- Email: [email protected]
Presynaptic endoplasmic reticulum and neurotransmission
Journal Pre-proof Presynaptic endoplasmic reticulum and neurotransmission Ilya Bezprozvanny, Ege T. Kavalali
PII:
S0143-4160(19)30202-7
DOI:
https://doi.org/10.1016/j.ceca.2019.102133
Reference:
YCECA 102133
To appear in:
Cell Calcium
Received Date:
18 November 2019
Revised Date:
25 November 2019
Accepted Date:
25 November 2019
Please cite this article as: Bezprozvanny I, Kavalali ET, Presynaptic endoplasmic reticulum and neurotransmission, Cell Calcium (2019), doi: https://doi.org/10.1016/j.ceca.2019.102133
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. 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. © 2019 Published by Elsevier.
Presynaptic endoplasmic reticulum and neurotransmission Ilya Bezprozvanny1 and Ege T. Kavalali2
1
Department of Physiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390-9040, USA. 2
of
Department of Pharmacology and Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, 37240-7933, USA.
Correspondence to:
ro
[email protected] or [email protected]
Jo
ur na
lP
re
-p
Graphical abstract
Highlights
Role of ER Ca2+ signaling in synaptic transmission is discussed
Abstract Synaptic transmission relies on rapid calcium (Ca2+) influx into presynaptic terminal via voltagegated Ca2+ channels. However, smooth ER is present in presynaptic terminals and 1
accumulating evidence indicate that ER Ca2+ signaling may play a modulatory role in synaptic transmission. Most recent publication by Lindhout and colleagues (EMBO J, 38 (2019) e101345) suggested that the fragmentation state of the ER affects synaptic vesicle release. Here we discuss these results as well as several key publications that addressed a connection between ER Ca2+ signaling and synaptic transmission.
-p
ro
of
The vast majority of synaptic transmission literature is focused on the role of voltage-gated Ca2+ channels in evoked neurotransmitter release. Rapid and local Ca2+ influx via voltage-gated Ca2+ channels elicits synchronized fusion of synaptic vesicles [1]. In this context, slow and delocalized Ca2+ release from the endoplasmic reticulum (ER) does not appear to have a significant role. However, smooth ER is present in presynaptic terminals [2] and a number of experimental observations suggest that ER Ca2+ stores may play a modulatory role in mediating synaptic transmission (Fig 1). Several lines of evidence over the last two decades support the premise that Ca2+ release from intracellular stores can increase baseline spontaneous release frequency in hippocampal synapses [3] as well as in the cerebellum [4]. This pathway can be activated by classical modulatory neurotransmitters such as acetylcholine [3] or by unconventional neuromodulators such as Reelin [5].
ur na
lP
re
In addition to the impact of Ca2+ release from stores on baseline spontaneous release, evoked release probability was also proposed to be affected by ER Ca2+ levels. Emptage and colleagues [6] performed electrophysiological and imaging experiments in organotypic hippocampal slices and showed that action potential-induced Ca2+ influx was followed by Ca2+induced Ca2+ release (CICR) in presynaptic terminals. In addition, they discovered that ryanodine (inhibitor of ryanodine receptors) or CPA (inhibitor of SERCA Ca2+ pump) caused significant reduction in paired-pulse facilitation. Moreover, they reported that store-operated Ca2+ entry (SOCE) in presynaptic terminals had major influence on the rate of spontaneous neurotransmitter release. These results suggested that not only Ca2+ release from presynaptic ER store but also Ca2+ entry activated by depletion of these stores (i.e. SOCE process) can impact neurotransmission. Although the direct impact of presynaptic ER Ca2+ on rapid evoked release remains controversial [7], the role of ER-mediated Ca2+ signaling in regulation of slower forms of release has been observed in multiple systems. It is important to note that these earlier studies were performed before molecular identity of SOCE components became known and as such they solely relied on pharmacological tools that may have non-specific effects.
Jo
More recently, the role of store-operated Ca2+ entry in neurotransmission was revisited with the advantage of molecular tools and advanced imaging methods. A recent study by de Juan-Sanz and colleagues, performed in primary hippocampal neuronal cultures, proposed an interesting and provocative idea [8]. These investigators reasoned that presynaptic ER Ca2+ stores modulate synaptic transmission not by changing Ca2+ levels in the terminal but by affecting clustering state of STIM1 (ER Ca2+ sensor that mediates SOCE) (Fig 1). Results obtained in this paper suggested existence of a negative feedback loop that links ER Ca2+ stores in the presynaptic terminal and action potential-evoked synaptic transmission events. Mechanistically, these authors argued that ER Ca2+ store depletion causes enhanced clustering of STIM1 and that clustered STIM1 exerts inhibitory effect on synaptic transmission. The authors speculated that STIM1 may exert direct inhibitory effect on voltage-gated Ca2+ channels or impair coupling between Ca2+ influx and synaptic vesicle fusion. These are very provocative and interesting findings, in future studies exploration of their potential mechanism will be extremely informative. 2
re
-p
ro
of
A more recent study by Lindhout et al [9] approached the same problem from a cell biological perspective. Using primary hippocampal neuronal cultures, these investigators evaluated a role of ER integrity and remodeling in presynaptic function. In these studies, they focused on ER membrane receptors VAPA and VABP and their binding partner SCRN1. Based on a series of gain-of-function and loss-of-function experiments, they demonstrated that VAP-SCRN1 association affects ER structure and dynamics. Disruption of VAP-SCRN1 association resulted in fragmentation of ER and also caused decreased cycling of synaptic vesicles as detected by diminished uptake of an antibody targeting luminal region of synaptic vesicle protein synaptotagmin1. The authors concluded that VAP-SCRN1 association and local ER Ca2+ morphology modulate steady state Ca2+ homeostasis at presynaptic terminals and affect action potential-driven Ca2+ influx. The authors argue that fragmentation of ER leads to elevated steady-state Ca2+ levels and reduced driving force for Ca2+ entry into presynaptic terminal. This explanation is not likely as steady-state Ca2+ levels remain in the submicromolar range in these experiments. Another suggestion is that elevated steady state Ca2+ levels lead to compensatory changes in presynaptic terminal that leads to downregulation of Ca2+ channel activity and synaptic vesicle cycling. This explanation appears more plausible. In particular, there is evidence that elevated steady state Ca2 levels can slow synaptic vesicle retrieval and trafficking [10]. However, it is difficult propose a clear explanation for these findings based on synaptotagmin1 antibody uptake alone. Future experiments using electrophysiological approaches combined with optical tools to monitor synaptic vesicle trafficking are needed to pinpoint the direct impact of VAP-SCRN1 function and presynaptic ER integrity on exocytosis and/or endocytosis in presynaptic terminals.
ur na
lP
Overall, the study by Lindhout and colleagues adds to the increasing lines of evidence that presynaptic ER Ca2+ stores do in fact play a modulatory role in control of synaptic vesicle cycling and synaptic transmission. Although, at this time it is difficult to reconcile several proposed models and ideas, future studies should provide additional insights into the role of ER integrity and various forms of ER-dependent Ca2+ signaling in presynaptic function.
Jo
Acknowledgments. IB is the Carl J. and Hortense M. Thomsen Chair in Alzheimer's Disease Research. E.T.K. is the William Stokes Chair in Experimental Therapeutics. Supported by R01AG055577 (I.B. and E.T.K.).
3
References
Jo
ur na
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re
-p
ro
of
[1] R. Llinas, I.Z. Steinberg, K. Walton, Relationship between presynaptic calcium current and postsynaptic potential in squid giant synapse, Biophys. J., 33 (1981) 323-351. [2] Y. Wu, C. Whiteus, C.S. Xu, K.J. Hayworth, R.J. Weinberg, H.F. Hess, P. De Camilli, Contacts between the endoplasmic reticulum and other membranes in neurons, Proc Natl Acad Sci U S A, (2017). [3] G. Sharma, S. Vijayaraghavan, Modulation of presynaptic store calcium induces release of glutamate and postsynaptic firing, Neuron, 38 (2003) 929-939. [4] I. Llano, J. Gonzalez, C. Caputo, F.A. Lai, L.M. Blayney, Y.P. Tan, A. Marty, Presynaptic calcium stores underlie large-amplitude miniature IPSCs and spontaneous calcium transients, Nat Neurosci, 3 (2000) 1256-1265. [5] M. Bal, J. Leitz, A.L. Reese, D.M. Ramirez, M. Durakoglugil, J. Herz, L.M. Monteggia, E.T. Kavalali, Reelin mobilizes a VAMP7-dependent synaptic vesicle pool and selectively augments spontaneous neurotransmission, Neuron, 80 (2013) 934-946. [6] N.J. Emptage, C.A. Reid, A. Fine, Calcium stores in hippocampal synaptic boutons mediate short-term plasticity, store-operated Ca2+ entry, and spontaneous transmitter release, Neuron, 29 (2001) 197-208. [7] A.G. Carter, K.E. Vogt, K.A. Foster, W.G. Regehr, Assessing the role of calcium-induced calcium release in short-term presynaptic plasticity at excitatory central synapses, J Neurosci, 22 (2002) 21-28. [8] J. de Juan-Sanz, G.T. Holt, E.R. Schreiter, F. de Juan, D.S. Kim, T.A. Ryan, Axonal Endoplasmic Reticulum Ca2+ Content Controls Release Probability in CNS Nerve Terminals, Neuron, 93 (2017) 867-881 e866. [9] F.W. Lindhout, Y. Cao, J.T. Kevenaar, A. Bodzeta, R. Stucchi, M.M. Boumpoutsari, E.A. Katrukha, M. Altelaar, H.D. MacGillavry, C.C. Hoogenraad, VAP-SCRN1 interaction regulates dynamic endoplasmic reticulum remodeling and presynaptic function, EMBO J, 38 (2019) e101345. [10] J. Leitz, E.T. Kavalali, Ca(2)(+) influx slows single synaptic vesicle endocytosis, J Neurosci, 31 (2011) 16318-16326.
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Fig 1. Presynaptic ER Ca2+ stores. Presynaptic terminal is filled with synaptic vesicles (SVs). Canonical evoked neurotransmission is driven by Ca2+ influx through voltage gated Ca2+ channels (VGCCs). Smooth ER is present in many presynpatic terminals. Ca2+ release from ER is mediated by ryanodine receptors (RyR) by a mechanism of Ca2+-induced Ca2+ release (CICR). ER Ca2+ depletion causes clustering of STIM1 Ca2+ sensor protein and activation of store-operated Ca2+ entry pathway (SOCE) via Ca2+ influx through Orai channels. There is increasing evidence that both CICR and SOCE can impact neurotransmitter release.
5
PII:
S0143-4160(19)30202-7
DOI:
https://doi.org/10.1016/j.ceca.2019.102133
Reference:
YCECA 102133
To appear in:
Cell Calcium
Received Date:
18 November 2019
Revised Date:
25 November 2019
Accepted Date:
25 November 2019
Please cite this article as: Bezprozvanny I, Kavalali ET, Presynaptic endoplasmic reticulum and neurotransmission, Cell Calcium (2019), doi: https://doi.org/10.1016/j.ceca.2019.102133
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. 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. © 2019 Published by Elsevier.
Presynaptic endoplasmic reticulum and neurotransmission Ilya Bezprozvanny1 and Ege T. Kavalali2
1
Department of Physiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390-9040, USA. 2
of
Department of Pharmacology and Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, 37240-7933, USA.
Correspondence to:
ro
[email protected] or [email protected]
Jo
ur na
lP
re
-p
Graphical abstract
Highlights
Role of ER Ca2+ signaling in synaptic transmission is discussed
Abstract Synaptic transmission relies on rapid calcium (Ca2+) influx into presynaptic terminal via voltagegated Ca2+ channels. However, smooth ER is present in presynaptic terminals and 1
accumulating evidence indicate that ER Ca2+ signaling may play a modulatory role in synaptic transmission. Most recent publication by Lindhout and colleagues (EMBO J, 38 (2019) e101345) suggested that the fragmentation state of the ER affects synaptic vesicle release. Here we discuss these results as well as several key publications that addressed a connection between ER Ca2+ signaling and synaptic transmission.
-p
ro
of
The vast majority of synaptic transmission literature is focused on the role of voltage-gated Ca2+ channels in evoked neurotransmitter release. Rapid and local Ca2+ influx via voltage-gated Ca2+ channels elicits synchronized fusion of synaptic vesicles [1]. In this context, slow and delocalized Ca2+ release from the endoplasmic reticulum (ER) does not appear to have a significant role. However, smooth ER is present in presynaptic terminals [2] and a number of experimental observations suggest that ER Ca2+ stores may play a modulatory role in mediating synaptic transmission (Fig 1). Several lines of evidence over the last two decades support the premise that Ca2+ release from intracellular stores can increase baseline spontaneous release frequency in hippocampal synapses [3] as well as in the cerebellum [4]. This pathway can be activated by classical modulatory neurotransmitters such as acetylcholine [3] or by unconventional neuromodulators such as Reelin [5].
ur na
lP
re
In addition to the impact of Ca2+ release from stores on baseline spontaneous release, evoked release probability was also proposed to be affected by ER Ca2+ levels. Emptage and colleagues [6] performed electrophysiological and imaging experiments in organotypic hippocampal slices and showed that action potential-induced Ca2+ influx was followed by Ca2+induced Ca2+ release (CICR) in presynaptic terminals. In addition, they discovered that ryanodine (inhibitor of ryanodine receptors) or CPA (inhibitor of SERCA Ca2+ pump) caused significant reduction in paired-pulse facilitation. Moreover, they reported that store-operated Ca2+ entry (SOCE) in presynaptic terminals had major influence on the rate of spontaneous neurotransmitter release. These results suggested that not only Ca2+ release from presynaptic ER store but also Ca2+ entry activated by depletion of these stores (i.e. SOCE process) can impact neurotransmission. Although the direct impact of presynaptic ER Ca2+ on rapid evoked release remains controversial [7], the role of ER-mediated Ca2+ signaling in regulation of slower forms of release has been observed in multiple systems. It is important to note that these earlier studies were performed before molecular identity of SOCE components became known and as such they solely relied on pharmacological tools that may have non-specific effects.
Jo
More recently, the role of store-operated Ca2+ entry in neurotransmission was revisited with the advantage of molecular tools and advanced imaging methods. A recent study by de Juan-Sanz and colleagues, performed in primary hippocampal neuronal cultures, proposed an interesting and provocative idea [8]. These investigators reasoned that presynaptic ER Ca2+ stores modulate synaptic transmission not by changing Ca2+ levels in the terminal but by affecting clustering state of STIM1 (ER Ca2+ sensor that mediates SOCE) (Fig 1). Results obtained in this paper suggested existence of a negative feedback loop that links ER Ca2+ stores in the presynaptic terminal and action potential-evoked synaptic transmission events. Mechanistically, these authors argued that ER Ca2+ store depletion causes enhanced clustering of STIM1 and that clustered STIM1 exerts inhibitory effect on synaptic transmission. The authors speculated that STIM1 may exert direct inhibitory effect on voltage-gated Ca2+ channels or impair coupling between Ca2+ influx and synaptic vesicle fusion. These are very provocative and interesting findings, in future studies exploration of their potential mechanism will be extremely informative. 2
re
-p
ro
of
A more recent study by Lindhout et al [9] approached the same problem from a cell biological perspective. Using primary hippocampal neuronal cultures, these investigators evaluated a role of ER integrity and remodeling in presynaptic function. In these studies, they focused on ER membrane receptors VAPA and VABP and their binding partner SCRN1. Based on a series of gain-of-function and loss-of-function experiments, they demonstrated that VAP-SCRN1 association affects ER structure and dynamics. Disruption of VAP-SCRN1 association resulted in fragmentation of ER and also caused decreased cycling of synaptic vesicles as detected by diminished uptake of an antibody targeting luminal region of synaptic vesicle protein synaptotagmin1. The authors concluded that VAP-SCRN1 association and local ER Ca2+ morphology modulate steady state Ca2+ homeostasis at presynaptic terminals and affect action potential-driven Ca2+ influx. The authors argue that fragmentation of ER leads to elevated steady-state Ca2+ levels and reduced driving force for Ca2+ entry into presynaptic terminal. This explanation is not likely as steady-state Ca2+ levels remain in the submicromolar range in these experiments. Another suggestion is that elevated steady state Ca2+ levels lead to compensatory changes in presynaptic terminal that leads to downregulation of Ca2+ channel activity and synaptic vesicle cycling. This explanation appears more plausible. In particular, there is evidence that elevated steady state Ca2 levels can slow synaptic vesicle retrieval and trafficking [10]. However, it is difficult propose a clear explanation for these findings based on synaptotagmin1 antibody uptake alone. Future experiments using electrophysiological approaches combined with optical tools to monitor synaptic vesicle trafficking are needed to pinpoint the direct impact of VAP-SCRN1 function and presynaptic ER integrity on exocytosis and/or endocytosis in presynaptic terminals.
ur na
lP
Overall, the study by Lindhout and colleagues adds to the increasing lines of evidence that presynaptic ER Ca2+ stores do in fact play a modulatory role in control of synaptic vesicle cycling and synaptic transmission. Although, at this time it is difficult to reconcile several proposed models and ideas, future studies should provide additional insights into the role of ER integrity and various forms of ER-dependent Ca2+ signaling in presynaptic function.
Jo
Acknowledgments. IB is the Carl J. and Hortense M. Thomsen Chair in Alzheimer's Disease Research. E.T.K. is the William Stokes Chair in Experimental Therapeutics. Supported by R01AG055577 (I.B. and E.T.K.).
3
References
Jo
ur na
lP
re
-p
ro
of
[1] R. Llinas, I.Z. Steinberg, K. Walton, Relationship between presynaptic calcium current and postsynaptic potential in squid giant synapse, Biophys. J., 33 (1981) 323-351. [2] Y. Wu, C. Whiteus, C.S. Xu, K.J. Hayworth, R.J. Weinberg, H.F. Hess, P. De Camilli, Contacts between the endoplasmic reticulum and other membranes in neurons, Proc Natl Acad Sci U S A, (2017). [3] G. Sharma, S. Vijayaraghavan, Modulation of presynaptic store calcium induces release of glutamate and postsynaptic firing, Neuron, 38 (2003) 929-939. [4] I. Llano, J. Gonzalez, C. Caputo, F.A. Lai, L.M. Blayney, Y.P. Tan, A. Marty, Presynaptic calcium stores underlie large-amplitude miniature IPSCs and spontaneous calcium transients, Nat Neurosci, 3 (2000) 1256-1265. [5] M. Bal, J. Leitz, A.L. Reese, D.M. Ramirez, M. Durakoglugil, J. Herz, L.M. Monteggia, E.T. Kavalali, Reelin mobilizes a VAMP7-dependent synaptic vesicle pool and selectively augments spontaneous neurotransmission, Neuron, 80 (2013) 934-946. [6] N.J. Emptage, C.A. Reid, A. Fine, Calcium stores in hippocampal synaptic boutons mediate short-term plasticity, store-operated Ca2+ entry, and spontaneous transmitter release, Neuron, 29 (2001) 197-208. [7] A.G. Carter, K.E. Vogt, K.A. Foster, W.G. Regehr, Assessing the role of calcium-induced calcium release in short-term presynaptic plasticity at excitatory central synapses, J Neurosci, 22 (2002) 21-28. [8] J. de Juan-Sanz, G.T. Holt, E.R. Schreiter, F. de Juan, D.S. Kim, T.A. Ryan, Axonal Endoplasmic Reticulum Ca2+ Content Controls Release Probability in CNS Nerve Terminals, Neuron, 93 (2017) 867-881 e866. [9] F.W. Lindhout, Y. Cao, J.T. Kevenaar, A. Bodzeta, R. Stucchi, M.M. Boumpoutsari, E.A. Katrukha, M. Altelaar, H.D. MacGillavry, C.C. Hoogenraad, VAP-SCRN1 interaction regulates dynamic endoplasmic reticulum remodeling and presynaptic function, EMBO J, 38 (2019) e101345. [10] J. Leitz, E.T. Kavalali, Ca(2)(+) influx slows single synaptic vesicle endocytosis, J Neurosci, 31 (2011) 16318-16326.
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Fig 1. Presynaptic ER Ca2+ stores. Presynaptic terminal is filled with synaptic vesicles (SVs). Canonical evoked neurotransmission is driven by Ca2+ influx through voltage gated Ca2+ channels (VGCCs). Smooth ER is present in many presynpatic terminals. Ca2+ release from ER is mediated by ryanodine receptors (RyR) by a mechanism of Ca2+-induced Ca2+ release (CICR). ER Ca2+ depletion causes clustering of STIM1 Ca2+ sensor protein and activation of store-operated Ca2+ entry pathway (SOCE) via Ca2+ influx through Orai channels. There is increasing evidence that both CICR and SOCE can impact neurotransmitter release.
5