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.

Ca2+channel and active zone protein abundance intersects with input-specific synapse organization to shape functional synaptic diversity

“…7D-F), indicating similar dynamics during chronic PHP. These data are consistent with the recent finding that in addition to its previously uncovered role in promoting an increase in the readily releasable pool of SVs (Wang et al 2016), Stj is required for the accumulation of Cac at type Ib AZs during both acute and chronic PHP (Zhang et al 2023). Thus, the abundance of multiple key AZ proteins distinguishes low- and high-P r synapses within, but not between, inputs at baseline and during homeostatic plasticity.…”

Specific presynaptic functions require distinct Drosophila Cav2 splice isoforms

“…By contrast, mutually exclusive splicing at the second site encoding the intracellular linker between the first and the second homologous repeat (I-II) does not affect Ca v 2 presynaptic active zone localization, but instead, fine- tunes multiple different aspects of presynaptic function. In vertebrates, substantial functional synaptic heterogeneity can result from different combinations of Ca v 2.1, Ca v 2.2, and/or Ca v 2.3 in the presynaptic AZ (reviewed in Zhang et al 2022). In Drosophila, the collective functions of mammalian Ca v 2.1, Ca v 2.2, and Ca v 2.3 must be portrayed by one Ca v 2 gene.…”

“…Despite these common organizational principles, fast chemical synapses are highly heterogeneous to accommodate the diverse computational requirements of different types of neurons and brain circuits (Moser et al 2023; Zhang et al 2022). One means of synapse diversification is to organize VGCCs heterogeneously at the AZ to modify either their nanoscale spatial relation to the SVs ready for release (Dittman, Ryan, 2019; Rebola et al 2019), or the profiles of the calcium dynamics that shape release probability (P r ; Zhang et al 2022). The calcium dynamics in nano- or microdomains are affected by VGCC number, clustering, and properties, and are thus strongly dependent on calcium channel subtype.…”

“…Ca v 2.1 and Ca v 2.2 trigger SV release at most synapses and Ca v 2.3 likely make only a small contribution (Dietrich et al 2003). However, all three Ca v 2 subtypes may co-localize to the same synapse and contribute to SV release (Takahashi, Momiyama 1993; Wheeler et al 1994; Wu et al 1998), and different types of mammalian synapses can utilize either only one subtype or combinations of Ca v 2 subtypes (reviewed in Zhang et al 2022).…”