More than a pore: How voltage-gated calcium channels act on different levels of neuronal communication regulation

Abstract

Voltage-gated calcium channels (VGCCs) represent key regulators of the calcium influx through the plasma membrane of excitable cells, like neurons. Activated by the depolarization of the membrane, the opening of VGCCs induces very transient and local changes in the intracellular calcium concentration, known as calcium nanodomains, that in turn trigger calcium-dependent signaling cascades and the release of chemical neurotransmitters. Based on their central importance as concierges of excitation-secretion coupling and therefore neuronal communication, VGCCs have been studied in multiple aspects of neuronal function and malfunction. However, studies on molecular interaction partners and recent progress in omics technologies have extended the actual concept of these molecules. With this review, we want to illustrate some new perspectives of VGCCs reaching beyond their function as calcium-permeable pores in the plasma membrane. Therefore, we will discuss the relevance of VGCCs as voltage sensors in functional complexes with ryanodine receptors, channel-independent actions of auxiliary VGCC subunits, and provide an insight into how VGCCs even directly participate in gene regulation. Furthermore, we will illustrate how structural changes in the intracellular C-terminus of VGCCs generated by alternative splicing events might not only affect the biophysical channel characteristics but rather determine their molecular environment and downstream signaling pathways.

cacna2d3, a voltage-gated calcium channel subunit, functions in vertebrate habituation learning and the startle sensitivity threshold

“…α2δ subunit function is not limited to the pre-synapse. α2δ subunits, in association with VGCCs, contribute to dendritic computations [ 41 ], shaping the action potential in the axon [ 42 ], and mediating calcium-channel dependent gene regulation [ 43 ]. In the context of the Mauthner neuron, dendritic calcium signaling determines startle probability [ 9 ].…”

Cortexa – a comprehensive resource for studying gene expression and alternative splicing in the murine brain

“…Alternative splicing is a prevalent regulatory mechanism in the brain that plays an important role during development and in specifying and maintaining neural cell types 6,7,9,22,28,35,36 . However, Mus musculus has ~22,000 protein-coding genes 37 of which almost all multi-exon genes undergo alternative splicing 38 .…”

The Molecular Basis for the Calcium-Dependent Slow Afterhyperpolarization in CA1 Hippocampal Pyramidal Neurons

“…This is important, as years of work on E-C coupling have identified multiple levels of interaction between these subunits. In particular, it emerged that Cav1.x and RyRs exhibit a bidirectional interplay, such that calcium- or voltage-dependent Cav1 activation can modify RyR-mediated calcium release in a tissue-specific manner ( Avila and Dirksen, 2000 ; Avila et al, 2001 , 2019 ; Dirksen, 2002 ; Heck et al, 2021 ). Indeed, calcium released by RyRs can augment Cav1 channel activity ( Mitterdorfer et al, 1996 ; Nakai et al, 1996 ; Grabner et al, 1999 ; Bers and Morotti, 2014 ), increase Cav1 channel expression levels ( Avila et al, 2001 ), or reduce Cav1 channel conductance by promoting CDI ( Bers and Morotti, 2014 ).…”