Synaptic efficacy is remodeled by neuronal firing activity at the presynaptic terminal. Presynaptic activity-dependent changes in transmitter release induce postsynaptic plasticity, including morphological change in spine, gene transcription, and protein synthesis and trafficking. The presynaptic transmitter release is triggered and regulated by Ca2+, which enters through voltage-gated Ca2+ (CaV) channels and diffuses into the presynaptic terminal accompanying action potential firings. Residual Ca2+ is sensed by Ca2+-binding proteins, among other potential actions, it mediates time- and space-dependent synaptic facilitation and depression via effects on CaV2 channel gating and vesicle replenishment in the readily releasable pool (RRP). Calmodulin, a Ca2+-sensor protein with an EF-hand motif that binds Ca2+, interacts with CaV2 channels and autoreceptors in modulation of SNARE-mediated exocytosis. 1. Introduction For memory formation in a neuronal circuit, the primary function of presynaptic terminals is the firing activity-dependent release of neurotransmitters and subsequent recycling of their carrier synaptic vesicles, processes which critically depend on ATP and Ca2+. Presynaptic firing of action potentials activates voltage-gated Ca2+？？(CaV) channels, and Ca2+ entry initiates release of neurotransmitters. Ca2+？？dependence on fast neurotransmitter release is thought to be conferred by the synaptotagmin, a family of Ca2+ sensors that interact with SNAREs [1]. Synaptotagmin 1 and 2 are synaptic vesicle proteins with tandem C2 domains that bind Ca2+ and ensure the synchronization of Ca2+-dependent exocytosis with the presynaptic action potential [2–5]. Neuronal firing activity also controls other protein functions and dynamically remodels synaptic efficacy. Ca2+-binding proteins sensing residual Ca2+, which accumulates locally in the presynaptic terminal during trains of action potentials, may act as potential effectors for these reactions. Considerable evidence supports a role for calmodulin (CaM), another family of Ca2+ sensors with an EF hand motif that binds Ca2+, in modulation of SNARE-mediated exocytosis [6, 7] and endocytosis [8, 9]. Targets of CaM include multiple proteins implicated in exocytosis (e.g., Ca2+ channels [10], Ca2+/ CaM kinase II [11], rab3 [12], and Munc13 [13]), and endocytosis (e.g., calcinulin [14]). Another Ca2+-binding protein with an EF hand motif, parvalbumin, acts as a mobile presynaptic Ca2+ buffer that accelerates withdrawal of residual Ca2+ and decay of short-term facilitation in the calyx of held [15] and GABAergic
References
[1]
T. C. Südhof, “The synaptic vesicle cycle,” Annual Review of Neuroscience, vol. 27, pp. 509–547, 2004.
[2]
T. I. Nishiki and G. J. Augustine, “Synaptotagmin I synchronizes transmitter release in mouse hippocampal neurons,” Journal of Neuroscience, vol. 24, no. 27, pp. 6127–6132, 2004.
[3]
Z. P. Pang, J. Sun, J. Rizo, A. Maximov, and T. C. Südhof, “Genetic analysis of synaptotagmin 2 in spontaneous and Ca2+ -triggered neurotransmitter release,” EMBO Journal, vol. 25, no. 10, pp. 2039–2050, 2006.
[4]
J. Sun, Z. P. Pang, D. Qin, A. T. Fahim, R. Adachi, and T. C. Südhof, “A dual-Ca2+-sensor model for neurotransmitter release in a central synapse,” Nature, vol. 450, no. 7170, pp. 676–682, 2007.
[5]
M. Yoshihara and J. T. Littleton, “Synaptotagmin functions as a calcium sensor to synchronize neurotransmitter release,” Neuron, vol. 36, no. 5, pp. 897–908, 2002.
[6]
Y. A. Chen and R. H. Scheller, “SNARE-mediated membrane fusion,” Nature Reviews Molecular Cell Biology, vol. 2, no. 2, pp. 98–106, 2001.
[7]
J. Di Giovanni, C. C. Iborra, Y. Maulet, C. Lévêque, O. El Far, and M. Seagar, “Calcium-dependent regulation of SNARE-mediated membrane fusion by calmodulin,” Journal of Biological Chemistry, vol. 285, no. 31, pp. 23665–23675, 2010.
[8]
R. Schneggenburger and E. Neher, “Intracellular calcium dependence of transmitter release rates at a fast central synapse,” Nature, vol. 406, no. 6798, pp. 889–993, 2000.
[9]
X. S. Wu, B. D. McNeil, J. Xu et al., “Ca2+ and calmodulin initiate all forms of endocytosis during depolarization at a nerve terminal,” Nature Neuroscience, vol. 12, no. 8, pp. 1003–1010, 2009.
[10]
A. Lee, S. T. Wong, D. Gallagher et al., “Ca2+/calmodulin binds to and modulates P/Q-type calcium channels,” Nature, vol. 399, no. 6732, pp. 155–159, 1999.
[11]
M. Popoli, “Synaptotagmin is endogenously phosphorylated by Ca2+/calmodulin protein kinase II in synaptic vesicles,” FEBS Letters, vol. 317, no. 1–2, pp. 85–88, 1993.
[12]
J. B. Park, C. C. Farnsworth, and J. A. Glomset, “Ca2+/calmodulin causes Rab3a to dissociate from synaptic membranes,” Journal of Biological Chemistry, vol. 272, no. 33, pp. 20857–20865, 1997.
[13]
H. J. Junge, J. S. Rhee, O. Jahn et al., “Calmodulin and Munc13 form a Ca2+ sensor/effector complex that controls short-term synaptic plasticity,” Cell, vol. 118, no. 3, pp. 389–401, 2004.
[14]
B. Marks and H. T. McMahon, “Calcium triggers calcineurin-dependent synaptic vesicle recycling in mammalian nerve terminals,” Current Biology, vol. 8, no. 13, pp. 740–749, 1998.
[15]
M. Müller, F. Felmy, B. Schwaller, and R. Schneggenburger, “Parvalbumin is a mobile presynaptic Ca2+ buffer in the calyx of held that accelerates the decay of Ca2+ and short-term facilitation,” Journal of Neuroscience, vol. 27, no. 9, pp. 2261–2271, 2007.
[16]
O. Caillard, H. Moreno, B. Schwaller, I. Llano, M. R. Celio, and A. Marty, “Role of the calcium-binding protein parvalbumin in short-term synaptic plasticity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 24, pp. 13372–13377, 2000.
[17]
F. Felmy and R. Schneggenburger, “Developmental expression of the Ca2+-binding proteins calretinin and parvalbumin at the calyx of Held of rats and mice,” European Journal of Neuroscience, vol. 20, no. 6, pp. 1473–1482, 2004.
[18]
S. Mochida, “Protein-protein interactions in neurotransmitter release,” Neuroscience Research, vol. 36, no. 3, pp. 175–182, 2000.
[19]
T. C. Sudhof, “The synaptic vesicle cycle: a cascade of protein-protein interactions,” Nature, vol. 375, no. 6533, pp. 645–653, 1995.
[20]
S. Takamori, M. Holt, K. Stenius et al., “Molecular anatomy of a trafficking organelle,” Cell, vol. 127, no. 4, pp. 831–846, 2006.
[21]
H. Ma and S. Mochida, “A cholinergic model synapse to elucidate protein function at presynatic terminals,” Neuroscience Research, vol. 57, no. 4, pp. 491–498, 2007.
[22]
S. Mochida, Y. Nonomura, and H. Kobayashi, “Analysis of the mechanism for acetylcholine release at the synapse formed between rat sympathetic neurons in culture,” Microscopy Research and Technique, vol. 29, no. 2, pp. 94–102, 1994.
[23]
S. Mochida, H. Kobayashi, Y. Matsuda, Y. Yuda, K. Muramoto, and Y. Nonomura, “Myosin II is involved in transmitter release at synapses formed between rat sympathetic neurons in culture,” Neuron, vol. 13, no. 5, pp. 1131–1142, 1994.
[24]
T. Baba, T. Sakisaka, S. Mochida, and Y. Takai, “PKA-catalyzed phosphorylation of tomosyn and its implication in Ca2+ -dependent exocytosis of neurotransmitter,” Journal of Cell Biology, vol. 170, no. 7, pp. 1113–1125, 2005.
[25]
G. Krapivinsky, S. Mochida, L. Krapivinsky, S. M. Cibulsky, and D. Clapham, “The TRPM7 ion channel functions in cholinergic synaptic vesicles and affects transmitter release,” Neuron, vol. 52, no. 3, pp. 485–496, 2006.
[26]
S. Mochida, A. P. Few, T. Scheuer, and W. A. Catterall, “Regulation of presynaptic C 2.1 Channels by Ca2+ sensor proteins mediates short-term synaptic plasticity,” Neuron, vol. 57, no. 2, pp. 210–216, 2008.
[27]
S. Mochida, R. E. Westenbroek, C. T. Yokoyama, K. Itoh, and W. A. Catterall, “Subtype-selective reconstitution of synaptic transmission in sympathetic ganglion neurons by expression of exogenous calcium channels,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 5, pp. 2813–2818, 2003.
[28]
Y. Nakajima, S. Mochida, K. Okawa, and S. Nakanishi, “Ca2+-dependent release of Munc18-1 from presynaptic mGluRs in short-term facilitation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 43, pp. 18385–18389, 2009.
[29]
H. Ma, Q. Cai, W. Lu, Z. H. Sheng, and S. Mochida, “KIF5B motor adaptor syntabulin maintains synaptic transmission in sympathetic neurons,” Journal of Neuroscience, vol. 29, no. 41, pp. 13019–13029, 2009.
[30]
R. E. Westenbroek, T. Sakurai, E. M. Elliott et al., “Immunochemical identification and subcellular distribution of the α(1A) subunits of brain calcium channels,” Journal of Neuroscience, vol. 15, no. 10, pp. 6403–6418, 1995.
[31]
K. Dunlap, J. I. Luebke, and T. Turner, “Exocytotic Ca2+ channels in mammalian central neurons,” Trends in Neurosciences, vol. 18, no. 2, pp. 89–98, 1995.
[32]
R. M. Evans and G. W. Zamponi, “Presynaptic Ca2+ channels—integration centers for neuronal signaling pathways,” Trends in Neurosciences, vol. 29, no. 11, pp. 617–624, 2006.
[33]
W. A. Catterall, “Structure and regulation of voltage-gated Ca2+ channels,” Annual Review of Cell and Developmental Biology, vol. 16, pp. 521–555, 2000.
[34]
C. D. DeMaria, T. W. Soong, B. A. Alseikhan, R. S. Alvania, and D. T. Yue, “Calmodulin bifurcates the local Ca2+ signal that modulates P/Q-type Ca2+ channels,” Nature, vol. 411, no. 6836, pp. 484–489, 2001.
[35]
A. Lee, T. Scheuer, and W. A. Catterall, “Ca2+/calmodulin-dependent facilitation and inactivation of P/Q-type Ca2+ channels,” Journal of Neuroscience, vol. 20, no. 18, pp. 6830–6838, 2000.
[36]
A. Lee, H. Zhou, T. Scheuer, and W. A. Catterall, “Molecular determinants of Ca2+/calmodulin-dependent regulation of C 2.1 channels,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 26, pp. 16059–16064, 2003.
[37]
A. P. Few, N. J. Lautermilch, R. E. Westenbroek, T. Scheuer, and W. A. Catterall, “Differential regulation of C 2.1 channels by calcium-binding protein 1 and visinin-like protein-2 requires N-terminal myristoylation,” Journal of Neuroscience, vol. 25, no. 30, pp. 7071–7080, 2005.
[38]
N. J. Lautermilch, A. P. Few, T. Scheuer, and W. A. Catterall, “Modulation of C 2.1 channels by the neuronal calcium-binding protein visinin-like protein-2,” Journal of Neuroscience, vol. 25, no. 30, pp. 7062–7070, 2005.
[39]
A. Lee, R. E. Westenbroek, F. Haeseleer, K. Palczewski, T. Scheuer, and W. A. Catterall, “Differential modulation of C 2.1 channels by calmodulin and Ca2+-binding protein 1,” Nature Neuroscience, vol. 5, no. 3, pp. 210–217, 2002.
[40]
I. D. Forsythe, T. Tsujimoto, M. Barnes-Davies, M. F. Cuttle, and T. Takahashi, “Inactivation of presynaptic calcium current contributes to synaptic depression at a fast central synapse,” Neuron, vol. 20, no. 4, pp. 797–807, 1998.
[41]
J. Xu and L. G. Wu, “The decrease in the presynaptic calcium current is a major cause of short-term depression at a calyx-type synapse,” Neuron, vol. 46, no. 4, pp. 633–645, 2005.
[42]
D. Chaudhuri, B. A. Alseikhan, S. Y. Chang, T. W. Soong, and D. T. Yue, “Developmental activation of calmodulin-dependent facilitation of cerebellar P-type Ca2+ current,” Journal of Neuroscience, vol. 25, no. 36, pp. 8282–8294, 2005.
[43]
J. G. G. Borst and B. Sakmann, “Facilitation of presynaptic calcium currents in the rat brainstem,” Journal of Physiology, vol. 513, no. 1, pp. 149–155, 1998.
[44]
R. S. Zucker and W. G. Regehr, “Short-term synaptic plasticity,” Annual Review of Physiology, vol. 64, pp. 355–405, 2002.
[45]
C. F. Stevens and J. F. Wesseling, “Augmentation is a potentiation of the exocytotic process,” Neuron, vol. 22, no. 1, pp. 139–146, 1999.
[46]
K. L. Magleby, “The effect of tetanic and post tetanic potentiation on facilitation of transmitter release at the frog neuromuscular junction,” Journal of Physiology, vol. 234, no. 2, pp. 353–371, 1973.
[47]
K. L. Magleby and J. E. Zengel, “A dual effect of repetitive stimulation on post tetanic potentiation of transmitter release at the frog neuromuscular junction,” Journal of Physiology, vol. 245, no. 1, pp. 163–182, 1975.
[48]
Y. G. Tang and R. S. Zucker, “Mitochondrial involvement in post-tetanic potentiation of synaptic transmission,” Neuron, vol. 18, no. 3, pp. 483–491, 1997.
[49]
M. Beierlein, D. Fioravante, and W. G. Regehr, “Differential expression of posttetanic potentiation and retrograde signaling mediate target-dependent short-term synaptic plasticity,” Neuron, vol. 54, no. 6, pp. 949–959, 2007.
[50]
D. H. Brager, X. Cai, and S. M. Thompson, “Activity-dependent activation of presynaptic protein kinase C mediates post-tetanic potentiation,” Nature Neuroscience, vol. 6, no. 6, pp. 551–552, 2003.
[51]
L. F. Abbott and W. G. Regehr, “Synaptic computation,” Nature, vol. 431, no. 7010, pp. 796–803, 2004.
[52]
M. Lorez, U. Humbel, M. C. Pflimlin, and J. N. C. Kew, “Group III metabotropic glutamate receptors as autoreceptors in the cerebellar cortex,” British Journal of Pharmacology, vol. 138, no. 4, pp. 614–625, 2003.
[53]
S. Nakanishi, “Molecular diversity of glutamate receptors and implications for brain function,” Science, vol. 258, no. 5082, pp. 597–603, 1992.
[54]
J. P. Pin and R. Duvoisin, “The metabotropic glutamate receptors: structure and functions,” Neuropharmacology, vol. 34, no. 1, pp. 1–26, 1995.
[55]
R. Shigemoto, A. Kinoshita, E. Wada et al., “Differential presynaptic localization of metabotropic glutamate receptor subtypes in the rat hippocampus,” Journal of Neuroscience, vol. 17, no. 19, pp. 7503–7522, 1997.
[56]
R. Pekhletski, R. Gerlai, L. S. Overstreet et al., “Impaired cerebellar synaptic plasticity and motor performance in mice lacking the mGluR4 subtype of metabotropic glutamate receptor,” Journal of Neuroscience, vol. 16, no. 20, pp. 6364–6373, 1996.
[57]
V. O'Connor, O. El Far, E. Bofill-Cardona et al., “Calmodulin dependence of presynaptic metabotropic glutamate receptor signaling,” Science, vol. 286, no. 5442, pp. 1180–1184, 1999.
[58]
D. Chin and A. R. Means, “Calmodulin: a prototypical calcium sensor,” Trends in Cell Biology, vol. 10, no. 8, pp. 322–328, 2000.
[59]
J. Rizo and T. C. Südhof, “Snares and munc18 in synaptic vesicle fusion,” Nature Reviews Neuroscience, vol. 3, no. 8, pp. 641–653, 2002.
[60]
J. Shen, D. C. Tareste, F. Paumet, J. E. Rothman, and T. J. Melia, “Selective activation of cognate SNAREpins by Sec1/Munc18 proteins,” Cell, vol. 128, no. 1, pp. 183–195, 2007.
[61]
K. M. S. Misura, R. H. Scheller, and W. I. Weis, “Three-dimensional structure of the neuronal-Sec1-syntaxin 1a complex,” Nature, vol. 404, no. 6776, pp. 355–362, 2000.
[62]
Y. Nakajima, T. Yamamoto, T. Nakayama, and S. Nakanishi, “A relationship between protein kinase C phosphorylation and calmodulin binding to the metabotropic glutamate receptor subtype 7,” Journal of Biological Chemistry, vol. 274, no. 39, pp. 27573–27577, 1999.
[63]
P. J. Kammermeier and S. R. Ikedal, “Metabotropic glutamate receptor expression in the rat superior cervical ganglion,” Neuroscience Letters, vol. 330, no. 3, pp. 260–264, 2002.
[64]
H. L. Atwood and S. Karunanithi, “Diversification of synaptic strength: presynaptic elements,” Nature Reviews Neuroscience, vol. 3, no. 7, pp. 497–516, 2002.
[65]
J. S. Dittman, A. C. Kreitzer, and W. G. Regehr, “Interplay between facilitation, depression, and residual calcium at three presynaptic terminals,” Journal of Neuroscience, vol. 20, no. 4, pp. 1374–1385, 2000.
[66]
S. Mochida, Z. -H. Sheng, C. Baker, H. Kobayashi, and W. A. Catterall, “Inhibition of neurotransmission by peptides containing the synaptic protein interaction site of N-type Ca2+ channels,” Neuron, vol. 17, no. 4, pp. 781–788, 1996.
