Pathophysiological Roles of Auxiliary Calcium Channel α2δ Subunits

Research output: Contribution to book/report/conference proceedingChapter in book/report

Abstract

α 2δ proteins serve as auxiliary subunits of voltage-gated calcium channels, which are essential components of excitable cells such as skeletal and heart muscles, nerve cells of the brain and the peripheral nervous system, as well as endocrine cells. Over the recent years, α 2δ proteins have been identified as critical regulators of synaptic functions, including the formation and differentiation of synapses. These functions require signalling mechanisms which are partly independent of calcium channels. Hence, in light of these features it is not surprising that the genes encoding for the four α 2δ isoforms have recently been linked to neurological and neurodevelopmental disorders including epilepsy, autism spectrum disorders, schizophrenia, and depressive and bipolar disorders. Despite the increasing number of identified disease-associated mutations, the underlying pathophysiological mechanisms are only beginning to emerge. However, a thorough understanding of the pathophysiological role of α 2δ proteins ideally serves two purposes: first, it will contribute to our understanding of general pathological mechanisms in synaptic disorders. Second, it may support the future development of novel and specific treatments for brain disorders. In this context, it is noteworthy that the antiepileptic and anti-allodynic drugs gabapentin and pregabalin both act via binding to α 2δ proteins and are among the top sold drugs for treating neuropathic pain. In this book chapter, we will discuss recent developments in our understanding of the functions of α 2δ proteins, both as calcium channel subunits and as independent regulatory entities. Furthermore, we present and summarize recently identified and likely pathogenic mutations in the genes encoding α 2δ proteins and discuss potential underlying pathophysiological consequences at the molecular and structural level.

Original languageEnglish
Title of host publicationHandbook of Experimental Pharmacology
PublisherSpringer
Pages289-316
Number of pages28
DOIs
Publication statusPublished - 05 Jan 2023

Publication series

NameHandbook of Experimental Pharmacology
Volume279
ISSN (Print)0171-2004
ISSN (Electronic)1865-0325

Keywords

  • Brain disorders
  • CACNA2D1–4
  • Ca
  • Gabapentin
  • Pregabalin
  • Synapse formation
  • Synaptic transmission
  • Synaptopathy
  • Voltage-gated calcium channels

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology, Toxicology and Pharmaceutics (all)

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