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.


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.

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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.


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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.

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

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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.


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


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.


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


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.

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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).

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