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Adenosine receptors: Intermembrane receptor–receptor interactions in the brain
Accepted Manuscript Title: Adenosine receptors: Intermembrane receptor-receptor interactions in the brain Author: Karen Nieber Sebastian Michael PII: DOI: Reference:
S2213-7130(14)00021-2 http://dx.doi.org/doi:10.1016/j.synres.2014.10.001 SYNRES 12
To appear in: Received date: Revised date: Accepted date:
30-5-2014 13-10-2014 14-10-2014
Please cite this article as: Nieber K, Michael S, Adenosine receptors: Intermembrane receptor-receptor interactions in the brain, Synergy Res. (2014), http://dx.doi.org/10.1016/j.synres.2014.10.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Adenosine receptors: Intermembrane receptor-receptor interactions in the brain Karen Nieber and Sebastian Michael1 University of Leipzig, Institute of Pharmacy Brüderstr. 34, 04103 Leipzig, Germany; 1
Loewen-Apotheke Waldheim Obermarkt 11 04736 Waldheim, Germany
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Correspondence address: Prof. Dr. Karen Nieber
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University of Leipzig, Institute of Pharmacy Brüderstr. 34, 04103 Leipzig; Germany Phone: ++49 39200 785880 or ++49 176 31123917
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[email protected]
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Abstract
In the vertebrate central nervous system (CNS) the modulation of synaptic
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transmission by metabotropic or ionotropic receptors is an important source of control and dynamical adjustment in synaptic activity and can contribute to synergistic or antagonistic effects. Adenosine is released from most cells, including neurons and
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glial cells. Once in the extracellular space, adenosine modifies cell functioning by
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operating G-protein-coupled receptors. In general, adenosine has been found to act in concert with other hormones or neurotransmitters in either an inhibitory or a
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stimulatory way. From the four cloned adenosine receptors (A1Rs, A2ARs, A2BRs and A3R), A1Rs and A2ARs are the main targets for the physiological effects of adenosine in the brain. A1R is a prototype of G-protein-coupled receptor able to form heterotypic interactions with other members of metabotropic and ionic receptors. The development of effective agonists, antagonists and in addition, gene-targeted mice deficient in the expression of each receptor subtype has made it possible to clarify the functional role with respect to synergistic effects with other receptors in both physiological and pathophysiological conditions. It is becoming increasingly obvious that the modulatory role of adenosine is related to the ability of A1Rs and A2ARs heteromerize with themselves and with other receptors, such as dopamine, glutamate or GABA. These interactions between adenosine receptors and other receptors for neurotransmitters might contribute to a fine-tuning of neuronal function, and therefore, to neuroprotection. Keywords: Adenosine, Receptor interaction,
Dopamine, GABA, Glutamate 1
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Contents 1. Introduction 2. Interaction between A1Rs and A2ARs
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3. Interaction between A1Rs and A3Rs 4. Interaction between adenosine receptors and dopamine receptors
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5. Interaction between adenosine receptors and NMDA receptors 6. Interaction between A1 receptors and GABAA receptors
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7. Concluding remarks Conflict of interest
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References 1. Introduction
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The vertebrate central nervous system (CNS) is characterized by a dynamic interplay between signal transduction molecules and their cellular targets. Modulation of synaptic transmission by metabotropic or ionotropic receptors is an important source
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of control and dynamical adjustment in synaptic activity and can contribute to
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synergistic, additive or antagonistic effects. (Bouvier, 2001; Marshall, 2001). G protein coupled receptors play a crucial role in mediating cellular responses to
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external stimuli, and increasing evidence suggests that they function as multiple units comprising homo/heterodimers and hetero-oligomers (Bouvier, 2001; Marshall, 2001). It all began in 1979-1980 in search of an explanation of where all the recently discovered neuropeptides in the brain could integrate their messages with those of classical transmitters such as the monoamines. The concept of “intramembrane receptor interactions” (receptor oligomerization) was first described by Luigi Agnati and Kjell Fuxe more than 25 years ago (Fuxe et al. 1983, Agnati et al. 2003). In these interactions, stimulation of one receptor changes the binding characteristics of an adjacent receptor in membrane preparations from brain tissue or transfected cells. Agnati and Fuxe postulated that an intramembrane interaction between neuropeptide and monoamine receptors could be involved, showing that substance P could modulate the high-affinity serotonin binding sites in spinal cord membrane preparations (Agnati et al., 1980). The same year, an interesting paper was published by Maggi and co-workers showing that the β-adrenergic receptor agonist 2
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isoproterenol could increase α 2 adrenergic receptor binding in cortical slices, supporting the concept of intramembrane receptor-receptor interactions of GPCR (Maggi et al. 1980). Thus, not only neuropeptide and monoamine receptors were involved in intramembrane receptor-receptor interactions but also certain types of
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glutamate and adenosine receptors (Agnati et al. 2003). Multi-protein complexes mediate most cellular functions. In neurons, these complexes are directly involved in the neuronal transmission, which is responsible for learning, memory and
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developments. Over the past decades, the number and outcomes of interactions between receptors has increased continuously (Agnati et al. 2003). Recent studies
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have demonstrated close physical interactions where activation of one receptor affects the function of the other.
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Extracellular adenosine acts as a local modulator of cell function via four adenosine receptor subtypes (A1Rs A2AR, A2BR, and A3R) that are involved in numerous Each is
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physiological and pathophysiological processes (Fredholm et al. 2001).
encoded by a separate gene and has different functions, although with some overlap (Gao and Jacobson 2007).
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Evidence for the existence of G protein-coupled receptor homomerization and
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heteromerization is growing continuously. There are numerous reviews about central nervous system that describe regulation of brain adenosine levels, adenosine
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receptors, their cellular and subcellular localization, signalling pathways and function in the brain under physiological and pathophysiological conditions as well as selective receptor agonists and antagonists (Fredholm et al. 2005, Jacobson and Gao 2005, Abbracchio et al. 2009, Müller and Jacobson 2011, Sheth et al 2014). Additionally, a set of publications has demonstrated the existence of potential adenosine receptor interactions. In this context, the excellent review of Ciurela and co-workers summarized the recent significant developments based on adenosine receptor interactions that are essential for acquiring a better understanding of neurotransmission in the central nervous system (Ciurela et al. 2011). Either through direct receptor–receptor modulation or beyond the receptor pathways, adenosine might synchronize or desynchronize synaptic transmission in order to fine-tune the nervous system. This opens novel possibilities for the action of this nucleoside (Burnstock 2013). Using adenosine receptors as paradigm of GPCRs, this review focuses
on
how
receptor-receptor
interactions
contribute
synergistically
or 3
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antagonistically to processes within the central nervous system. Considering the various types of receptors, one may expect to find three principle paths of receptor interaction: (i) interactions between metabotropic receptors (ii) interactions between a metabotropic receptor and an ionotropic receptor and (iii) interactions between
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ionotropic receptors. The examples mentioned below stem from the first and second type of interaction. Synergistic, additive and antagonistic effect will be discussed.
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Insert Figure 1
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2. Interaction between A1Rs and A2ARs
The A1Rs are the best characterized of the widely distributed purinergic receptor family. This might result from a highly localized distribution of A1Rs in the active zone
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and postsynaptic density of CNS synapses, especially in hippocampus (Rebola et al 2003) and prefrontal cortex (Ochiishi et al. 1999). A1Rs can be clearly distinguished from A2Rs on the basis of structure activity relationships with selective ligands. A2ARs
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are widely distributed in the CNS, but local and subcellular differences in allocation exist. The A2ARs occur predominantly on neurons in the striatum, especially the
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GABAergic projection neurons and on cholinergic interneurons (Ongini and Fredholm
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1996). A2ARs are also found in lower density in neurons in the neocortex and limbic cortex (Fredholm et al. 2005). There is abundant evidence from biochemical and
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electrophysiological investigations that the activation of A2ARs promotes the release of neurotransmitters (Cunha et al. 1994) Co-localization of A1Rs and A2ARs was approved for glutamatergic nerve terminals in the hippocampus (Rebola et al. 2005). In the striatum, A1R-A2AR heteromers were found on synapses of medium spiny neurons and integrated in the presynaptic membrane of glutamatergic terminals that represent the cortical-limbic-thalamic input (Ferre at al. 2007). A1R and A2ARs may closely interact in such a way that activation of A2AR receptors can lead to inhibition of A1R-mediated responses (Lopes et al. 1999).. However, problems arise due to long-term desensitization of A1Rs. Evidence should be that A2ARs do not up-regulate after antagonist administration, but have a low abundance in hippocampal and cortical areas compared with A1Rs (Cuhna 2005; Xu et al. 2002; Popoli et al. 2000). A1Rs and A2ARs cannot be regarded in isolation from one another since cross talk between the subtypes has been described several times (Dixon et al. 1997; Lopes et al. 2002; Quarta et al. 2004; Ciruela et al. 2006a; Ciruela et al. 2006b). A2AR activation by agonists caused A1R desensitization resulting in decreased binding 4
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affinity for agonists in the hippocampus of young rats. Controlling A1Rs by A2ARs was mediated by protein kinase C in a cAMP-independent manner. A2AR activation was seen to play a role in fine-tuning A1Rs by attenuating the tonic effect of presynaptic A1Rs located on glutamatergic nerve terminals (Dixon et al. 1997; Lopes et al. 1999;
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Lopes et al. 2002; Ciruela et al. 2006a; Ciruela et al. 2006b). One implication of this interaction is that, when the extracellular level of adenosine reaches levels sufficient to activate A2ARs, as it can do after hypoxia, it may inhibit A1Rs function (Forrest et
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al. 2003). Some results support this assumption. It has recently been demonstrated that A2ARs receptors localized in striatal glutamatergic terminals play a very important form
heteromers
with
A1Rs,
and
the
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role in control of striatal glutamate release (Ciruela et al. 2006b). These receptors A1R-A2AR
heteromer
constitutes
a
an
“concentration-dependent switch” that regulates glutamate release depending on the extracellular concentration of adenosine. As in the hippocampus, A2AR stimulation decreased the affinity of A1Rs for agonists. The A1R-A2AR heteromer allows
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adenosine to perform a detailed modulation of glutamate release (Quarta et al. 2004; Ciruela et al. 2006b). Finally, Cristovao-Ferreira et al. (2013) showed in primary
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through A1R-A2AR heteromers.
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cultures of rat astrocytes that a further level of regulation of GABA uptake occurs
Regarding A1Rs and A2ARs, basal conditions generate a low tone of endogenous
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adenosine and cause A1R activation, in contrast to situations of increased adenosine where A2AR activation becomes dominant. When adenosine concentrations rise, e.g. during hypoxia, also time appears likely important in regulating A2AR activity. That means A2ARs are “active” under prolonged stimulation (Latini et al. 1999). Finally, activation of the A1R/A2AR heteromer contributes to A2AR signalling when adenosine level is elevated, and may provide a mechanism to facilitate plastic changes in the excitatory synapse (Ferre et al. 2006). Consequently, the results of the above mentioned studies support the notion that A1Rs and A2AR regulate the synaptic transmission synergistically via forming A1R-A2AR heteromers. 3. Interaction between A1Rs and A3Rs The A3R was the latest receptor subtype of the adenosine receptor family to be identified, and its functional role is still controversially discussed (Fredholm et al. 2001). A dual, biphasic role in neuroprotection has been described depending on experimental approach, both in vitro and in vivo (von Lubitz et al. 1994; von Lubitz et 5
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al. 1999a, von Lubitz et al. 1999b; Rubay et al. 2001; Sei et al. 2006; Pugliese et al. 2003; Pugliese et al. 2006). A3Rs couple to inhibition of adenylyl cyclase as well as to activation of PLC, and to elevation of inositol triphosphate levels (Ramkumar et al. 1993; Abbracchio et al. 1995). Furthermore, an increase in intracellular Ca2+ levels
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due to release from intracellular stores and Ca2+ influx has been described (Gessi et al. 2002; Kohno et al 1996). One interesting example of A3Rs functional role is their involvement in acute neurotoxic situations and interplay with A1Rs. A potential of
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A3Rs to modify responses via A1Rs in the hippocampus has been postulated (Dunwiddie et al. 1997). In vitro experiments on rat brain slices approved that the
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activation of hippocampal A3Rs induced a desensitization of A1Rs. This phenomenon was thought to reduce the protective effects of endogenous adenosine caused by the
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lack of sensitivity of A1Rs. Further investigations on pyramidal cells of the rat cingulate cortex did not confirm these results (Brand et al. 2000). In this brain area, A1Rs and A3Rs did not show any interaction. The receptor subtypes were unable to
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affect each other. The discrepancy was taken to be a genetic phenomenon, such as alternative splicing of the rat A3R transcript causing distinguished pharmacological and functional properties in the brain. Furthermore, Hentschel et al. (2003)
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demonstrated the involvement of A3Rs in inhibition of excitatory neurotransmission
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during hypoxic conditions, indicating a neuroprotective action of endogenously released adenosine on A3Rs in addition to A1Rs. Lastly, Lopes et al. (2003)
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attempted to define the possible role of A3Rs in the rat hippocampus using experiments in non-stressful and stressful situations, with particular attention to whether A3Rs control A1Rs. These data suggested that no interaction between the two receptor subtypes exist, but confirm that A3Rs do not affect synaptic transmission on superfusion with an A3R agonist or an A3R antagonist. The authors pointed out that the agonist binds to A1Rs even at low nanomolar concentrations and to the A3Rs in higher concentration. Herterodimerization between both receptor subtypes was not described so far. It seems that these receptors subtypes act additively or were activated at different concentration of extracellular adenosine. Another explanation is that the A3Rs are active after desensitization of the A1Rs. This could be a functional synergistic effect. Thus, the existence of a possible interaction between A1Rs and A3Rs has to wait for reliable ligands. 4. Interaction between adenosine receptors and dopamine receptors
6
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Dopamine is an important transmitter in the striatum, and is noted for influencing motor activity, playing an important role in Parkinson’s disease. In vivo and in vitro data on adenosine-dopamine interactions were mostly obtained from investigations in the basal ganglia and limbic regions (Mayfield et al. 1999; Floran et al. 2002) due to
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the high abundance of A1Rs, A2ARs, dopamine D1 receptors (D1Rs) and dopamine D2 receptors (D2Rs) in these areas and their involvement in the pathology of Parkinson’s disease. Sufficient endogenous adenosine is present interstitially in the substantia
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nigra pars reticulata to control dopaminergic effects. The effects of adenosine are absent when dopaminergic influence is suppressed (Floran et al. 2002). There also is
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an anatomical basis for the existence of functional interactions between A1Rs and D1Rs in the same neurons. Moreover, recently it has been shown in caudate-
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putamen slices that adenosine modulates dopamine release also via A1R (Ross and Venton 2014)
While A1Rs communicate mainly with the D1R subtype (Gines et al. 2000), A2AR and
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D2R interaction occurs mainly in basal ganglia. D2Rs colocalizes with A2ARs in this brain area where they are preferentially localized postsynaptically in the soma and
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dendrites of GABAergic striatopallidal neurons (Quiroz et al. 2009). This interaction
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plays a very important role in striatal function. A2AR-D2R interaction provides an example of the capabilities of information processing by just two different G proteinhere is evidence for the coexistence of two
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coupled receptors. Interestingly,
reciprocal antagonistic interactions between A2ARs and D2Rs in the same neurons. In one type of interaction, A2ARs and D2R are forming heteromers and, by means of an allosteric interaction, A2ARs counteracts D2Rs-mediated inhibitory modulation of the effects of NMDA receptor stimulation in the striatopallidal neuron. This antagonistic interaction is probably mostly responsible for the locomotor depressant and activating effects of A2AR agonist and antagonists, respectively. The second type of interaction involves A2ARs and D2Rs that do not form heteromers and takes place at the level of adenylyl cyclase (Ferre et al. 2011) indicating two different populations of postsynaptic striatal A2ARs. In summary, signalling through A2ARs and D2Rs is distinctive and synergistic, supporting their unique and yet integrative roles in regulating neuronal functions when both receptors are present. The results of the above mentioned studies support the notion that receptor heteromers may be used as selective targets for drug 7
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development. Their opposing roles in regulating neuronal activities, such as locomotion and alcohol consumption, are mediated by their opposite actions on adenylate cyclase, which often serves as “co-incidence detector” of various activators (Tang and Demarest 2005). On the other hand, the neural actions of A2ARs and D2Rs
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are also, at least partially, independent of each other, as indicated by studies using D2Rs and A2ARs knock out mice. Studies on mice and monkeys suggest that some degree of dopaminergic activity is needed to obtain adenosine induced antagonistic
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effects on motor activity. The blockade of dopaminergic neurotransmission counteracts the antagonistic effect induced by adenosine (Ferre et al. 2001, Ferre et
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al. 2011).
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Insert Figure 2
5. Interaction between adenosine receptors and NMDA receptors Glutamate is the major excitatory neurotransmitter in the mammalian central nervous
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system. In most brain areas, glutamate mediates fast synaptic transmission by activating ionotropic receptors of the AMPA, kainate and NMDA subtype.
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Additionally, NMDA receptors play a critical role in synaptic plasticity, synaptic
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development and neurotoxicity. In a recent study, Arrigoni et al. (2001) have investigated the role of exogenous and endogenous adenosine in regulating synaptic
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glutamatergic transmission. From their electrophysiological results a presynaptic site of action for
A1R receptors on glutamatergic afferents was suggested by the
following: (1) adenosine did not affect exogenous glutamate-mediated current, (2) adenosine reduced glutamatergic miniature EPSC frequency, without affecting the amplitude, and (3) inhibition of the evoked EPSC was mimicked by an A1R agonist but not by an A2R agonist. Applicable with these findings is the study of Li and Henry, (2000) indicated that endogenous adenosine present in the extracellular fluid of hippocampal slices inhibits NMDA receptor-mediated dendritic spikes as well as AMPA/kainate receptor-mediated excitatory synaptic potentials by activation of A1Rs in CA1 pyramidal cells and with results of Schotanus et al. (2006) showing that the activation of A1Rs by ambient adenosine depressed field potentials in the striatum. The effect of adenosine in the striatum (Schotanus et al. 2006) or hippocampus (Masino et al. 2002) has not been found in A1R knockout mice, and clearly demonstrates the involvement of A1Rs. The involvement of A1Rs was also supported by experiments using a selective receptor ligand. On the other hand, NMDA is known 8
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to increase the extracellular level of adenosine via bi-directional adenosine transporters or from released adenine nucleotides degraded by a chain of ectonucleotidases (Hebb et al. 1998; Cunha et al. 1996) Another interesting interaction concerns NMDA preconditioning to protect against
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glutamate neurotoxicity. It has been shown that an A1R antagonist prevented neuroprotection evoked by NMDA preconditioning against glutamate-induced cellular
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damage in cerebellar granule cells. In this study, the functionality of A1Rs was not affected by NMDA preconditioning, but this treatment promoted A2AR desensitization
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in concert with A1R activation (Boeck et al. 2005). These results are in line with other studies indicating that adenosine down regulates excitatory and inhibitory synaptic transmission in several brain areas through activation of A1Rs and A2AR (Dunwiddie
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et al. 1981; Mori et al. 1996). Furthermore, activation of A1Rs mediates reversal of long-term potentiation (LTP) produced by brief application of NMDA in hippocampal
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CA1 neurons (Huang et al. 2001).
Finally, it has recently been demonstrated that A2ARs receptors localized in striatal glutamatergic terminals play a very important role in control of striatal glutamate
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release (Ciruela et al. 2006b). These receptors form heteromers with A1Rs, and the
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A1R-A2AR heteromer constitutes a “concentration-dependent switch” that regulates glutamate release depending on the extracellular concentration of adenosine. Thus,
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low concentrations of adenosine inhibit glutamate release by stimulating the A1Rs, while higher concentrations induce glutamate release by also stimulating A2AR, which shuts down A1R signalling by means of an antagonistic intramembrane receptor interaction (Ferre et al. 2008). However, the A2ARs-dependent modulation of glutamate release seems to be under an inhibitory control by co-localized D2Rs. Taken together, there are several ways in which adenosine may interact synergistic with
glutamatergic
neurotransmission.
Adenosine
can
affect
glutamatergic
transmission via A1Rs or A2ARs. NMDA receptors and A1Rs to down regulate glutamate release presynaptically in pyramidal cells of the cingulate cortex (Brand et al. 2000), neurons of the hippocampus (Scammell et al. 2003), and striatal neurons (Schotanus et al. 2006). Another putative mechanism is the elevation of the threshold to
open
NMDA
receptor-operated
channels
by
antagonizing
membrane
depolarization (Wardas 2002).
9
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Insert Figure 3 6. Interaction between A1 receptors and GABAA receptors Fast synaptic inhibition in the brain and spinal cord is largely mediated by GABAA
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receptors that are also targeted by drugs such as benzodiazepines, barbiturates, neurosteroids and some anesthetics. The modulation of their function will have important consequences for neuronal excitation (Kittner and Moss 2003). One
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accepted mean of modifying the efficacy is a functional interaction with adenosine. Cristovao-Ferreira et al. (2013) showed that GABA uptake by astrocytes is under
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modulation by extracellular adenosine. They found that A1R-A2AR heteromers in astrocytes regulating GABA transport in an opposite way, with A1R mediating
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inhibition of GABA transport and A2AR mediating facilitation of GABA transport. This A1R–A2AR functional unit may, therefore, operate as a dual amplifier to control ambient GABA levels at synapses. In addition, adenosine may have an effect on
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either GABA release in interneurons and/or on GABAA receptors in projection neurons. The site of action may be studied electrophysiologically by inducing fast inhibitory postsynaptic potentials or application of GABA directly onto the cell.
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Adenosine and selective A1R agonists reduced the amplitude of the inhibitory
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postsynaptic potentials in lateral amygdala slice preparations. The effect was blocked by an A1R antagonist, indicating an interaction of A1Rs with GABA receptors.
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Additionally, adenosine did not block currents evoked by local application of GABA (Heinbockel and Pape 1999). Thus, the modulatory effect of adenosine on the GABAergic neurotransmission appears to take place directly by inhibiting GABA release from nerve terminals (Heinbockel and Pape 1999; Shen and Johnson 1997). The assumption that the activation of A1Rs can modulate inhibitory postsynaptic responses agrees with findings in several brain areas, such as the thalamus (Ulrich and Huguenard 1997), suprachiasmatic and arcuate nucleus (Neary et al. 1996), and substantia nigra pars compacta (Shen and Johnson 1997). There is some evidence that activation of A1Rs is also involved in GABAA receptor down-regulation, implying a facilitation of the neurotransmission. The GABA-induced neurotransmission was significantly reduced be adenosine via activation of A1Rs (Li et al. 2004). The mode of this interaction seems due to a regulation of the GABAA chloride channel (Akhondzadeh and Stone 1994).
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Further investigations were concerned to study the mechanisms by which GABA modulates adenosine-mediated effects in hippocampal tissue. From these results it can be concluded that endogenous GABA exerts an inhibitory effect through GABAA receptors via a predominant adenosine-mediated action and this is an A1R-mediated
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ability to inhibit synaptic transmission (Fragata et al. 2006). It is well documented that activation of GABAA receptors is effective in limiting
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neuronal ischemic damage (Madden 1994) and endogenous adenosine that arises during hypoxia acts neuroprotectively partly by activating A1Rs (Hentschel et al.
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2003). Therefore, the contribution and potential interactions of GABA and adenosine as modulators of synaptic transmission during hypoxia has been investigated. Activation of A1Rs inhibits the release of GABA from the ischemic cerebral cortex in
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vivo (O´Regan et al. 1992). In contrast, the administration of an A1R agonist in the hippocampus failed to affect the release of GABA during ischemia (Heron et al. 1994). In the light of these controversial results, the role of the two neuromodulators
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was investigated in the CA1 area of rat hippocampal slices during hypoxia using selective A1R antagonists (Lucchi et al. 1996). Indeed, activation of A1R and GABAA
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receptors is partly involved in the inhibition of synaptic transmission during hypoxia.
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The action of GABA becomes evident when A1Rs are blocked. Regarding the desensitization of A1Rs during hypoxia (Rufke et al. 2006; Wetherington and Lambert
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2002), it may be assumed that GABAA-mediated inhibition of the synaptic transmission is evident when the A1R is desensitized or down regulated (Lucchi et al. 1996).
Co-modulation by A1Rs and GABAA receptors was also suggested in acute cerebellar ethanol-induced ataxia. Using GABAA and A1R agonists and antagonists, respectively, a functional similarity between GABAA receptors and A1Rs has been shown even through both receptor types are known to couple to different signalling systems (Dar 2002). This provides conclusive evidence that A1Rs and GABAA receptors both play a co-modulatory role in ethanol-induced cerebellar ataxia without any direct interaction. 7. Concluding remarks As a consequence of its ubiquitous distribution and because of its linkage to the energy pool, adenosine has evolved as an important messenger in extracellular 11
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signalling. Modifications in extracellular adenosine levels with subsequent alterations in the activation of its receptors interfere synergistic, antagonistic and additive with the action of other receptors systems. The receptor-receptor interaction involves receptor hetodimerization, interaction through signalling mechanism or changes in
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the level of the transmitters. In conclusion, we begin to understand the complexities of receptor-receptor
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interactions, which play a very important role in physiological and pathophysiological processes. Furthermore, it is obvious that the analysis of the different receptor-
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receptor interactions will have important general implications about the processing of information of GPCRs.
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There is evidence that various regulatory mechanisms exist as well as multiple mechanisms act independent of each other on the same cell depending on the brain region and cell type. The overacting and redundancy principle ensures transmitter
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homeostasis under pathophysiological conditions in a specific time window. The function of adenosine receptors in the regulation of the synaptic transmission is
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complex.
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The key receptor in regulation the neuronal transmission may be the A2AR, whereas the interaction of the A1R with metabotropic and ionotropic receptors serves as fine-
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tuning to inhibit synaptic transmission. However, they play an important protective role during pathophysiological conditions. The activation initiates a fast inhibition of the glutamatergic neurotransmission and the receptor interactions may contribute to its maintenance or can support the A1R mediated effects. Most of our knowledge on receptor-receptor interactions involves results from experiments on cell cultures, slice preparation or, to a lower extent, from in vivo experiments, where regulation can be studied in principle or new drug targets can be characterized. These findings may contribute to a better understanding of disturbances in transmitter homeostasis. As our understanding of the complexity of receptor signalling and interaction develops, we may well gain new perspectives in therapy and drug development. The clinical relevance of the testing models has often been questioned, however. Discordance between studies on cells and animal and human studies may be due to bias or failure of models to mimic clinical disease to an adequate degree. There are new techniques such as neuroimaging, nanotechnology, 12
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siPCR and new selective receptor ligands that will help to overcome some of these aspects in the near future. In conclusion, in the central nervous system, functional modules in which receptors for neurotransmitters or neuromodulators interact synergistic or additive with each other are crucial to understand the physiology of the
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neuron and higher neuronal functions. Refined knowledge of the molecular mechanism of these interactions would be beneficial to improve our therapeutic
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arsenal against neurological and neuropsychiatric diseases. Conflict of interest
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The authors declare that there is no conflict of interest whatsoever.
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Figure 1: Participation of adenosine receptors in neuroprotection. A1R and A2AR may influence sleep and arousal, cognition and memory, neuronal damage and degeneration. The therapeutic implications for neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, epilepsy, sleep deprivation and multiple sclerosis is well documented in in vivo and in vitro studies.
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Figure 2: Schematic representation of possible interactions of adenosine receptors. Heteromerization between A1Rs and A2ARs or D1Rs causes changes in influencing glutamate release by adenosine. During elevated adenosine levels, A2AR signalling becomes dominant in the A1R/A2AR complex, providing enhancement of glutamate release. The A1R/D1R heteromer requires both adenosine and dopamine to be activated, and inhibits transmitter release.
Figure 3: Schematic representation of possible interactions of A1Rs with glutamatergic and GABAergic receptors contributing to the fine tuning of neurotransmission. Adenosine acting via presynaptic A1Rs may attenuate the influx of Ca2+ through voltage-dependent calcium cannels, and thus decrease the release of glutamate and GABA, which inhibits or facilitates the activation of postsynaptic located NMDA receptors, respectively. Adenosine acting through postsynaptic A1Rs may activate KATP, which leads to hyperpolarization of postsynaptic neurons and inhibits directly the activity of NMDA and GABAA receptors.
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S2213-7130(14)00021-2 http://dx.doi.org/doi:10.1016/j.synres.2014.10.001 SYNRES 12
To appear in: Received date: Revised date: Accepted date:
30-5-2014 13-10-2014 14-10-2014
Please cite this article as: Nieber K, Michael S, Adenosine receptors: Intermembrane receptor-receptor interactions in the brain, Synergy Res. (2014), http://dx.doi.org/10.1016/j.synres.2014.10.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Adenosine receptors: Intermembrane receptor-receptor interactions in the brain Karen Nieber and Sebastian Michael1 University of Leipzig, Institute of Pharmacy Brüderstr. 34, 04103 Leipzig, Germany; 1
Loewen-Apotheke Waldheim Obermarkt 11 04736 Waldheim, Germany
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Correspondence address: Prof. Dr. Karen Nieber
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University of Leipzig, Institute of Pharmacy Brüderstr. 34, 04103 Leipzig; Germany Phone: ++49 39200 785880 or ++49 176 31123917
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[email protected]
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Abstract
In the vertebrate central nervous system (CNS) the modulation of synaptic
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transmission by metabotropic or ionotropic receptors is an important source of control and dynamical adjustment in synaptic activity and can contribute to synergistic or antagonistic effects. Adenosine is released from most cells, including neurons and
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glial cells. Once in the extracellular space, adenosine modifies cell functioning by
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operating G-protein-coupled receptors. In general, adenosine has been found to act in concert with other hormones or neurotransmitters in either an inhibitory or a
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stimulatory way. From the four cloned adenosine receptors (A1Rs, A2ARs, A2BRs and A3R), A1Rs and A2ARs are the main targets for the physiological effects of adenosine in the brain. A1R is a prototype of G-protein-coupled receptor able to form heterotypic interactions with other members of metabotropic and ionic receptors. The development of effective agonists, antagonists and in addition, gene-targeted mice deficient in the expression of each receptor subtype has made it possible to clarify the functional role with respect to synergistic effects with other receptors in both physiological and pathophysiological conditions. It is becoming increasingly obvious that the modulatory role of adenosine is related to the ability of A1Rs and A2ARs heteromerize with themselves and with other receptors, such as dopamine, glutamate or GABA. These interactions between adenosine receptors and other receptors for neurotransmitters might contribute to a fine-tuning of neuronal function, and therefore, to neuroprotection. Keywords: Adenosine, Receptor interaction,
Dopamine, GABA, Glutamate 1
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Contents 1. Introduction 2. Interaction between A1Rs and A2ARs
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3. Interaction between A1Rs and A3Rs 4. Interaction between adenosine receptors and dopamine receptors
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5. Interaction between adenosine receptors and NMDA receptors 6. Interaction between A1 receptors and GABAA receptors
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7. Concluding remarks Conflict of interest
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References 1. Introduction
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The vertebrate central nervous system (CNS) is characterized by a dynamic interplay between signal transduction molecules and their cellular targets. Modulation of synaptic transmission by metabotropic or ionotropic receptors is an important source
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of control and dynamical adjustment in synaptic activity and can contribute to
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synergistic, additive or antagonistic effects. (Bouvier, 2001; Marshall, 2001). G protein coupled receptors play a crucial role in mediating cellular responses to
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external stimuli, and increasing evidence suggests that they function as multiple units comprising homo/heterodimers and hetero-oligomers (Bouvier, 2001; Marshall, 2001). It all began in 1979-1980 in search of an explanation of where all the recently discovered neuropeptides in the brain could integrate their messages with those of classical transmitters such as the monoamines. The concept of “intramembrane receptor interactions” (receptor oligomerization) was first described by Luigi Agnati and Kjell Fuxe more than 25 years ago (Fuxe et al. 1983, Agnati et al. 2003). In these interactions, stimulation of one receptor changes the binding characteristics of an adjacent receptor in membrane preparations from brain tissue or transfected cells. Agnati and Fuxe postulated that an intramembrane interaction between neuropeptide and monoamine receptors could be involved, showing that substance P could modulate the high-affinity serotonin binding sites in spinal cord membrane preparations (Agnati et al., 1980). The same year, an interesting paper was published by Maggi and co-workers showing that the β-adrenergic receptor agonist 2
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isoproterenol could increase α 2 adrenergic receptor binding in cortical slices, supporting the concept of intramembrane receptor-receptor interactions of GPCR (Maggi et al. 1980). Thus, not only neuropeptide and monoamine receptors were involved in intramembrane receptor-receptor interactions but also certain types of
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glutamate and adenosine receptors (Agnati et al. 2003). Multi-protein complexes mediate most cellular functions. In neurons, these complexes are directly involved in the neuronal transmission, which is responsible for learning, memory and
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developments. Over the past decades, the number and outcomes of interactions between receptors has increased continuously (Agnati et al. 2003). Recent studies
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have demonstrated close physical interactions where activation of one receptor affects the function of the other.
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Extracellular adenosine acts as a local modulator of cell function via four adenosine receptor subtypes (A1Rs A2AR, A2BR, and A3R) that are involved in numerous Each is
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physiological and pathophysiological processes (Fredholm et al. 2001).
encoded by a separate gene and has different functions, although with some overlap (Gao and Jacobson 2007).
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Evidence for the existence of G protein-coupled receptor homomerization and
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heteromerization is growing continuously. There are numerous reviews about central nervous system that describe regulation of brain adenosine levels, adenosine
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receptors, their cellular and subcellular localization, signalling pathways and function in the brain under physiological and pathophysiological conditions as well as selective receptor agonists and antagonists (Fredholm et al. 2005, Jacobson and Gao 2005, Abbracchio et al. 2009, Müller and Jacobson 2011, Sheth et al 2014). Additionally, a set of publications has demonstrated the existence of potential adenosine receptor interactions. In this context, the excellent review of Ciurela and co-workers summarized the recent significant developments based on adenosine receptor interactions that are essential for acquiring a better understanding of neurotransmission in the central nervous system (Ciurela et al. 2011). Either through direct receptor–receptor modulation or beyond the receptor pathways, adenosine might synchronize or desynchronize synaptic transmission in order to fine-tune the nervous system. This opens novel possibilities for the action of this nucleoside (Burnstock 2013). Using adenosine receptors as paradigm of GPCRs, this review focuses
on
how
receptor-receptor
interactions
contribute
synergistically
or 3
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antagonistically to processes within the central nervous system. Considering the various types of receptors, one may expect to find three principle paths of receptor interaction: (i) interactions between metabotropic receptors (ii) interactions between a metabotropic receptor and an ionotropic receptor and (iii) interactions between
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ionotropic receptors. The examples mentioned below stem from the first and second type of interaction. Synergistic, additive and antagonistic effect will be discussed.
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Insert Figure 1
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2. Interaction between A1Rs and A2ARs
The A1Rs are the best characterized of the widely distributed purinergic receptor family. This might result from a highly localized distribution of A1Rs in the active zone
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and postsynaptic density of CNS synapses, especially in hippocampus (Rebola et al 2003) and prefrontal cortex (Ochiishi et al. 1999). A1Rs can be clearly distinguished from A2Rs on the basis of structure activity relationships with selective ligands. A2ARs
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are widely distributed in the CNS, but local and subcellular differences in allocation exist. The A2ARs occur predominantly on neurons in the striatum, especially the
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GABAergic projection neurons and on cholinergic interneurons (Ongini and Fredholm
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1996). A2ARs are also found in lower density in neurons in the neocortex and limbic cortex (Fredholm et al. 2005). There is abundant evidence from biochemical and
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electrophysiological investigations that the activation of A2ARs promotes the release of neurotransmitters (Cunha et al. 1994) Co-localization of A1Rs and A2ARs was approved for glutamatergic nerve terminals in the hippocampus (Rebola et al. 2005). In the striatum, A1R-A2AR heteromers were found on synapses of medium spiny neurons and integrated in the presynaptic membrane of glutamatergic terminals that represent the cortical-limbic-thalamic input (Ferre at al. 2007). A1R and A2ARs may closely interact in such a way that activation of A2AR receptors can lead to inhibition of A1R-mediated responses (Lopes et al. 1999).. However, problems arise due to long-term desensitization of A1Rs. Evidence should be that A2ARs do not up-regulate after antagonist administration, but have a low abundance in hippocampal and cortical areas compared with A1Rs (Cuhna 2005; Xu et al. 2002; Popoli et al. 2000). A1Rs and A2ARs cannot be regarded in isolation from one another since cross talk between the subtypes has been described several times (Dixon et al. 1997; Lopes et al. 2002; Quarta et al. 2004; Ciruela et al. 2006a; Ciruela et al. 2006b). A2AR activation by agonists caused A1R desensitization resulting in decreased binding 4
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affinity for agonists in the hippocampus of young rats. Controlling A1Rs by A2ARs was mediated by protein kinase C in a cAMP-independent manner. A2AR activation was seen to play a role in fine-tuning A1Rs by attenuating the tonic effect of presynaptic A1Rs located on glutamatergic nerve terminals (Dixon et al. 1997; Lopes et al. 1999;
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Lopes et al. 2002; Ciruela et al. 2006a; Ciruela et al. 2006b). One implication of this interaction is that, when the extracellular level of adenosine reaches levels sufficient to activate A2ARs, as it can do after hypoxia, it may inhibit A1Rs function (Forrest et
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al. 2003). Some results support this assumption. It has recently been demonstrated that A2ARs receptors localized in striatal glutamatergic terminals play a very important form
heteromers
with
A1Rs,
and
the
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role in control of striatal glutamate release (Ciruela et al. 2006b). These receptors A1R-A2AR
heteromer
constitutes
a
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“concentration-dependent switch” that regulates glutamate release depending on the extracellular concentration of adenosine. As in the hippocampus, A2AR stimulation decreased the affinity of A1Rs for agonists. The A1R-A2AR heteromer allows
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adenosine to perform a detailed modulation of glutamate release (Quarta et al. 2004; Ciruela et al. 2006b). Finally, Cristovao-Ferreira et al. (2013) showed in primary
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through A1R-A2AR heteromers.
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cultures of rat astrocytes that a further level of regulation of GABA uptake occurs
Regarding A1Rs and A2ARs, basal conditions generate a low tone of endogenous
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adenosine and cause A1R activation, in contrast to situations of increased adenosine where A2AR activation becomes dominant. When adenosine concentrations rise, e.g. during hypoxia, also time appears likely important in regulating A2AR activity. That means A2ARs are “active” under prolonged stimulation (Latini et al. 1999). Finally, activation of the A1R/A2AR heteromer contributes to A2AR signalling when adenosine level is elevated, and may provide a mechanism to facilitate plastic changes in the excitatory synapse (Ferre et al. 2006). Consequently, the results of the above mentioned studies support the notion that A1Rs and A2AR regulate the synaptic transmission synergistically via forming A1R-A2AR heteromers. 3. Interaction between A1Rs and A3Rs The A3R was the latest receptor subtype of the adenosine receptor family to be identified, and its functional role is still controversially discussed (Fredholm et al. 2001). A dual, biphasic role in neuroprotection has been described depending on experimental approach, both in vitro and in vivo (von Lubitz et al. 1994; von Lubitz et 5
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al. 1999a, von Lubitz et al. 1999b; Rubay et al. 2001; Sei et al. 2006; Pugliese et al. 2003; Pugliese et al. 2006). A3Rs couple to inhibition of adenylyl cyclase as well as to activation of PLC, and to elevation of inositol triphosphate levels (Ramkumar et al. 1993; Abbracchio et al. 1995). Furthermore, an increase in intracellular Ca2+ levels
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due to release from intracellular stores and Ca2+ influx has been described (Gessi et al. 2002; Kohno et al 1996). One interesting example of A3Rs functional role is their involvement in acute neurotoxic situations and interplay with A1Rs. A potential of
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A3Rs to modify responses via A1Rs in the hippocampus has been postulated (Dunwiddie et al. 1997). In vitro experiments on rat brain slices approved that the
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activation of hippocampal A3Rs induced a desensitization of A1Rs. This phenomenon was thought to reduce the protective effects of endogenous adenosine caused by the
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lack of sensitivity of A1Rs. Further investigations on pyramidal cells of the rat cingulate cortex did not confirm these results (Brand et al. 2000). In this brain area, A1Rs and A3Rs did not show any interaction. The receptor subtypes were unable to
M
affect each other. The discrepancy was taken to be a genetic phenomenon, such as alternative splicing of the rat A3R transcript causing distinguished pharmacological and functional properties in the brain. Furthermore, Hentschel et al. (2003)
d
demonstrated the involvement of A3Rs in inhibition of excitatory neurotransmission
te
during hypoxic conditions, indicating a neuroprotective action of endogenously released adenosine on A3Rs in addition to A1Rs. Lastly, Lopes et al. (2003)
Ac ce p
attempted to define the possible role of A3Rs in the rat hippocampus using experiments in non-stressful and stressful situations, with particular attention to whether A3Rs control A1Rs. These data suggested that no interaction between the two receptor subtypes exist, but confirm that A3Rs do not affect synaptic transmission on superfusion with an A3R agonist or an A3R antagonist. The authors pointed out that the agonist binds to A1Rs even at low nanomolar concentrations and to the A3Rs in higher concentration. Herterodimerization between both receptor subtypes was not described so far. It seems that these receptors subtypes act additively or were activated at different concentration of extracellular adenosine. Another explanation is that the A3Rs are active after desensitization of the A1Rs. This could be a functional synergistic effect. Thus, the existence of a possible interaction between A1Rs and A3Rs has to wait for reliable ligands. 4. Interaction between adenosine receptors and dopamine receptors
6
Page 6 of 23
Dopamine is an important transmitter in the striatum, and is noted for influencing motor activity, playing an important role in Parkinson’s disease. In vivo and in vitro data on adenosine-dopamine interactions were mostly obtained from investigations in the basal ganglia and limbic regions (Mayfield et al. 1999; Floran et al. 2002) due to
ip t
the high abundance of A1Rs, A2ARs, dopamine D1 receptors (D1Rs) and dopamine D2 receptors (D2Rs) in these areas and their involvement in the pathology of Parkinson’s disease. Sufficient endogenous adenosine is present interstitially in the substantia
cr
nigra pars reticulata to control dopaminergic effects. The effects of adenosine are absent when dopaminergic influence is suppressed (Floran et al. 2002). There also is
us
an anatomical basis for the existence of functional interactions between A1Rs and D1Rs in the same neurons. Moreover, recently it has been shown in caudate-
an
putamen slices that adenosine modulates dopamine release also via A1R (Ross and Venton 2014)
While A1Rs communicate mainly with the D1R subtype (Gines et al. 2000), A2AR and
M
D2R interaction occurs mainly in basal ganglia. D2Rs colocalizes with A2ARs in this brain area where they are preferentially localized postsynaptically in the soma and
d
dendrites of GABAergic striatopallidal neurons (Quiroz et al. 2009). This interaction
te
plays a very important role in striatal function. A2AR-D2R interaction provides an example of the capabilities of information processing by just two different G proteinhere is evidence for the coexistence of two
Ac ce p
coupled receptors. Interestingly,
reciprocal antagonistic interactions between A2ARs and D2Rs in the same neurons. In one type of interaction, A2ARs and D2R are forming heteromers and, by means of an allosteric interaction, A2ARs counteracts D2Rs-mediated inhibitory modulation of the effects of NMDA receptor stimulation in the striatopallidal neuron. This antagonistic interaction is probably mostly responsible for the locomotor depressant and activating effects of A2AR agonist and antagonists, respectively. The second type of interaction involves A2ARs and D2Rs that do not form heteromers and takes place at the level of adenylyl cyclase (Ferre et al. 2011) indicating two different populations of postsynaptic striatal A2ARs. In summary, signalling through A2ARs and D2Rs is distinctive and synergistic, supporting their unique and yet integrative roles in regulating neuronal functions when both receptors are present. The results of the above mentioned studies support the notion that receptor heteromers may be used as selective targets for drug 7
Page 7 of 23
development. Their opposing roles in regulating neuronal activities, such as locomotion and alcohol consumption, are mediated by their opposite actions on adenylate cyclase, which often serves as “co-incidence detector” of various activators (Tang and Demarest 2005). On the other hand, the neural actions of A2ARs and D2Rs
ip t
are also, at least partially, independent of each other, as indicated by studies using D2Rs and A2ARs knock out mice. Studies on mice and monkeys suggest that some degree of dopaminergic activity is needed to obtain adenosine induced antagonistic
cr
effects on motor activity. The blockade of dopaminergic neurotransmission counteracts the antagonistic effect induced by adenosine (Ferre et al. 2001, Ferre et
us
al. 2011).
an
Insert Figure 2
5. Interaction between adenosine receptors and NMDA receptors Glutamate is the major excitatory neurotransmitter in the mammalian central nervous
M
system. In most brain areas, glutamate mediates fast synaptic transmission by activating ionotropic receptors of the AMPA, kainate and NMDA subtype.
d
Additionally, NMDA receptors play a critical role in synaptic plasticity, synaptic
te
development and neurotoxicity. In a recent study, Arrigoni et al. (2001) have investigated the role of exogenous and endogenous adenosine in regulating synaptic
Ac ce p
glutamatergic transmission. From their electrophysiological results a presynaptic site of action for
A1R receptors on glutamatergic afferents was suggested by the
following: (1) adenosine did not affect exogenous glutamate-mediated current, (2) adenosine reduced glutamatergic miniature EPSC frequency, without affecting the amplitude, and (3) inhibition of the evoked EPSC was mimicked by an A1R agonist but not by an A2R agonist. Applicable with these findings is the study of Li and Henry, (2000) indicated that endogenous adenosine present in the extracellular fluid of hippocampal slices inhibits NMDA receptor-mediated dendritic spikes as well as AMPA/kainate receptor-mediated excitatory synaptic potentials by activation of A1Rs in CA1 pyramidal cells and with results of Schotanus et al. (2006) showing that the activation of A1Rs by ambient adenosine depressed field potentials in the striatum. The effect of adenosine in the striatum (Schotanus et al. 2006) or hippocampus (Masino et al. 2002) has not been found in A1R knockout mice, and clearly demonstrates the involvement of A1Rs. The involvement of A1Rs was also supported by experiments using a selective receptor ligand. On the other hand, NMDA is known 8
Page 8 of 23
to increase the extracellular level of adenosine via bi-directional adenosine transporters or from released adenine nucleotides degraded by a chain of ectonucleotidases (Hebb et al. 1998; Cunha et al. 1996) Another interesting interaction concerns NMDA preconditioning to protect against
ip t
glutamate neurotoxicity. It has been shown that an A1R antagonist prevented neuroprotection evoked by NMDA preconditioning against glutamate-induced cellular
cr
damage in cerebellar granule cells. In this study, the functionality of A1Rs was not affected by NMDA preconditioning, but this treatment promoted A2AR desensitization
us
in concert with A1R activation (Boeck et al. 2005). These results are in line with other studies indicating that adenosine down regulates excitatory and inhibitory synaptic transmission in several brain areas through activation of A1Rs and A2AR (Dunwiddie
an
et al. 1981; Mori et al. 1996). Furthermore, activation of A1Rs mediates reversal of long-term potentiation (LTP) produced by brief application of NMDA in hippocampal
M
CA1 neurons (Huang et al. 2001).
Finally, it has recently been demonstrated that A2ARs receptors localized in striatal glutamatergic terminals play a very important role in control of striatal glutamate
d
release (Ciruela et al. 2006b). These receptors form heteromers with A1Rs, and the
te
A1R-A2AR heteromer constitutes a “concentration-dependent switch” that regulates glutamate release depending on the extracellular concentration of adenosine. Thus,
Ac ce p
low concentrations of adenosine inhibit glutamate release by stimulating the A1Rs, while higher concentrations induce glutamate release by also stimulating A2AR, which shuts down A1R signalling by means of an antagonistic intramembrane receptor interaction (Ferre et al. 2008). However, the A2ARs-dependent modulation of glutamate release seems to be under an inhibitory control by co-localized D2Rs. Taken together, there are several ways in which adenosine may interact synergistic with
glutamatergic
neurotransmission.
Adenosine
can
affect
glutamatergic
transmission via A1Rs or A2ARs. NMDA receptors and A1Rs to down regulate glutamate release presynaptically in pyramidal cells of the cingulate cortex (Brand et al. 2000), neurons of the hippocampus (Scammell et al. 2003), and striatal neurons (Schotanus et al. 2006). Another putative mechanism is the elevation of the threshold to
open
NMDA
receptor-operated
channels
by
antagonizing
membrane
depolarization (Wardas 2002).
9
Page 9 of 23
Insert Figure 3 6. Interaction between A1 receptors and GABAA receptors Fast synaptic inhibition in the brain and spinal cord is largely mediated by GABAA
ip t
receptors that are also targeted by drugs such as benzodiazepines, barbiturates, neurosteroids and some anesthetics. The modulation of their function will have important consequences for neuronal excitation (Kittner and Moss 2003). One
cr
accepted mean of modifying the efficacy is a functional interaction with adenosine. Cristovao-Ferreira et al. (2013) showed that GABA uptake by astrocytes is under
us
modulation by extracellular adenosine. They found that A1R-A2AR heteromers in astrocytes regulating GABA transport in an opposite way, with A1R mediating
an
inhibition of GABA transport and A2AR mediating facilitation of GABA transport. This A1R–A2AR functional unit may, therefore, operate as a dual amplifier to control ambient GABA levels at synapses. In addition, adenosine may have an effect on
M
either GABA release in interneurons and/or on GABAA receptors in projection neurons. The site of action may be studied electrophysiologically by inducing fast inhibitory postsynaptic potentials or application of GABA directly onto the cell.
d
Adenosine and selective A1R agonists reduced the amplitude of the inhibitory
te
postsynaptic potentials in lateral amygdala slice preparations. The effect was blocked by an A1R antagonist, indicating an interaction of A1Rs with GABA receptors.
Ac ce p
Additionally, adenosine did not block currents evoked by local application of GABA (Heinbockel and Pape 1999). Thus, the modulatory effect of adenosine on the GABAergic neurotransmission appears to take place directly by inhibiting GABA release from nerve terminals (Heinbockel and Pape 1999; Shen and Johnson 1997). The assumption that the activation of A1Rs can modulate inhibitory postsynaptic responses agrees with findings in several brain areas, such as the thalamus (Ulrich and Huguenard 1997), suprachiasmatic and arcuate nucleus (Neary et al. 1996), and substantia nigra pars compacta (Shen and Johnson 1997). There is some evidence that activation of A1Rs is also involved in GABAA receptor down-regulation, implying a facilitation of the neurotransmission. The GABA-induced neurotransmission was significantly reduced be adenosine via activation of A1Rs (Li et al. 2004). The mode of this interaction seems due to a regulation of the GABAA chloride channel (Akhondzadeh and Stone 1994).
10
Page 10 of 23
Further investigations were concerned to study the mechanisms by which GABA modulates adenosine-mediated effects in hippocampal tissue. From these results it can be concluded that endogenous GABA exerts an inhibitory effect through GABAA receptors via a predominant adenosine-mediated action and this is an A1R-mediated
ip t
ability to inhibit synaptic transmission (Fragata et al. 2006). It is well documented that activation of GABAA receptors is effective in limiting
cr
neuronal ischemic damage (Madden 1994) and endogenous adenosine that arises during hypoxia acts neuroprotectively partly by activating A1Rs (Hentschel et al.
us
2003). Therefore, the contribution and potential interactions of GABA and adenosine as modulators of synaptic transmission during hypoxia has been investigated. Activation of A1Rs inhibits the release of GABA from the ischemic cerebral cortex in
an
vivo (O´Regan et al. 1992). In contrast, the administration of an A1R agonist in the hippocampus failed to affect the release of GABA during ischemia (Heron et al. 1994). In the light of these controversial results, the role of the two neuromodulators
M
was investigated in the CA1 area of rat hippocampal slices during hypoxia using selective A1R antagonists (Lucchi et al. 1996). Indeed, activation of A1R and GABAA
d
receptors is partly involved in the inhibition of synaptic transmission during hypoxia.
te
The action of GABA becomes evident when A1Rs are blocked. Regarding the desensitization of A1Rs during hypoxia (Rufke et al. 2006; Wetherington and Lambert
Ac ce p
2002), it may be assumed that GABAA-mediated inhibition of the synaptic transmission is evident when the A1R is desensitized or down regulated (Lucchi et al. 1996).
Co-modulation by A1Rs and GABAA receptors was also suggested in acute cerebellar ethanol-induced ataxia. Using GABAA and A1R agonists and antagonists, respectively, a functional similarity between GABAA receptors and A1Rs has been shown even through both receptor types are known to couple to different signalling systems (Dar 2002). This provides conclusive evidence that A1Rs and GABAA receptors both play a co-modulatory role in ethanol-induced cerebellar ataxia without any direct interaction. 7. Concluding remarks As a consequence of its ubiquitous distribution and because of its linkage to the energy pool, adenosine has evolved as an important messenger in extracellular 11
Page 11 of 23
signalling. Modifications in extracellular adenosine levels with subsequent alterations in the activation of its receptors interfere synergistic, antagonistic and additive with the action of other receptors systems. The receptor-receptor interaction involves receptor hetodimerization, interaction through signalling mechanism or changes in
ip t
the level of the transmitters. In conclusion, we begin to understand the complexities of receptor-receptor
cr
interactions, which play a very important role in physiological and pathophysiological processes. Furthermore, it is obvious that the analysis of the different receptor-
us
receptor interactions will have important general implications about the processing of information of GPCRs.
an
There is evidence that various regulatory mechanisms exist as well as multiple mechanisms act independent of each other on the same cell depending on the brain region and cell type. The overacting and redundancy principle ensures transmitter
M
homeostasis under pathophysiological conditions in a specific time window. The function of adenosine receptors in the regulation of the synaptic transmission is
d
complex.
te
The key receptor in regulation the neuronal transmission may be the A2AR, whereas the interaction of the A1R with metabotropic and ionotropic receptors serves as fine-
Ac ce p
tuning to inhibit synaptic transmission. However, they play an important protective role during pathophysiological conditions. The activation initiates a fast inhibition of the glutamatergic neurotransmission and the receptor interactions may contribute to its maintenance or can support the A1R mediated effects. Most of our knowledge on receptor-receptor interactions involves results from experiments on cell cultures, slice preparation or, to a lower extent, from in vivo experiments, where regulation can be studied in principle or new drug targets can be characterized. These findings may contribute to a better understanding of disturbances in transmitter homeostasis. As our understanding of the complexity of receptor signalling and interaction develops, we may well gain new perspectives in therapy and drug development. The clinical relevance of the testing models has often been questioned, however. Discordance between studies on cells and animal and human studies may be due to bias or failure of models to mimic clinical disease to an adequate degree. There are new techniques such as neuroimaging, nanotechnology, 12
Page 12 of 23
siPCR and new selective receptor ligands that will help to overcome some of these aspects in the near future. In conclusion, in the central nervous system, functional modules in which receptors for neurotransmitters or neuromodulators interact synergistic or additive with each other are crucial to understand the physiology of the
ip t
neuron and higher neuronal functions. Refined knowledge of the molecular mechanism of these interactions would be beneficial to improve our therapeutic
cr
arsenal against neurological and neuropsychiatric diseases. Conflict of interest
us
The authors declare that there is no conflict of interest whatsoever.
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Figure 1: Participation of adenosine receptors in neuroprotection. A1R and A2AR may influence sleep and arousal, cognition and memory, neuronal damage and degeneration. The therapeutic implications for neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, epilepsy, sleep deprivation and multiple sclerosis is well documented in in vivo and in vitro studies.
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Figure 2: Schematic representation of possible interactions of adenosine receptors. Heteromerization between A1Rs and A2ARs or D1Rs causes changes in influencing glutamate release by adenosine. During elevated adenosine levels, A2AR signalling becomes dominant in the A1R/A2AR complex, providing enhancement of glutamate release. The A1R/D1R heteromer requires both adenosine and dopamine to be activated, and inhibits transmitter release.
Figure 3: Schematic representation of possible interactions of A1Rs with glutamatergic and GABAergic receptors contributing to the fine tuning of neurotransmission. Adenosine acting via presynaptic A1Rs may attenuate the influx of Ca2+ through voltage-dependent calcium cannels, and thus decrease the release of glutamate and GABA, which inhibits or facilitates the activation of postsynaptic located NMDA receptors, respectively. Adenosine acting through postsynaptic A1Rs may activate KATP, which leads to hyperpolarization of postsynaptic neurons and inhibits directly the activity of NMDA and GABAA receptors.
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