Calcium homeostasis modulator 1 (CALHM1) is the pore-forming subunit of an ion channel that mediates extracellular Ca2+ regulation of neuronal excitability

Zhongming Ma, Adam P. Siebert, King Ho Cheung, Robert J. Lee, Brian Johnson, Akiva S. Cohen, Valérie Vingtdeux, Philippe Marambaud, J. Kevin Foskett*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

116 Citations (Scopus)

Abstract

Extracellular Ca2+ (Ca2+o) plays important roles in physiology. Changes of Ca2+o concentration ([Ca2+]o) have been observed to modulate neuronal excitability in various physiological and pathophysiological settings, but the mechanisms by which neurons detect [Ca2+]o are not fully understood. Calcium homeostasis modulator 1 (CALHM1) expression was shown to induce cation currents in cells and elevate cytoplasmic Ca2+ concentration ([Ca2+] i) in response to removal of Ca2+o and its subsequent addback. However, it is unknown whether CALHM1 is a pore-forming ion channel or modulates endogenous ion channels. Here we identify CALHM1 as the pore-forming subunit of a plasma membrane Ca2+-permeable ion channel with distinct ion permeability properties and unique coupled allosteric gating regulation by voltage and [Ca2+]o. Furthermore, we show that CALHM1 is expressed in mouse cortical neurons that respond to reducing [Ca2+]o with enhanced conductance and action potential firing and strongly elevated [Ca2+]iupon Ca 2+o removal and its addback. In contrast, these responses are strongly muted in neurons from mice with CALHM1 genetically deleted. These results demonstrate that CALHM1 is an evolutionarily conserved ion channel family that detects membrane voltage and extracellular Ca2+ levels and plays a role in cortical neuronal excitability and Ca2+ homeostasis, particularly in response to lowering [Ca2+]o and its restoration to normal levels.

Original languageEnglish
Pages (from-to)E1963-E1971
Number of pages9
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number28
DOIs
Publication statusPublished - 10 Jul 2012

Scopus Subject Areas

  • General

User-Defined Keywords

  • Alzheimer's disease
  • Mutagenesis
  • Neurodegeneration
  • Polymorphism
  • Selectivity

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