Diverse organization of voltage-gated calcium channels at presynaptic active zones

Abstract

Synapses are highly organized but are also highly diverse in their organization and properties to allow for optimizing the computing power of brain circuits. Along these lines, voltage-gated calcium (CaV) channels at the presynaptic active zone are heterogeneously organized, which creates a variety of calcium dynamics profiles that can shape neurotransmitter release properties of individual synapses. Extensive studies have revealed striking diversity in the subtype, number, and distribution of CaV channels, as well as the nanoscale topographic relationships to docked synaptic vesicles. Further, multi-protein complexes including RIMs, RIM-binding proteins, CAST/ELKS, and neurexins are required for coordinating the diverse organization of CaV channels at the presynaptic active zone. In this review, we highlight major advances in the studies of the functional organization of presynaptic CaV channels and discuss their physiological implications for synaptic transmission and short-term plasticity.

Keywords: active zone; calcium channels; microdomain; modulation; nanodomain; neurotransmitter release; synaptic computation; synaptic plasticity.

Figure 1

Diagrammatic structure of CaV channels. (A) Structure of the α1 subunit, which contains four homologous domains (I-IV) each with six transmembrane segments (S1-S6) and a long intracellular C-terminal. The cytoplasmic tail contains the conserved PxxP motif, PNGY motif, and C-terminal motif DxWC, which are known to be crucial for the synaptic assembly of CaV2 channels (see details in text). (B) Model of CaV channels showing the central pore-forming α1 subunit, interacting with intracellular β subunit and extracellular α₂δ subunit through a GPI anchor into the plasma membrane.

Figure 2

Molecular organization of CaV2 channels at the presynaptic active zone. (A) Diagram of domain structures of evolutionarily conserved key active zone proteins. (B) Model of nanoscale organization of CaV channels interacting with complex active zone proteins and synaptic vesicles. Adapted with permission from Südhof (2012).