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Regulation of Calcium Channels and Synaptic Function by Auxiliary α2δ Subunits

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Voltage-Gated Calcium Channels

Abstract

Voltage-gated calcium channels of the CaV1 (L-type) and CaV2 (N-type, P/Q-type, R-type) classes associate with auxiliary β and α2δ subunits that are both important for the function of these channels. While the β subunits are cytoplasmic, α2δ subunits are entirely extracellular and provide a critical link between channel and extracellular signaling functions. Here we describe what is known about the structure of α2δ subunits, and their importance both for channel trafficking and for their physiological function. We also describe distinct roles of α2δ proteins in synapse development and synaptic transmission, potentially beyond their classical role as auxiliary calcium channel subunits. Dysregulation and mutations of specific α2δ subunits are associated with several diseases, and α2δ-1 represents an important therapeutic target for the anti-epileptic and anti-allodynic gabapentinoid drugs. A detailed understanding of specific and potentially redundant α2δ functions may pave the way for developing novel treatment options, particularly for neuropsychiatric disorders.

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Abbreviations

AMPA:

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

CaV:

voltage-dependent calcium

DRG:

dorsal root ganglion

eGFP:

enhanced green fluorescent protein

ER:

endoplasmic reticulum

GABA:

Gamma-aminobutyric acid

GPI:

glycosylphosphatidylinositol

gSTED microscopy:

gated stimulated emission depletion microscopy

LRP1:

low-density lipoprotein receptor-related protein 1

mCherry:

monomeric Cherry fluorescent protein

MIDAS:

metal ion-dependent adhesion site

NMDA:

N-methyl-D-aspartate

PSD95:

postsynaptic density protein 95

TSP:

thrombospondin

VWA:

von Willebrand factor-A

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Authors and Affiliations

  1. Department of Neuroscience Physiology and Pharmacology, University College London, London, UK

    Annette C. Dolphin

  2. Division Physiology, Department Pharmacology, Physiology and Microbiology, Karl Landsteiner University of Health Sciences, Krems, Austria

    Gerald J. Obermair

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Correspondence to Annette C. Dolphin or Gerald J. Obermair .

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  1. Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada

    Gerald Werner Zamponi

  2. Department of Pathophysiology, Third Faculty of Medicine, Charles University, Prague, Czech Republic

    Norbert Weiss

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Dolphin, A.C., Obermair, G.J. (2022). Regulation of Calcium Channels and Synaptic Function by Auxiliary α2δ Subunits. In: Zamponi, G.W., Weiss, N. (eds) Voltage-Gated Calcium Channels . Springer, Cham. https://doi.org/10.1007/978-3-031-08881-0_5

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