Nanodomain coupling between Ca2+ channels and sensors of exocytosis at fast mammalian synapses

Key Points

  • The coupling between Ca2+ channels and Ca2+ sensors of exocytosis is a key determinant of speed and efficacy of synaptic transmission at peripheral and central synapses.

  • Previous studies of the young calyx of Held revealed that Ca2+ channels are loosely coupled to the Ca2+ sensors and that several Ca2+ channels have to open to trigger transmitter release.

  • Recent studies of inhibitory synapses in the hippocampus and cerebellum indicated that Ca2+ channels are tightly coupled to their Ca2+ sensors at these synapses and that only a small number of open Ca2+ channels are required for evoked transmitter release.

  • Likewise, analysis of synaptic transmission at the calyx of Held at different developmental stages indicated that both the coupling distance and the number of open Ca2+ channels decrease during development.

  • Molecular analysis suggests that coupling at the nanometre scale is generated by protein–protein interactions involving Ca2+ channels and Ca2+ sensors, but also several other proteins enriched in presynaptic terminals.

  • Tight coupling of a small number of Ca2+ channels to the transmitter release machinery offers several functional advantages, as it increases efficacy, speed and energy efficiency of synaptic transmission.

Abstract

The physical distance between presynaptic Ca2+ channels and the Ca2+ sensors that trigger exocytosis of neurotransmitter-containing vesicles is a key determinant of the signalling properties of synapses in the nervous system. Recent functional analysis indicates that in some fast central synapses, transmitter release is triggered by a small number of Ca2+ channels that are coupled to Ca2+ sensors at the nanometre scale. Molecular analysis suggests that this tight coupling is generated by protein–protein interactions involving Ca2+ channels, Ca2+ sensors and various other synaptic proteins. Nanodomain coupling has several functional advantages, as it increases the efficacy, speed and energy efficiency of synaptic transmission.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Model synapses used for the analysis of Ca2+ channel–sensor coupling.
Figure 2: Experimental determination of the coupling distance and the number of open Ca2+ channels that mediate transmitter release.
Figure 3: Molecular mechanisms of nanodomain coupling.
Figure 4: Functional consequences of nanodomain coupling.

References

  1. 1

    Katz, B. & Miledi, R. The measurement of synaptic delay, and the time course of acetylcholine release at the neuromuscular junction. Proc. R. Soc. Lond. B 161, 483–495 (1965).

  2. 2

    Llinás, R., Sugimori, M. & Simon, S. M. Transmission by presynaptic spike-like depolarization in the squid giant synapse. Proc. Natl Acad. Sci. USA 79, 2415–2419 (1982).

  3. 3

    Borst, J. G. G. & Sakmann, B. Calcium influx and transmitter release in a fast CNS synapse. Nature 383, 431–434 (1996).

  4. 4

    Sabatini, B. L. & Regehr, W. G. Timing of neurotransmission at fast synapses in the mammalian brain. Nature 384, 170–172 (1996).

  5. 5

    Geiger, J. R. P. & Jonas, P. Dynamic control of presynaptic Ca2+ inflow by fast-inactivating K+ channels in hippocampal mossy fiber boutons. Neuron 28, 927–939 (2000).

  6. 6

    Einstein, A. Über die von der molekularkinetischen Theorie der Wärme geforderte Bewegung von in ruhenden Flüssigkeiten suspendierten Teilchen. Annalen der Physik 17, 549–560 (1905).

  7. 7

    Katz, B. The Release of Neural Transmitter Substances (Liverpool Univ. Press, Liverpool, 1969).

  8. 8

    Llinás, R. R. The Squid Giant Synapse (Oxford Univ. Press, New York, 1999).

  9. 9

    Harlow, M. L., Ress, D., Stoschek, A., Marshall, R. M. & McMahan U. J. The architecture of active zone material at the frog's neuromuscular junction. Nature 409, 479–484 (2001). A classical electron microscopy tomography study of the active zone at the frog neuromuscular junction. Four rows of presynaptic Ca2+ channels are opposed to two rows of synaptic vesicles, with 20 nm between the individual elements.

  10. 10

    Shahrezaei, V., Cao, A. & Delaney, K. R. Ca2+ from one or two channels controls fusion of a single vesicle at the frog neuromuscular junction. J. Neurosci. 26, 13240–13249 (2006). The authors cleverly exploit the advantage of the Monte-Carlo simulation to monitor individual Ca2+ ions. By backtracing the Ca2+ from the vesicle to the Ca2+ channels through which they entered, the authors conclude that only one or two open Ca2+ channels contribute to transmitter release at the frog neuromuscular junction.

  11. 11

    Adler, E. M., Augustine, G. J., Duffy, S. N. & Charlton, M. P. Alien intracellular calcium chelators attenuate neurotransmitter release at the squid giant synapse. J. Neurosci. 11, 1496–1507 (1991). A classical paper that uses exogenous Ca2+ chelators with different binding rates to probe the distance between Ca2+ source and Ca2+ sensor at the squid giant synapse. Based on the lack of effects of the slow Ca2+ chelator EGTA, the authors suggest that nanodomain coupling exists between Ca2+ channels and Ca2+ sensors at this invertebrate synapse.

  12. 12

    Augustine, G. J. Regulation of transmitter release at the squid giant synapse by presynaptic delayed rectifier potassium current. J. Physiol. 431, 343–364 (1990).

  13. 13

    Augustine, G. J., Adler, E. M. & Charlton, M. P. The calcium signal for transmitter secretion from presynaptic nerve terminals. Ann. NY Acad. Sci. 635, 365–381 (1991).

  14. 14

    Stanley, E. F. Single calcium channels and acetylcholine release at a presynaptic nerve terminal. Neuron 11, 1007–1011 (1993). The first direct evidence that a single Ca2+ channel triggers exocytosis at a chick calyx synapse. In enzymatically treated preparations, the release face of the calyx (that is, the side that is normally attached to the postsynaptic ciliary neuron) is sometimes partially separated from the postsynaptic cell, allowing simultaneous electrophysiological recording of presynaptic Ca2+ channel activity and chemoluminescent detection of acetylcholine release.

  15. 15

    Stanley, E. F. The calcium channel and the organization of the presynaptic transmitter release face. Trends Neurosci. 20, 404–409 (1997).

  16. 16

    Nicoll, R. A. & Schmitz, D. Synaptic plasticity at hippocampal mossy fibre synapses. Nature Rev. Neurosci. 6, 863–876 (2005).

  17. 17

    Neher, E. Usefulness and limitations of linear approximations to the understanding of Ca++ signals. Cell Calcium 24, 345–357 (1998).

  18. 18

    Forsythe, I. D. Direct patch recording from identified presynaptic terminals mediating glutamatergic EPSCs in the rat CNS, in vitro. J. Physiol. 479, 381–387 (1994).

  19. 19

    von Gersdorff, H. & Borst, J. G. G. Short-term plasticity at the calyx of Held. Nature Rev. Neurosci. 3, 53–64 (2002).

  20. 20

    Kraushaar, U. & Jonas, P. Efficacy and stability of quantal GABA release at a hippocampal interneuron-principal neuron synapse. J. Neurosci. 20, 5594–5607 (2000).

  21. 21

    Caillard, O. et al. Role of the calcium-binding protein parvalbumin in short-term synaptic plasticity. Proc. Natl Acad. Sci. USA 97, 13372–13377 (2000).

  22. 22

    Meinrenken, C. J., Borst, J. G. G. & Sakmann, B. Calcium secretion coupling at calyx of Held governed by nonuniform channel-vesicle topography. J. Neurosci. 22, 1648–1667 (2002).

  23. 23

    Fedchyshyn, M. J. & Wang, L. Y. Developmental transformation of the release modality at the calyx of Held synapse. J. Neurosci. 25, 4131–4140 (2005). This paper demonstrates a developmental decrease of sensitivity of evoked transmitter release to EGTA at the calyx of Held, indicating a tightening of Ca2+ channel–sensor coupling. Furthermore, it shows a reduction in Ca2+ current cooperativity during development. Although the power coefficients in this study cannot be correlated to the number of open channels required for release (they exceed the upper bound of biochemical cooperativity), the results may indicate a reduction of this number during development.

  24. 24

    Ohana, O. & Sakmann, B. Transmitter release modulation in nerve terminals of rat neocortical pyramidal cells by intracellular calcium buffers. J. Physiol. 513, 135–148 (1998).

  25. 25

    Rozov, A., Burnashev, N., Sakmann, B. & Neher, E. Transmitter release modulation by intracellular Ca2+ buffers in facilitating and depressing nerve terminals of pyramidal cells in layer 2/3 of the rat neocortex indicates a target cell-specific difference in presynaptic calcium dynamics. J. Physiol. 531, 807–826 (2001). This paper reports that the Ca2+ chelator BAPTA induces pseudofacilitation. Careful quantitative analysis reveals buffer saturation as the underlying mechanism.

  26. 26

    Bucurenciu, I., Kulik, A., Schwaller, B., Frotscher, M. & Jonas, P. Nanodomain coupling between Ca2+ channels and Ca2+ sensors promotes fast and efficient transmitter release at a cortical GABAergic synapse. Neuron 57, 536–545 (2008).

  27. 27

    Christie, J. M., Chiu, D. N. & Jahr, C. E. Ca2+-dependent enhancement of release by subthreshold somatic depolarization. Nature Neurosci. 14, 62–68 (2011).

  28. 28

    Atluri, P. P. & Regehr, W. G. Determinants of the time course of facilitation at the granule cell to Purkinje cell synapse. J. Neurosci. 16, 5661–5671 (1996).

  29. 29

    Chad, J. E. & Eckert, R. Calcium domains associated with individual channels can account for anomalous voltage relations of Ca-dependent responses. Biophys. J. 45, 993–999 (1984).

  30. 30

    Llinás, R., Sugimori, M. & Silver, R. B. Microdomains of high calcium concentration in a presynaptic terminal. Science 256, 677–679 (1992).

  31. 31

    Fogelson, A. L. & Zucker, R. S. Presynaptic calcium diffusion from various arrays of single channels. Implications for transmitter release and synaptic facilitation. Biophys. J. 48, 1003–1017 (1985).

  32. 32

    Roberts, W. M. Localization of calcium signals by a mobile calcium buffer in frog saccular hair cells. J. Neurosci. 14, 3246–3262 (1994).

  33. 33

    Naraghi, M. & Neher, E. Linearized buffered Ca2+ diffusion in microdomains and its implications for calculation of [Ca2+] at the mouth of a calcium channel. J. Neurosci. 17, 6961–6973 (1997).

  34. 34

    Wadel, K., Neher, E. & Sakaba, T. The coupling between synaptic vesicles and Ca2+ channels determines fast neurotransmitter release. Neuron 53, 563–575 (2007).

  35. 35

    Neher, E. & Sakaba, T. Multiple roles of calcium ions in the regulation of neurotransmitter release. Neuron 59, 861–872 (2008).

  36. 36

    Moulder, K. L. & Mennerick, S. Reluctant vesicles contribute to the total readily releasable pool in glutamatergic hippocampal neurons. J. Neurosci. 25, 3842–3850 (2005).

  37. 37

    Moser, T. & Beutner, D. Kinetics of exocytosis and endocytosis at the cochlear inner hair cell afferent synapse of the mouse. Proc. Natl Acad. Sci. USA 97, 883–888 (2000).

  38. 38

    Mennerick, S. & Matthews, G. Ultrafast exocytosis elicited by calcium current in synaptic terminals of retinal bipolar neurons. Neuron 17, 1241–1249 (1996).

  39. 39

    Jarsky, T., Tian, M. & Singer, J. H. Nanodomain control of exocytosis is responsible for the signaling capability of a retinal ribbon synapse. J. Neurosci. 30, 11885–11895 (2010).

  40. 40

    Taschenberger, H., Leão, R. M., Rowland, K. C., Spirou, G. A. & von Gersdorff, H. Optimizing synaptic architecture and efficiency for high-frequency transmission. Neuron 36, 1127–1143 (2002).

  41. 41

    Wang, L. Y., Neher, E. & Taschenberger, H. Synaptic vesicles in mature calyx of Held synapses sense higher nanodomain calcium concentrations during action potential-evoked glutamate release. J. Neurosci. 28, 14450–14458 (2008).

  42. 42

    Wang, L. Y., Fedchyshyn, M. J. & Yang, Y. M. Action potential evoked transmitter release in central synapses: insights from the developing calyx of Held. Mol. Brain 2, 36 (2009).

  43. 43

    Hefft, S. & Jonas, P. Asynchronous GABA release generates long-lasting inhibition at a hippocampal interneuron–principal neuron synapse. Nature Neurosci. 8, 1319–1328 (2005).

  44. 44

    Glickfeld, L. L. & Scanziani, M. Distinct timing in the activity of cannabinoid-sensitive and cannabinoid-insensitive basket cells. Nature Neurosci. 9, 807–815 (2006).

  45. 45

    Daw, M. I., Tricoire, L., Erdelyi, F., Szabo, G. & McBain, C. J. Asynchronous transmitter release from cholecystokinin-containing inhibitory interneurons is widespread and target-cell independent. J. Neurosci. 29, 11112–11122 (2009).

  46. 46

    Brandt, A., Khimich, D. & Moser, T. Few CaV1.3 channels regulate the exocytosis of a synaptic vesicle at the hair cell ribbon synapse. J. Neurosci. 25, 11577–11585 (2005). Evidence that a few Ca2+ channels trigger exocytosis at auditory hair cell ribbon synapses.

  47. 47

    Erazo-Fischer, E., Striessnig, J. & Taschenberger, H. The role of physiological afferent nerve activity during in vivo maturation of the calyx of Held synapse. J. Neurosci. 27, 1725–1737 (2007).

  48. 48

    Ahmed, M. S. & Siegelbaum, S. A. Recruitment of N-type Ca2+ channels during LTP enhances low release efficacy of hippocampal CA1 perforant path synapses. Neuron 63, 372–385 (2009). This paper shows that distal perforant path synapses on CA1 pyramidal neurons exhibit a presynaptic form of long-term potentiation dependent on Ca2+ channel recruitment. This may suggest that the coupling between Ca2+ channels and transmitter release is altered during presynaptic forms of plasticity.

  49. 49

    Pumplin, D. W., Reese, T. S. & Llinás, R. Are the presynaptic membrane particles the calcium channels? Proc. Natl Acad. Sci. USA 78, 7210–7213 (1981).

  50. 50

    Yoshikami, D., Bagabaldo, Z. & Olivera, B. M. The inhibitory effects of omega-conotoxins on Ca channels and synapses. Ann. NY Acad. Sci. 560, 230–248 (1989).

  51. 51

    Matveev, V., Bertram, R. & Sherman, A. Ca2+ current versus Ca2+ channel cooperativity of exocytosis. J. Neurosci. 29, 12196–12209 (2009).

  52. 52

    Chapman, E. R. How does synaptotagmin trigger neurotransmitter release? Annu. Rev. Biochem. 77, 615–641 (2008).

  53. 53

    Pang, Z. P. & Südhof, T. C. Cell biology of Ca2+-triggered exocytosis. Curr. Opin. Cell Biol. 22, 496–505 (2010).

  54. 54

    Takamori, S. et al. Molecular anatomy of a trafficking organelle. Cell 127, 831–846 (2006). A classical paper that quantitatively determines the protein content of synaptic vesicles. Among other proteins, 15 synaptotagmin copies and ten RAB3A copies are present per vesicle.

  55. 55

    Wu, L. G., Westenbroek, R. E., Borst, J. G. G., Catterall, W. A. & Sakmann, B. Calcium channel types with distinct presynaptic localization couple differentially to transmitter release in single calyx-type synapses. J. Neurosci. 19, 726–736 (1999).

  56. 56

    Bucurenciu, I., Bischofberger, J. & Jonas, P. A small number of open Ca2+ channels trigger transmitter release at a central GABAergic synapse. Nature Neurosci. 13, 19–21 (2010).

  57. 57

    Kochubey, O., Han, Y. & Schneggenburger, R. Developmental regulation of the intracellular Ca2+ sensitivity of vesicle fusion and Ca2+-secretion coupling at the rat calyx of Held. J. Physiol. 587, 3009–3023 (2009).

  58. 58

    von Gersdorff, H., Sakaba, T., Berglund, K. & Tachibana, M. Submillisecond kinetics of glutamate release from a sensory synapse. Neuron 21, 1177–1188 (1998).

  59. 59

    Borst, J. G. G. & Sakmann B. Calcium current during a single action potential in a large presynaptic terminal of the rat brainstem. J. Physiol. 506, 143–157 (1998).

  60. 60

    Li, L., Bischofberger, J. & Jonas, P. Differential gating and recruitment of P/Q-, N-, and R-type Ca2+ channels in hippocampal mossy fiber boutons. J. Neurosci. 27, 13420–13429 (2007).

  61. 61

    Yang, Y. M. & Wang, L. Y. Amplitude and kinetics of action potential-evoked Ca2+ current and its efficacy in triggering transmitter release at the developing calyx of Held synapse. J. Neurosci. 26, 5698–5708 (2006).

  62. 62

    Lin, K. H., Oleskevich, S. & Taschenberger, H. Presynaptic Ca2+ influx and vesicle exocytosis at the mouse endbulb of Held: a comparison of two auditory nerve terminals. J. Physiol. 589, 4301–4320 (2011).

  63. 63

    Stevens, C. F. Neurotransmitter release at central synapses. Neuron 40, 381–388 (2003).

  64. 64

    Sätzler, K. et al. Three-dimensional reconstruction of a calyx of Held and its postsynaptic principal neuron in the medial nucleus of the trapezoid body. J. Neurosci. 22, 10567–10579 (2002).

  65. 65

    Roberts, W. M., Jacobs, R. A. & Hudspeth, A. J. Colocalization of ion channels involved in frequency selectivity and synaptic transmission at presynaptic active zones of hair cells. J. Neurosci. 10, 3664–3684 (1990).

  66. 66

    Celio, M. R. Calbindin D-28k and parvalbumin in the rat nervous system. Neuroscience 35, 375–475 (1990).

  67. 67

    Freund, T. F. & Buzsáki, G. Interneurons of the hippocampus. Hippocampus 6, 347–470 (1996).

  68. 68

    Collin, T. et al. Developmental changes in parvalbumin regulate presynaptic Ca2+ signaling. J. Neurosci. 25, 96–107 (2005).

  69. 69

    Müller, M., Felmy, F., Schwaller, B. & Schneggenburger, R. Parvalbumin is a mobile presynaptic Ca2+ buffer in the calyx of Held that accelerates the decay of Ca2+ and short-term facilitation. J. Neurosci. 27, 2261–2271 (2007).

  70. 70

    Felmy, F. & Schneggenburger, R. Developmental expression of the Ca2+-binding proteins calretinin and parvalbumin at the calyx of Held of rats and mice. Eur. J. Neurosci. 20, 1473–1482 (2004).

  71. 71

    Edmonds, B., Reyes, R., Schwaller, B. & Roberts, W. M. Calretinin modifies presynaptic calcium signaling in frog saccular hair cells. Nature Neurosci. 3, 786–790 (2000).

  72. 72

    Hackney, C. M., Mahendrasingam, S., Penn, A. & Fettiplace, R. The concentrations of calcium buffering proteins in mammalian cochlear hair cells. J. Neurosci. 25, 7867–7875 (2005).

  73. 73

    Lee, A., Zhou, H., Scheuer, T. & Catterall, W. A. Molecular determinants of Ca2+/calmodulin-dependent regulation of Ca2.1 channels. Proc. Natl Acad. Sci. USA 100, 16059–16064 (2003).

  74. 74

    Mori, M. X., Erickson, M. G. & Yue, D. T. Functional stoichiometry and local enrichment of calmodulin interacting with Ca2+ channels. Science 304, 432–435 (2004).

  75. 75

    Aponte, Y., Bischofberger, J. & Jonas, P. Efficient Ca2+ buffering in fast-spiking basket cells of rat hippocampus. J. Physiol. 586, 2061–2075 (2008).

  76. 76

    Eggermann, E. & Jonas, P. How the 'slow' Ca2+ buffer parvalbumin affects transmitter release in nanodomain-coupling regimes. Nature Neurosci. 4 Dec 2011 (doi:10.1038/nn.3002).

  77. 77

    Nägerl, U. V., Novo, D., Mody, I. & Vergara, J. L. Binding kinetics of calbindin-D28k determined by flash photolysis of caged Ca2+. Biophys. J. 79, 3009–3018 (2000).

  78. 78

    Faas, G. C., Schwaller, B., Vergara, J. L. & Mody, I. Resolving the fast kinetics of cooperative binding: Ca2+ buffering by calretinin. PLoS Biol. 5, e311 (2007).

  79. 79

    Faas, G. C., Raghavachari, S., Lisman, J. E. & Mody, I. Calmodulin as a direct detector of Ca2+ signals. Nature Neurosci. 14, 301–304 (2011). This paper measures the Ca2+-binding rates of different Ca2+-binding proteins directly, using fast Ca2+ uncaging in a cuvette. Surprisingly, the binding rate for the N-lobe of calmodulin (relaxed form) is even faster than that of BAPTA.

  80. 80

    Schneggenburger, R. & Neher, E. Intracellular calcium dependence of transmitter release rates at a fast central synapse. Nature 406, 889–893 (2000).

  81. 81

    Bollmann, J. H., Sakmann, B. & Borst J. G. G. Calcium sensitivity of glutamate release in a calyx-type terminal. Science 289, 953–957 (2000).

  82. 82

    Lou, X., Scheuss, V. & Schneggenburger, R. Allosteric modulation of the presynaptic Ca2+ sensor for vesicle fusion. Nature 435, 497–501 (2005).

  83. 83

    Nowycky, M. C. & Pinter, M. J. Time courses of calcium and calcium-bound buffers following calcium influx in a model cell. Biophys. J. 64, 77–91 (1993).

  84. 84

    Matveev, V., Zucker, R. S. & Sherman, A. Facilitation through buffer saturation: constraints on endogenous buffering properties. Biophys. J. 86, 2691–2709 (2004).

  85. 85

    Jackson, M. B. & Redman, S. J. Calcium dynamics, buffering, and buffer saturation in the boutons of dentate granule-cell axons in the hilus. J. Neurosci. 23, 1612–1621 (2003).

  86. 86

    Blatow, M., Caputi, A., Burnashev, N., Monyer, H. & Rozov, A. Ca2+ buffer saturation underlies paired pulse facilitation in calbindin-D28k-containing terminals. Neuron 38, 79–88 (2003).

  87. 87

    Felmy, F., Neher, E. & Schneggenburger, R. Probing the intracellular calcium sensitivity of transmitter release during synaptic facilitation. Neuron 37, 801–811 (2003).

  88. 88

    Dodge, F. A. & Rahamimoff, R. Co-operative action of calcium ions in transmitter release at the neuromuscular junction. J. Physiol. 193, 419–432 (1967).

  89. 89

    Lee, S. H., Schwaller, B. & Neher, E. Kinetics of Ca2+ binding to parvalbumin in bovine chromaffin cells: implications for [Ca2+] transients of neuronal dendrites. J. Physiol. 525, 419–432 (2000).

  90. 90

    Schwaller, B., Meyer, M. & Schiffmann, S. 'New' functions for 'old' proteins: the role of the calcium-binding proteins calbindin D-28k, calretinin and parvalbumin, in cerebellar physiology. Studies with knockout mice. Cerebellum 1, 241–258 (2002).

  91. 91

    Schwaller, B. Cytosolic Ca2+ buffers. Cold Spring Harb. Perspect. Biol. 2, a004051 (2010).

  92. 92

    Schmidt, H., Brown, E. B., Schwaller, B. & Eilers, J. Diffusional mobility of parvalbumin in spiny dendrites of cerebellar Purkinje neurons quantified by fluorescence recovery after photobleaching. Biophys. J. 84, 2599–2608 (2003). This paper directly measures the diffusion coefficient of the Ca2+-binding protein parvalbumin from the time course of recovery of fluorescence after photobleaching. Unlike many other Ca2+-binding proteins, parvalbumin is highly mobile.

  93. 93

    Schmidt, H., Schwaller, B. & Eilers, J. Calbindin D28k targets myo-inositol monophosphatase in spines and dendrites of cerebellar Purkinje neurons. Proc. Natl Acad. Sci. USA 102, 5850–5855 (2005).

  94. 94

    Müller C. S. et al. Quantitative proteomics of the Cav2 channel nano-environments in the mammalian brain. Proc. Natl Acad. Sci. USA 107, 14950–14957 (2010).

  95. 95

    Sheng, Z. H., Yokoyama, C. T. & Catterall, W. A. Interaction of the synprint site of N-type Ca2+ channels with the C2B domain of synaptotagmin I. Proc. Natl Acad. Sci. USA 94, 5405–5410 (1997).

  96. 96

    Bezprozvanny, I., Scheller, R. H. & Tsien, R. W. Functional impact of syntaxin on gating of N-type and Q-type calcium channels. Nature 378, 623–626 (1995).

  97. 97

    Rettig, J. et al. Isoform-specific interaction of the α1A subunits of brain Ca2+ channels with the presynaptic proteins syntaxin and SNAP-25. Proc. Natl Acad. Sci. USA 93, 7363–7368 (1996).

  98. 98

    Zhong, H., Yokoyama, C. T., Scheuer, T. & Catterall, W. A. Reciprocal regulation of P/Q-type Ca2+ channels by SNAP-25, syntaxin and synaptotagmin. Nature Neurosci. 2, 939–941 (1999).

  99. 99

    Atlas, D. Functional and physical coupling of voltage-sensitive calcium channels with exocytotic proteins: ramifications for the secretion mechanism. J. Neurochem. 77, 972–985 (2001).

  100. 100

    Kittel, R. J. et al. Bruchpilot promotes active zone assembly, Ca2+ channel clustering, and vesicle release. Science 312, 1051–1054 (2006).

  101. 101

    Wang, Y., Liu, X., Biederer, T. & Südhof, T. C. A family of RIM-binding proteins regulated by alternative splicing: implications for the genesis of synaptic active zones. Proc. Natl. Acad. Sci. USA 99, 14464–14469 (2002).

  102. 102

    Kaeser, P. S. et al. ELKS2α/CAST deletion selectively increases neurotransmitter release at inhibitory synapses. Neuron 64, 227–239 (2009).

  103. 103

    Missler, M. et al. α-neurexins couple Ca2+ channels to synaptic vesicle exocytosis. Nature 423, 939–948 (2003).

  104. 104

    Boucard, A. A., Chubykin, A. A., Comoletti, D., Taylor, P. & Südhof, T. C. A splice code for trans-synaptic cell adhesion mediated by binding of neuroligin 1 to α- and β-neurexins. Neuron 48, 229–236 (2005).

  105. 105

    Kaeser, P. S. et al. RIM proteins tether Ca2+ channels to presynaptic active zones via a direct PDZ-domain interaction. Cell 144, 282–295 (2011). This paper shows that RIM acts as a tethering molecule linking presynaptic Ca2+ channels to the exocytosis machinery.

  106. 106

    Han, Y., Kaeser, P. S., Südhof, T. C. & Schneggenburger, R. RIM determines Ca2+ channel density and vesicle docking at the presynaptic active zone. Neuron 69, 304–316 (2011).

  107. 107

    Hibino, H. et al. RIM binding proteins (RBPs) couple Rab3-interacting molecules (RIMs) to voltage-gated Ca2+ channels. Neuron 34, 411–423 (2002).

  108. 108

    Beites, C. L., Xie, H., Bowser, R. & Trimble, W. S. The septin CDCrel-1 binds syntaxin and inhibits exocytosis. Nature Neurosci. 2, 434–439 (1999).

  109. 109

    Yang, Y. M. et al. Septins regulate developmental switching from microdomain to nanodomain coupling of Ca2+ influx to neurotransmitter release at a central synapse. Neuron 67, 100–115 (2010).

  110. 110

    Siksou, L. et al. Three-dimensional architecture of presynaptic terminal cytomatrix. J. Neurosci. 27, 6868–6877 (2007).

  111. 111

    Iwasaki, S. & Takahashi, T. Developmental changes in calcium channel types mediating synaptic transmission in rat auditory brainstem. J. Physiol. 509, 419–423 (1998).

  112. 112

    Forti, L., Pouzat, C. & Llano, I. Action potential-evoked Ca2+ signals and calcium channels in axons of developing rat cerebellar interneurones. J. Physiol. 527, 33–48 (2000).

  113. 113

    Stephens, G. J., Morris, N. P., Fyffe, R. E. W. & Robertson, B. The Cav2.1/α1A (P/Q-type) voltage-dependent calcium channel mediates inhibitory neurotransmission onto mouse cerebellar Purkinje cells. Eur. J. Neurosci. 13, 1902–1912 (2001).

  114. 114

    Cao Y. Q. & Tsien, R. W. Different relationship of N- and P/Q-type Ca2+ channels to channel-interacting slots in controlling neurotransmission at cultured hippocampal synapses. J. Neurosci. 30, 4536–4546 (2010).

  115. 115

    Mochida, S., Westenbroek, R. E., Yokoyama, C. T., Itoh. K. & Catterall, W. A. Subtype-selective reconstitution of synaptic transmission in sympathetic ganglion neurons by expression of exogenous calcium channels. Proc. Natl Acad. Sci. USA 100, 2813–2818 (2003).

  116. 116

    Mochida, S. et al. Requirement for the synaptic protein interaction site for reconstitution of synaptic transmission by P/Q-type calcium channels. Proc. Natl Acad. Sci. USA 100, 2819–2824 (2003).

  117. 117

    Sun, J. et al. A dual-Ca2+-sensor model for neurotransmitter release in a central synapse. Nature 450, 676–682 (2007).

  118. 118

    Sakaba, T. Two Ca2+-dependent steps controlling synaptic vesicle fusion and replenishment at the cerebellar basket cell terminal. Neuron 57, 406–419 (2008).

  119. 119

    Atluri, P. P. & Regehr, W. G. Delayed release of neurotransmitter from cerebellar granule cells. J. Neurosci. 18, 8214–8227 (1998).

  120. 120

    Matsui, K. & Jahr, C. E. Ectopic release of synaptic vesicles. Neuron 40, 1173–1183 (2003). This paper shows that EGTA-AM leaves synaptic release on Purkinje cells unaffected, but inhibits ectopic release on Bergmann glial cells. This suggests that synaptic release is triggered by Ca2+ nanodomains, whereas ectopic release is driven by Ca2+ microdomains.

  121. 121

    Matsui, K. & Jahr, C. E. Differential control of synaptic and ectopic vesicular release of glutamate. J. Neurosci. 24, 8932–8939 (2004).

  122. 122

    Kim, M. H., Korogod, N., Schneggenburger, R., Ho, W. K. & Lee, S. H. Interplay between Na+/Ca2+ exchangers and mitochondria in Ca2+ clearance at the calyx of Held. J. Neurosci. 25, 6057–6065 (2005).

  123. 123

    Ribrault, C., Sekimoto, K. & Triller A. From the stochasticity of molecular processes to the variability of synaptic transmission. Nature Rev. Neurosci. 12, 375–387 (2011).

  124. 124

    Goswami, S. P., Jonas, P. & Bucurenciu, I. Differential dependence of miniature IPSC and EPSC frequency on presynaptic Ca2+ channels at hippocampal synapses. Soc. Neurosci. Abstr. 446.07 (Washington DC, 12–16 Nov 2011).

  125. 125

    Zucker, R. S. & Regehr, W. G. Short-term synaptic plasticity. Annu. Rev. Physiol. 64, 355–405 (2002).

  126. 126

    Bean, B. P. Neurotransmitter inhibition of neuronal calcium currents by changes in channel voltage dependence. Nature 340, 153–156 (1989).

  127. 127

    Hefft, S., Kraushaar, U., Geiger, J. R. P. & Jonas, P. Presynaptic short-term depression is maintained during regulation of transmitter release at a GABAergic synapse in rat hippocampus. J. Physiol. 539, 201–208 (2002).

  128. 128

    Meinrenken, C. J., Borst, J. G. G. & Sakmann, B. Local routes revisited: the space and time dependence of the Ca2+ signal for phasic transmitter release at the rat calyx of Held. J. Physiol. 547, 665–689 (2003).

  129. 129

    Cao, Y. Q. et al. Presynaptic Ca2+ channels compete for channel type-preferring slots in altered neurotransmission arising from Ca2+ channelopathy. Neuron 43, 387–400 (2004).

  130. 130

    Lansman, J. B., Hess, P. & Tsien, R. W. Blockade of current through single calcium channels by Cd2+, Mg2+, and Ca2+. Voltage and concentration dependence of calcium entry into the pore. J. Gen. Physiol. 88, 321–347 (1986).

  131. 131

    Wheeler, D. B., Randall, A. & Tsien, R. W. Roles of N-type and Q-type Ca2+ channels in supporting hippocampal synaptic transmission. Science 264, 107–111 (1994).

  132. 132

    Castillo, P. E., Weisskopf, M. G. & Nicoll, R. A. The role of Ca2+ channels in hippocampal mossy fiber synaptic transmission and long-term potentiation. Neuron 12, 261–269 (1994).

  133. 133

    Mintz, I. M., Sabatini, B. L. & Regehr, W. G. Calcium control of transmitter release at a cerebellar synapse. Neuron 15, 675–688 (1995).

  134. 134

    Bertram, R., Smith, G. D. & Sherman, A. Modeling study of the effects of overlapping Ca2+ microdomains on neurotransmitter release. Biophys. J. 76, 735–750 (1999). A detailed modelling paper that cleans up several misconceptions regarding the cooperativity of Ca2+ inflow and transmitter release.

  135. 135

    Wu, L. G. & Saggau, P. Pharmacological identification of two types of presynaptic voltage-dependent calcium channels at CA3-CA1 synapses of the hippocampus. J. Neurosci. 14, 5613–5622 (1994).

  136. 136

    Bullock, T. H. & Hagiwara, S. Intracellular recording from the giant synapse of the squid. J. Gen. Physiol. 40, 565–577 (1957).

  137. 137

    Nicholls, J. G., Martin, R. A. & Wallace, B. G. From Neuron to Brain (Sinauer, Sunderland, Massachusetts, USA, 1992).

  138. 138

    Pernía-Andrade, A. & Jonas, P. The multiple faces of RIM. Neuron 69, 185–187 (2011).

  139. 139

    Naraghi, M. T-jump study of calcium binding kinetics of calcium chelators. Cell Calcium 22, 255–268 (1997).

  140. 140

    Singer, J. H. & Diamond, J. S. Sustained Ca2+ entry elicits transient postsynaptic currents at a retinal ribbon synapse. J. Neurosci. 23, 10923–10933 (2003).

  141. 141

    Borst, J. G. G., Helmchen, F. & Sakmann, B. Pre- and postsynaptic whole-cell recordings in the medial nucleus of the trapezoid body of the rat. J. Physiol. 489, 825–840 (1995).

  142. 142

    Kruglikov, I. & Rudy, B. Perisomatic GABA release and thalamocortical integration onto neocortical excitatory cells are regulated by neuromodulators. Neuron 58, 911–924 (2008).

Download references

Acknowledgements

We thank D. Tsien and E. Neher for their comments on this Review, J. Guzmán and A. Pernía-Andrade for reading earlier versions and E. Kramberger for perfect editorial support. Work of the authors was funded by grants of the Deutsche Forschungsgemeinschaft to P.J. (grants SFB 780/A5, TR 3/B10 and the Leibniz programme), a European Research Council Advanced grant to P.J. and a Swiss National Foundation fellowship to E.E. We apologize that owing to space constraints, not all relevant papers could be cited.

Author information

Correspondence to Peter Jonas.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information S1 (box)

Modelling the effects of buffers in realistic coupling regimes (PDF 175 kb)

Related links

Related links

FURTHER INFORMATION

Peter Jonas's homepage

Glossary

Synaptic delay

The time interval between the presynaptic action potential and the postsynaptic response. A synaptic delay is comprised of several components: opening of presynaptic Ca2+ channels, diffusion of Ca2+ from the channels to the Ca2+ sensors, activation of Ca2+ sensors, exocytosis, diffusion of transmitter across the synaptic cleft and activation of postsynaptic receptors.

Ca2+ chelators

Chemical substances that bind Ca2+. In synaptic physiology, BAPTA and EGTA are widely used Ca2+ chelators. Both chelators are also available in membrane-permeable acetoxymethyl ester (AM) forms.

BAPTA

1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid

EGTA

ethylene glycol-bis(2-aminoethylether)-N,N,N′,N′-tetraacetic acid

Ca2+ microdomains

Domains of elevated Ca2+ concentration that extend over more than 100 nanometres. Note that this definition does not imply that the size of the domain is in the micrometre range (1 μm = 10−6 m).

Basket cells

Types of perisomatic inhibitory GABAergic interneurons in the hippocampus and cerebellum. The name was given as the axon forms 'baskets' around somata of postsynaptic target cells.

Ca2+ nanodomains

Domains of elevated Ca2+ concentration that extend over less than 100 nanometres (1 nm = 10−9 m).

Intrinsic or biochemical cooperativity

Nonlinear dependence of transmitter release on the intracellular Ca2+ concentration, presumably owing to multiple Ca2+-binding sites on the Ca2+ sensor synaptotagmin and multiple copies of synaptotagmin on individual synaptic vesicles.

Rab3-interacting molecules

(RIMs). Active zone proteins that serve as central organizers, tethering presynaptic Ca2+ channels and Ca2+ sensors of exocytosis. RIMs are encoded by four genes, which drive the expression of seven known isoforms. For synaptic transmission, only the long RIM versions are relevant.

Length constant

The distance in which a quantity declines to the fraction 1/e. In the case of buffered diffusion of Ca2+, the length constant represents the mean distance Ca2+ diffuses before it is captured by the buffer.

Fixed buffers

Fixed buffers always remain at the same location. In contrast to mobile buffers, fixed buffers can only be regenerated by Ca2+ unbinding, not by diffusion.

SNARE

Soluble N-ethylmaleimide-sensitive-factor attachment protein (SNAP) receptor.

ELKS

Glutamic acid, leucine, lysine and serine-rich protein (also known as cytomatrix of the active zone-associated structural protein (CAST)).

Synaptic depression

Decrease in efficacy of synaptic transmission during and after stimulation of the presynaptic neuron. Synaptic depression is often interpreted as a depletion of the releasable pool of synaptic vesicles, although other mechanisms such as changes in presynaptic action potential shape and inactivation of presynaptic Ca2+ channels may also contribute.

Synaptic facilitation

Short-lasting increase in efficacy of synaptic transmission during and after repetitive stimulation. Synaptic facilitation is often attributed to residual Ca2+ following the action potential, although other mechanisms such as saturation of endogenous buffers may also contribute.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Eggermann, E., Bucurenciu, I., Goswami, S. et al. Nanodomain coupling between Ca2+ channels and sensors of exocytosis at fast mammalian synapses. Nat Rev Neurosci 13, 7–21 (2012). https://doi.org/10.1038/nrn3125

Download citation

Further reading