of a multitude of ‘delayed rectifier’ channels with a broad spectrum of physiological properties. They are closed at resting membrane potentials; on activation by depolarization they directly hyperpolarize the membrane potential and indirectly influence membrane time-constant and synaptic conductances by a shunt mechanism. Voltage-clamp is a powerful means of exploring the full activation range of a conductance but it is important to appreciate that a physiological response need trigger only a small proportion of the full conductance. From a functional perspective, three broad subdivisions of voltagegated Kþ conductances are relevant. (i) Low-voltage-activated channels (Figure Ic) produce sustained outward currents in response to small depolarizations from rest to , 2 60 mV (straddling the threshold for action potential generation) and are half-activated at , –50 mV. Although Kv1 channels will start to activate during the first action potential, their slightly slower activation and deactivation (compared with high-voltage-activated Kþ currents) mean that they will have only a minor impact on the first action potential but instead raise the threshold for generation of subsequent action potentials. (ii) High voltage-activated currents require substantial depolarization for activation (Figure Ic); consequently, these currents contribute principally to action potential repolarization. Kv3 conductances are typical high-voltage-activated currents; in postsynaptic neurons, expression of non-inactivating Kv3 conductances has been clearly linked to generation of short-duration action potentials [68] in cortical interneurons [86 –91] and fast spiking neurons in the auditory pathway [69,83]. (iii) Transient outward Kþ currents (also termed A-currents) form a third functional subdivision of outward Kþ currents. Both low-voltageand high-voltage-activated channels can exhibit inactivation, dependent on incorporation of specific subunits. Their activation upon depolarization is followed by inactivation, generating a transient conductance change (Figure Id) owing to ‘ball and chain’ N-terminal mechanisms or slower C-type inactivation [3] (e.g. Kv1.4 and Kv1 channels possessing a Kvb1 subunit [79]). These inactivating channels therefore make a significant contribution to outward currents only transiently after large depolarizations, because inactivation renders the conductance of little significance at later times. However, in the classic A-currents (e.g. Kv4) the channels are often partially inactivated at resting membrane potentials (not shown), so small changes in voltage can strongly affect this baseline level of inactivation (the so-called ‘steady-state inactivation’). A-current activation is therefore enhanced by hyperpolarization, so permitting synaptic activity to modulate intrinsic excitability. A-currents can transiently slow the latency to the first few spikes and/or change interspike interval during a train. Inactivating currents might also play a role in synaptic integration by rapidly inactivating during an initial excitatory postsynaptic potential (EPSP) and reducing the threshold on summation with a second coincident EPSP to trigger an action potential [92].
in the auditory pathway [35– 39], neocortical pyramidal neurons [40], vestibular neurons [41,42], nodose ganglia [43,44], superior cervical ganglia [45], some cells of the dorsal root ganglia [46] and hippocampal pyramidal neurons [47]. Low-voltage-activated Kþ channels might also have a role in coincidence detection by enhancing rapid decay of excitatory postsynaptic potentials, decreasing the membrane time-constant [48]. A striking early indication that low-voltage-activated Kþ channels are located in nerve terminals came from immunohistochemical labelling of Kv1.1 and Kv1.2 (Figure 2a) in cerebellar basket cells [49 –52]. These specialized terminals provide an inhibitory input to www.sciencedirect.com
(a)
50 ms 10 mV –50 mV –100 mV
(b)
(c)
(d)
Low-voltageactivated (e.g. Kv1.1)
High-voltageactivated (e.g. Kv3.1)
A-current (e.g. Kv4.1 or Kv1.4)
TRENDS in Neurosciences
Figure I. Functional classification of voltage-gated Kþ channels. (a) Voltage protocol for the stylized outward Kþ current traces (b –d); each trace is a nominal 50 ms duration and generated by depolarizations from 2100 mV. Voltage steps to 2 50 mV and þ10 mV are shown superimposed. As a broad generalization, the response of Kv channels to depolarization can be divided into three groups. (b) Low-voltage-activated channels activate upon depolarization to voltages around the threshold for action potential generation. The majority activate rapidly and some can partially or completely inactivate (d). (c) High-voltage-activated channels activate little until the membrane potential is raised substantially above threshold, so little response is observed on voltage steps to 250 mV but large currents are evoked at þ10 mV. Consequently, these channels contribute predominantly to action potential repolarization. (d) A transient outward Kþ current is shown activating on voltage steps from a potential of 2100 mV (hence no steady-state inactivation is present). Following rapid activation giving a peak outward current, the channels inactivate and the current declines despite the fact that the depolarization is maintained.
Purkinje neurons via a ‘basket’ of terminals around the soma and endings (called pinceau) on the axon hillock. Using direct presynaptic recordings, Southan and Robertson [53] demonstrated that the basket cell terminals possess lowvoltage-activated Kv1 currents. Blockade or deletion of these channels increased spontaneous inhibitory postsynaptic current (sIPSC) frequency and amplitude in Purkinje neurons [32,54– 56], suggesting that the physiological function of these presynaptic Kv1 channels is to suppress hyper-excitability and reduce aberrant action potential generation. In phrenic nerve terminals, Kv1.1 is localized to the transition zone between the myelinated nerve and
Review
terminal region (Figure 2d) and is absent from the terminal. Repetitive discharges are generated on channel block [57] or on cooling in Kv1.1-deficient mice [58]. In several CNS nerve terminals, Kv1 channels are also found at the end of the axon within the transition zone (or ‘neck’) between the axon and the synaptic terminal. For example, in the middle molecular layer of the hippocampus, immunoreactivity for an inactivating Kþ channel subunit (Kv1.4) has been detected in the ‘necks’ of presynaptic terminals of perforant path axons [59]. Kv1.1 and Kv1.2 subunits are similarly localized in the last portion of the presynaptic axon at the calyx of Held (Figure 2c) and direct recordings from the calyx [18] show that it possesses substantial non-inactivating Kþ currents. Blockade of these presynaptic Kv1 channels results in additional
(a)
213
TRENDS in Neurosciences Vol.27 No.4 April 2004
Kv1.1
action potentials being fired (Figure 3a) in the hyperexcitable period during the depolarizing after-potential (DAP) that follows each orthodromic action potential [60,61]. Kv1 channels at internodal regions [62] and axon terminals [31] reduce the DAP amplitude, raising action potential threshold and preventing aberrant firing, but without contributing to the action potential waveform. A physiological consequence of this phenomenon is to minimize ‘reflection’ [63] of action potentials at axon terminals. This occurs because the DAP time-course is long enough to outlast the orthodromic action potential absolute refractory period – hence, the DAP can trigger an action potential that propagates in the antidromic direction (and collides with the next orthodromic spike, so further corrupting the firing pattern). Given the importance of timing for coincidence detection in binaural auditory pathways, one might predict early maturation
Kv1.2 (a)
Block of low-voltageactivated currents
40 mV 10 ms (b)
MAP2
+ Biocytin + Kv1.2 (b) Block of high-voltageactivated currents
(c)
(d)
40 mV 1 ms
α-BTX
(c)
Kv3.1
Cumulative inactivation of transient currents
∗ 1st Kv1.2
Kv1.1
Figure 2. Presynaptic localization of Kþ channel subunits in different terminals. (a) Basket cell terminals. Immunolocalization of Kv1.1 (blue) and Kv1.2 (green) subunits to basket cell terminals (arrows) surrounding cerebellar Purkinje cells. Reproduced, with permission, from Ref. [52] q (1997) by the Society for Neuroscience. (b) Vestibular primary afferent terminals. The spoon terminals of primary vestibular fibres (labelled blue with biocytin) synapse onto principal cells of the tangential nucleus [labelled green with microtubule-associated protein 2 (MAP2)]. Labelling with antibodies to Kv1.2 (red) shows that Kv1.2 is localized presynaptically. Reproduced, with permission, from Ref. [65] q (2003) Wiley-Liss, Inc and John Wiley and Sons, Inc. (c) Calyx of Held. Antibody labelling of Kv1.2 (green) is concentrated at the transition zone between the axon and presynaptic terminal, whereas the highvoltage-activated channel subunit Kv3.1b (red) is localized in the terminal itself. Reproduced, with permission, from Ref. [31] q (2003) Blackwell Publishing. (d) Phrenic neuromuscular junction. Labelling with antibodies to Kv1.1 (green) reveals juxtaparanodal location (asterisk indicates node) in fibre bundles but shows that Kv1.1 is not present at the endplate (nicotinic ACh receptors are labelled red with a-bungarotoxin). Reproduced, with permission, from Ref. [93] q (1998) by the Society for Neuroscience. Scale bar in (b), ,20 mm in (a,b,d); Scale bar in (c), 20 mm. www.sciencedirect.com
100th 40 mV 1 ms
Figure 3. The role of presynaptic Kþ channels in regulating action potential firing. (a) Low-voltage-activated currents prevent hyperexcitability at the calyx of Held. Blocking Kv1 channels results in the generation of an aberrant action potential (red trace) during the depolarizing after-potential that follows the orthodromic action potential (first spike, black). Arrow indicates stimulation of the presynaptic axon. Reproduced, with permission, from Ref. [31] q (2003) Blackwell Publishing. (b) High-voltage-activated currents ensure rapid repolarization of the presynaptic action potential at the calyx of Held. Blocking Kv3 channels with 1 mM tetraethylammonium results in presynaptic action potential broadening (red trace), potentiating transmitter release. Reproduced, with permission, from Ref. [33] q (1998) Macmillan Magazines Limited. (c) Transient currents contribute to activity-dependent plasticity in mossy fibre boutons. Cumulative inactivation of the transient current during a 50 Hz train results in broadening of the action potential (1st, 25th, 50th and 100th action potentials are shown), increasing transmitter release. Reproduced, with permission, from Ref. [34].
214
Review
TRENDS in Neurosciences Vol.27 No.4 April 2004
of presynaptic Kv1; there is certainly little change in the magnitude of Kv1 currents observed at the calyx of Held [31] between postnatal-days 9 – 14. However, Kv1.1deficient mice show a peak in spontaneous backfiring of phrenic axons at postnatal-day 17 that declines in adults [58], consistent with further developmental refinement. Modelling suggested a morphological explanation, but redistribution of Kv1 channels [64] or their interaction with other conductances are possible and deserve further enquiry. Other evidence points to presynaptic channels containing Kv1.2 subunit (Figure 2c). Immunoreactivity for Kv1.2, but not Kv1.1 [65], has been detected in the terminal region of vestibular ‘spoon’ terminals (Figure 2b). Kv1.2 is also important in preventing hyperexcitability in thalamocortical axon terminals, because blockade of Kv1.2 channels increased spontaneous excitatory postsynaptic current frequency in layer 5 pyramidal neurons of the prefrontal cortex. Interestingly, blocking Kv1.2 channels occludes the increase in excitability observed upon application of 5-HT, suggesting that 5-HT acts via modulation of these Kþ channels [66]. Similarly, blocking presynaptic Kv1.2-containing channels increased the frequency and amplitude of sIPSCs in the entorhinal cortex, [67]. All these data support a common role for presynaptic low-voltage-activated Kþ currents in preventing hyperexcitability in both central and peripheral nerve terminals. Action potential repolarization by presynaptic highvoltage-activated channels High-voltage-activated currents generally activate during the depolarizing phase of the action potential and therefore play important roles in repolarization and in facilitating high-frequency firing at somatic sites (Box 2) with little impact on firing threshold. Expression of Kv3 channels is clearly linked to fast-spiking interneuron phenotypes [68] and underlies the short action potentials in neurons of the auditory pathway [69]. Immunoreactivity for Kv3 channel subunits has been detected at several synaptic terminals, including the calyx of Held [22,31,70] (Figure 2c) and the terminals of hippocampal interneurons [71]. At the calyx of Held, these channels ensure extremely rapid repolarization, producing action potentials that last , 260 ms at 36 8C [60]. Intriguingly, the location of presynaptic Kv3.1 appears not to overlap with presynaptic Kv1.2 located in the last axonal segment [31], the presynaptic Kv3 channels being located only on the non-release face [70] of the terminal. The significance of this observation needs further investigation but even if propagation of the action potential into the terminal were passive, then a Kv3 current would be ideally localized close to the Ca2þ channels to shunt the action potential waveform and minimize action potential duration. Indeed, blocking the high-voltage-activated currents results in a considerable broadening of the presynaptic action potential (Figure 3b) and potentiation of neurotransmitter release. Such brief action potentials limit transmitter release and thus help to maintain reliable high-frequency firing at the synapse [33]. Similar highwww.sciencedirect.com
voltage-activated currents have also been observed in cerebellar basket cell terminals [53], suggesting similar roles at other synapses. Inactivating currents mediate activity-dependent changes in transmitter release Inactivating Kþ conductances add a further dimension to presynaptic control by introducing short-term activitydependent changes to the net outward current responsible for action potential repolarization. A-currents are not present in all presynaptic terminals and can activate at either low or high voltages, thus permitting short-term modulation of action potential thresholds or spike waveform. They clearly play a role in action potential repolarization, particularly when there are modest densities of non-inactivating Kþ currents. Cumulative inactivation during action potential trains leads to activitydependent changes in action potential duration and, hence, in neurotransmitter release. For example, at neurohypophysial presynaptic terminals, inactivation of the transient current during trains of stimuli results in broadening of the action potential waveform by 37% [16], augmenting Ca2þ entry and potentiating neuropeptide release. The pharmacology of the transient current in these terminals suggests that it might be mediated by Kv1.4-containing channels or members of the Kv4 family [17]. In the hippocampus, axonal swellings of mossy fibre axons (mossy fibre boutons), which form en passant synapses with CA3 pyramidal neurons, also exhibit activity-dependent changes. Geiger and Jonas [34] were able to make direct electrophysiological recordings from mossy fibre boutons, demonstrating that these too possess a fast inactivating current that is likely to be mediated by Kv1.1 –Kv1.4 heteromers. As in pituitary terminals, trains of stimuli resulted in cumulative inactivation of the transient current, causing broadening of the action potential waveform (Figure 3c) and potentiating transmitter release. This activity-dependent broadening could contribute to induction of long-term potentiation (LTP) during theta burst activity; intriguingly, antisense knockdown of Kv1.4 eliminated early-phase and late-phase LTP in hippocampal CA1 pyramidal neurons [72], suggesting that channels containing Kv1.4 might play important roles in other presynaptic terminals in the hippocampus. Modulation of K1 currents shapes neurotransmitter release Presynaptic Kþ currents play diverse roles in the regulation of action potential firing, and modulation of these channels can influence neurotransmitter release dramatically. In neurohypophysial nerve terminals, psychotropic drugs acting at sigma receptors modulate Kþ channels through direct protein – protein interactions [73], inhibiting the presynaptic transient current [74] and potentiating release. Similarly, application of 5-HT causes local spiking in thalamocortical terminals, mimicking the effect of blocking presynaptic Kv1.2-containing channels [66]. Intriguingly, activation of protein kinase C (PKC) had no effect on presynaptic Kv3 currents at the calyx of Held [75], despite the fact that PKC activation resulted in significant inhibition of postsynaptic Kv3 currents [76].
Review
TRENDS in Neurosciences Vol.27 No.4 April 2004
Conclusion and future directions The synaptic terminal is not merely an electrically passive extension of the axon – it possesses many presynaptic Kþ channels which serve to fine-tune excitability, maintain fidelity and modulate transmitter release. Localization of Kv1 channels in the last axonal segment is analogous to that observed at the initial segment and is associated with similar functions in regulating excitability. At some presynaptic terminals, repolarization is dominated by high-voltage-activated currents (e.g. that of Kv3) that, like similar somatic conductances, minimize action potential half-width and raise maximal firing rates. Other terminals express transient presynaptic Kþ currents, which allow short-term changes in presynaptic activity to influence release probability. Future work should examine how the Kv conductances integrate with other low-threshold conductances (e.g. BK, IH and KCNQ) and explore developmental changes. Further development of subunit-specific toxins, pharmacology and labelling will enable comparison of presynaptic and postsynaptic channel composition. Insights into location with respect to voltage-gated Naþ and Ca2þ channels and modelling of axon terminal excitability could then further our understanding of physiological function. Other interesting questions concern the intracellular signalling mechanisms that mediate competition between the factors enhancing and depressing excitability [10], including the mechanisms regulating channel insertion, clustering and localization. Acknowledgements We thank Helen Brew for comments on the manuscript and the Wellcome Trust and the UK Medical Research Council for research support. Paul D. Dodson’s present address is the Department of Neurobiology and Brain Research Institute, University of California at Los Angeles School of Medicine, Los Angeles, CA 90095, USA.
References 1 Hodgkin, A.L. and Huxley, A.F. (1952) A quantitative description of membrane current and its application to conduction and excitation in nerve. J. Physiol. 117, 500 – 544 2 Doyle, D.A. et al. (1998) The structure of the potassium channel: molecular basis of Kþ conduction and selectivity. Science 280, 69 – 77 3 Yellen, G. (2002) The voltage-gated potassium channels and their relatives. Nature 419, 35 – 42 4 Robitaille, R. et al. (1993) Functional colocalization of calcium and calcium-gated potassium channels in control of transmitter release. Neuron 11, 645– 655 5 Frick, A. et al. (2003) Normalization of Ca2þ signals by small oblique dendrites of CA1 pyramidal neurons. J. Neurosci. 23, 3243– 3250 6 Barnes-Davies, M. et al. (2004) Kv1 currents mediate a gradient of principal neuron excitability across the tonotopic axis in the rat lateral superior olive. Eur. J. Neurosci. 19, 325 – 333 7 Parameshwaran, S. et al. (2001) Expression of the Kv3.1 potassium channel in the avian auditory brainstem. J. Neurosci. 21, 485 – 494 8 Rasband, M.N. and Shrager, P. (2000) Ion channel sequestration in central nervous system axons. J. Physiol. 525, 63 – 73 9 Colbert, C.M. and Johnston, D. (1996) Axonal action-potential initiation and Naþ channel densities in the soma and axon initial segment of subicular pyramidal neurons. J. Neurosci. 16, 6676 – 6686 10 Rasband, M.N. et al. (2001) Distinct potassium channels on painsensing neurons. Proc. Natl. Acad. Sci. U. S. A. 98, 13373 – 13378 11 Chiu, S.Y. and Ritchie, J.M. (1980) Potassium channels in nodal and internodal axonal membrane of mammalian myelinated fibres. Nature 284, 170 – 171 www.sciencedirect.com
215
12 Devaux, J. et al. (2003) Kv3.1b is a novel component of CNS nodes. J. Neurosci. 23, 4509– 4518 13 Augustine, G.J. (1990) Regulation of transmitter release at the squid giant synapse by presynaptic delayed rectifier potassium current. J. Physiol. 431, 343 – 364 14 Sivaramakrishnan, S. et al. (1991) Calcium-activated potassium conductance in presynaptic terminals at the crayfish neuromuscular junction. J. Gen. Physiol. 98, 1161– 1179 15 Klein, M. et al. (1982) Serotonin modulates a specific potassium current in the sensory neurons that show presynaptic facilitation in Aplysia. Proc. Natl. Acad. Sci. U. S. A. 79, 5713 – 5717 16 Jackson, M. et al. (1991) Action potential broadening and frequencydependent facilitation of calcium signals in pituitary nerve terminals. Proc. Natl. Acad. Sci. U. S. A. 88, 380 – 384 17 Thorn, P.J. et al. (1991) A fast, transient Kþ current in neurohypophysial nerve terminals of the rat. J. Physiol. 432, 313 – 326 18 Forsythe, I.D. (1994) Direct patch recording from identified presynaptic terminals mediating glutamatergic EPSCs in the rat CNS, in vitro. J. Physiol. 479, 381 – 387 19 Meir, A. et al. (1999) Ion channels in presynaptic nerve terminals and control of transmitter release. Physiol. Rev. 79, 1019– 1088 20 Bielefeldt, K. et al. (1992) Three potassium channels in rat posterior pituitary nerve terminals. J. Physiol. 458, 41 – 67 21 Hu, H. et al. (2001) Presynaptic Ca2þ-activated Kþ channels in glutamatergic hippocampal terminals and their role in spike repolarization and regulation of transmitter release. J. Neurosci. 21, 9585– 9597 22 Ishikawa, T. et al. (2003) Distinct roles of Kv1 and Kv3 potassium channels at the calyx of Held presynaptic terminal. J. Neurosci. 23, 10445 – 10453 23 Sun, X-P. et al. (1999) Single-channel properties of BK-type calciumactivated potassium channels at a cholinergic presynaptic nerve terminal. J. Physiol. 518, 639 – 651 24 Augustine, G.J. et al. (1988) Role of calcium-activated potassium channels in transmitter release at the squid giant synapse. J. Physiol. 398, 149 – 164 25 Cuttle, M.F. et al. (2001) Modulation of a presynaptic hyperpolarization-activated cationic current IH at an excitatory synaptic terminal in the rat auditory brainstem. J. Physiol. 534, 733 – 744 26 Southan, A.P. et al. (2000) Hyperpolarization-activated currents in presynaptic terminals of mouse cerebellar basket cells. J. Physiol. 526, 91 – 97 27 Beaumont, V. and Zucker, R.S. (2000) Enhancement of synaptic transmission by cAMP modulation of presynaptic IH channels. Nat. Neurosci. 3, 133 – 141 28 LeBeau, F.E. et al. (2003) The role of electrical signaling via gap junctions in the generation of fast network oscillations. Brain Res. Bull. 62, 3 – 13 29 Dryer, S.E. and Chiappinelli, V.A. (1985) Properties of choroid and ciliary neurons in the avian ciliary ganglion and evidence for substance P as a neurotransmitter. J. Neurosci. 5, 2654 – 2661 30 Pereda, A. et al. (2003) Connexin35 mediates electrical transmission at mixed synapses on Mauthner cells. J. Neurosci. 23, 7489 – 7503 31 Dodson, P.D. et al. (2003) Presynaptic Kv1.2 channels suppress synaptic terminal hyperexcitability following action potential invasion. J. Physiol. 550, 27– 33 32 Southan, A.P. and Robertson, B. (1998) Patch-clamp recordings from cerebellar basket cell bodies and their presynaptic terminals reveal an asymmetric distribution of voltage-gated potassium channels. J. Neurosci. 18, 948 – 955 33 Wang, L.Y. and Kaczmarek, L.K. (1998) High-frequency firing helps replenish the readily releasable pool of synaptic vesicles. Nature 394, 384– 388 34 Geiger, J.R. and Jonas, P. (2000) Dynamic control of presynaptic Ca2þ inflow by fast-inactivating Kþ channels in hippocampal mossy fiber boutons. Neuron 28, 927 – 939 35 Manis, P.B. and Marx, S.O. (1991) Outward currents in isolated ventral cochlear nucleus neurons. J. Neurosci. 11, 2865– 2880 36 Rathouz, M. and Trussell, L. (1998) Characterization of outward currents in neurons of the avian nucleus magnocellularis. J. Neurophysiol. 80, 2824 – 2835 37 Mo, Z.L. et al. (2002) Dendrotoxin-sensitive Kþ currents contribute to
Review
216
38
39
40
41
42
43
44
45
46
47
48
49
50 51
52
53
54
55
56
57
58 59
60
TRENDS in Neurosciences Vol.27 No.4 April 2004
accommodation in murine spiral ganglion neurons. J. Physiol. 542, 763 – 778 Dodson, P.D. et al. (2002) Two heteromeric Kv1 potassium channels differentially regulate action potential firing. J. Neurosci. 22, 6953 – 6961 Brew, H.M. et al. (2003) Hyperexcitability and reduced low threshold potassium currents in auditory neurons of mice lacking the channel subunit Kv1.1. J. Physiol. 548, 1 – 20 Bekkers, J.M. and Delaney, A.J. (2001) Modulation of excitability by a-dendrotoxin-sensitive potassium channels in neocortical pyramidal neurons. J. Neurosci. 21, 6553– 6560 Gamkrelidze, G. et al. (1998) The differential expression of lowthreshold sustained potassium current contributes to the distinct firing patterns in embryonic central vestibular neurons. J. Neurosci. 18, 1449 – 1464 Chabbert, C. et al. (2001) Three types of depolarization-activated potassium currents in acutely isolated mouse vestibular neurons. J. Neurophysiol. 85, 1017– 1026 Glazebrook, P.A. et al. (2002) Potassium channels Kv1.1, Kv1.2 and Kv1.6 influence excitability of rat visceral sensory neurons. J. Physiol. 541, 467 – 482 Stansfeld, C.E. et al. (1986) 4-Aminopyridine and dendrotoxin induce repetitive firing in rat visceral sensory neurones by blocking a slowly inactivating outward current. Neurosci. Lett. 64, 299 – 304 Wang, H.S. and McKinnon, D. (1995) Potassium currents in rat prevertebral and paravertebral sympathetic neurones: control of firing properties. J. Physiol. 485, 319 – 335 Everill, B. et al. (1998) Morphologically identified cutaneous afferent DRG neurons express three different potassium currents in varying proportions. J. Neurophysiol. 79, 1814 – 1824 Wu, R.L. and Barish, M.E. (1992) Two pharmacologically and kinetically distinct transient potassium currents in cultured embryonic mouse hippocampal neurons. J. Neurosci. 12, 2235– 2246 Rothman, J.S. and Manis, P.B. (2003) The roles potassium currents play in regulating the electrical activity of ventral cochlear nucleus neurons. J. Neurophysiol. 89, 3097 – 3113 Veh, R.W. et al. (1995) Immunohistochemical localization of five members of the Kv1 channel subunits: contrasting subcellular locations and neuron-specific co-localizations in rat brain. Eur. J. Neurosci. 7, 2189 – 2205 Wang, H. et al. (1993) Heteromultimeric Kþ channels in terminal and juxtaparanodal regions of neurons. Nature 365, 75 – 79 Wang, H. et al. (1994) Localization of Kv1.1 and Kv1.2, Kþ channel proteins, to synaptic terminals, somata and dendrites in the mouse brain. J. Neurosci. 14, 4588– 4599 Rhodes, K.J. et al. (1997) Association and colocalization of the Kvb1 and Kvb2 b-subunits with Kv1 a-subunits in mammalian brain Kþ channel complexes. J. Neurosci. 17, 8246 – 8258 Southan, A.P. and Robertson, B. (2000) Electrophysiological characterization of voltage-gated Kþ currents in cerebellar basket and Purkinje cells: Kv1 and Kv3 channel subfamilies are present in basket cell nerve terminals. J. Neurosci. 20, 114– 122 Southan, A.P. and Robertson, B. (1998) Modulation of inhibitory postsynaptic currents (IPSCs) in mouse cerebellar Purkinje and basket cells by snake and scorpion toxin Kþ channel blockers. Br. J. Pharmacol. 125, 1375– 1381 Tan, Y.P. and Llano, I. (1999) Modulation by Kþ channels of action potential-evoked intracellular Ca2þ concentration rises in rat cerebellar basket cell axons. J. Physiol. 520, 65– 78 Zhang, C-L. et al. (1999) Specific alteration of spontaneous GABAergic inhibition in cerebellar Purkinje cells in mice lacking the potassium channel Kv1.1. J. Neurosci. 19, 2852 – 2864 Vatanpour, H. and Harvey, A.L. (1995) Modulation of acetylcholine release at mouse neuromuscular junctions by interaction of three homologous scorpion toxins with Kþ channels. Br. J. Pharmacol. 114, 1502–1506 Zhou, L. et al. (1999) Determinants of excitability at transition zones in Kv1.1-deficient myelinated nerves. J. Neurosci. 19, 5768 – 5781 Cooper, E.C. et al. (1998) Presynaptic localization of Kv1.4-containing A-type potassium channels near excitatory synapses in the hippocampus. J. Neurosci. 18, 965– 974 Borst, J.G. et al. (1995) Pre- and postsynaptic whole-cell recordings in the medial nucleus of the trapezoid body of the rat. J. Physiol. 489, 825 – 840
www.sciencedirect.com
61 Barrett, E.F. and Barrett, J.N. (1982) Intracellular recording from vertebrate myelinated axons: mechanism of the depolarizing afterpotential. J. Physiol. 323, 117 – 144 62 David, G. et al. (1995) Electrical and morphological factors influencing the depolarizing after-potential in rat and lizard myelinated axons. J. Physiol. 489, 141 – 157 63 Luscher, H.R. and Shiner, J.S. (1990) Computation of action potential propagation and presynaptic bouton activation in terminal arborizations of different geometries. Biophys. J. 58, 1377 – 1388 64 Vabnick, I. et al. (1999) Dynamic potassium channel distributions during axonal development prevent aberrant firing patterns. J. Neurosci. 19, 747 – 758 65 Popratiloff, A. et al. (2003) Developmental change in expression and subcellular localization of two Shaker-related potassium channel proteins (Kv1.1 and Kv1.2) in the chick tangential vestibular nucleus. J. Comp. Neurol. 461, 466 – 482 66 Lambe, E.K. and Aghajanian, G.K. (2001) The role of Kv1.2-containing potassium channels in serotonin-induced glutamate release from thalamocortical terminals in rat frontal cortex. J. Neurosci. 21, 9955– 9963 67 Cunningham, M.O. and Jones, R.S. (2001) Dendrotoxin sensitive potassium channels modulate GABA but not glutamate release in the rat entorhinal cortex in vitro. Neuroscience 107, 395 – 404 68 Rudy, B. and McBain, C.J. (2001) Kv3 channels: voltage-gated Kþ channels designed for high-frequency repetitive firing. Trends Neurosci. 24, 517 – 526 69 Wang, L.Y. et al. (1998) Contribution of the Kv3.1 potassium channel to high-frequency firing in mouse auditory neurones. J. Physiol. 509, 183– 194 70 Elezgarai, I. et al. (2003) Subcellular localization of the voltagedependent potassium channel Kv3.1b in postnatal and adult rat medial nucleus of the trapezoid body. Neuroscience 118, 889– 898 71 Sekirnjak, C. et al. (1997) Subcellular localization of the Kþ channel subunit Kv3.1b in selected rat CNS neurons. Brain Res. 766, 173 – 187 72 Meiri, N. et al. (1998) Memory and long-term potentiation (LTP) dissociated: Normal spatial memory despite CA1 LTP elimination with Kv1.4 antisense. Proc. Natl. Acad. Sci. U. S. A. 95, 15037 – 15042 73 Aydar, E. et al. (2002) The sigma receptor as a ligand-regulated auxiliary potassium channel subunit. Neuron 34, 399 – 410 74 Lupardus, P.J. et al. (2000) Membrane-delimited coupling between sigma receptors and Kþ channels in rat neurohypophysial terminals requires neither G-protein nor ATP. J. Physiol. 526, 527 – 539 75 Hori, T. et al. (1999) Presynaptic mechanism for phorbol ester-induced synaptic potentiation. J. Neurosci. 19, 7262 – 7267 76 Macica, C.M. et al. (2003) Modulation of the Kv3.1b potassium channel isoform adjusts the fidelity of the firing pattern of auditory neurons. J. Neurosci. 23, 1133 – 1141 77 Papazian, D.M. et al. (1987) Cloning of genomic and complementary DNA from shaker, a putative potassium channel gene from Drosophila. Science 237, 749– 753 78 Coetzee, W.A. et al. (1999) Molecular diversity of Kþ channels. Ann. N Y Acad. Sci. 868, 233 – 285 79 Robertson, B. (1997) The real life of voltage-gated Kþ channels: more than model behaviour. Trends Pharmacol. Sci. 18, 474 – 483 80 Wang, F.C. et al. (1999) Alpha subunit compositions of Kv1.1containing Kþ channel subtypes fractionated from rat brain using dendrotoxins. Eur. J. Biochem. 263, 230 – 237 81 Shamotienko, O.G. et al. (1997) Subunit combinations defined for Kþ channel Kv1 subtypes in synaptic membranes from bovine brain. Biochemistry 36, 8195 – 8201 82 Coleman, S.K. et al. (1999) Subunit composition of Kv1 channels in human CNS. J. Neurochem. 73, 849 – 858 83 Brew, H.M. and Forsythe, I.D. (1995) Two voltage-dependent Kþ conductances with complementary functions in postsynaptic integration at a central auditory synapse. J. Neurosci. 15, 8011 – 8022 84 Nisenbaum, E.S. et al. (1994) Contribution of a slowly inactivating potassium current to the transition to firing of neostriatal spiny projection neurons. J. Neurophysiol. 71, 1174– 1189 85 Connor, J.A. and Stevens, C.F. (1971) Prediction of repetitive firing behaviour from voltage clamp data on an isolated neurone soma. J. Physiol. 213, 31 – 53 86 Du, J. et al. (1996) Developmental expression and functional characterization of the potassium-channel subunit Kv3.1b in
Review
TRENDS in Neurosciences Vol.27 No.4 April 2004
parvalbumin-containing interneurons of the rat hippocampus. J. Neurosci. 16, 506 – 518 87 Erisir, A. et al. (1999) Function of specific Kþ channels in sustained high-frequency firing of fast-spiking neocortical interneurons. J. Neurophysiol. 82, 2476– 2489 88 Martina, M. et al. (1998) Functional and molecular differences between voltage-gated Kþ channels of fast-spiking interneurons and pyramidal neurons of rat hippocampus. J. Neurosci. 18, 8111 – 8125 89 Lien, C.C. and Jonas, P. (2003) Kv3 potassium conductance is necessary and kinetically optimized for high-frequency action potential generation in hippocampal interneurons. J. Neurosci. 23, 2058 – 2068
90 Lau, D. et al. (2000) Impaired fast-spiking, suppressed cortical inhibition and increased susceptibility to seizures in mice lacking Kv3.2 Kþ channel proteins. J. Neurosci. 20, 9071 – 9085 91 Baranauskas, G. et al. (1999) Delayed rectifier currents in rat globus pallidus neurons are attributable to Kv2.1 and Kv3.1/3.2 Kþ channels. J. Neurosci. 19, 6394– 6404 92 Pongs, O. (1999) Voltage-gated potassium channels: from hyperexcitability to excitement. FEBS Lett. 452, 31– 35 93 Zhou, L. et al. (1998) Temperature-sensitive neuromuscular transmission in Kv1.1 null mice: role of potassium channels under the myelin sheath in young nerves. J. Neurosci. 18, 7200 – 7215
Articles of interest in other Trends journals Vertebrate floor-plate specification: variations on common themes Uwe Stra¨ hle et al. Trends in Genetics 10.1016/j.tig.2004.01.002 Developmental cognitive neuroscience: progress and potential Yuko Munakata, B. J. Casey and Adele Diamond Trends in Cognitive Sciences 10.1016/j.tics.2004.01.005 Thinking the voice: neural correlates of voice perception Pascal Belin, Shirley Fecteau and Catherine Be´ dard Trends in Cognitive Sciences 10.1016/j.tics.2004.01.008 Cortical midline structures and the self Georg Northoff and Felix Bermpohl Trends in Cognitive Sciences 10.1016/j.tics.2004.01.004 Can language restructure cognition? The case for space Asifa Majid et al. Trends in Cognitive Sciences 10.1016/j.tics.2004.01.003 Do pediatric drugs cause developing neurons to commit suicide? John W. Olney et al. Trends in Pharmacological Sciences 10.1016/j.tips.2004.01.002 Virus-induced neurobehavioral disorders: mechanisms and implications, Keizo Tomonaga Trends in Molecular Medicine (February 2004) 10, 71–77 Huntingtin-protein interactions and the pathogenesis of Huntington’s disease Shi-Hua Li and Xiao-Jiang Li Trends in Genetics 10.1016/j.tig.2004.01.008 The CD4–Th1 model for multiple sclerosis: a crucial re-appraisal Hans Lassmann and Richard M. Ransohoff Trends in Immunology 10.1016/j.it.2004.01.007 Parkinson’s disease, pesticides and individual vulnerability Moreno Paolini, Andrea Sapone and Frank J. Gonzalez Trends in Pharmacological Sciences 10.1016/j.tips.2004.01.007 Antidepressant effects of inhibitors of cAMP phosphodiesterase (PDE4) James M. O’Donnell and Han-Ting Zhang Trends in Pharmacological Sciences 10.1016/j.tips.2004.01.003 Non-invasive measurement of brain damage in a primate model of multiple sclerosis Bert A. ’t Hart et al. Trends in Molecular Medicine (February 2004) 10, 85–91 Immunomodulatory and neuroprotective effects of inosine Gyo¨ rgy Hasko´ , Michail V. Sitkovsky and Csaba Szabo´ Trends in Pharmacological Sciences 10.1016/j.tips.2004.01.006 www.sciencedirect.com
217