Document Detail

Calcium homeostasis modulator 1 (CALHM1) is the pore-forming subunit of an ion channel that mediates extracellular Ca2+ regulation of neuronal excitability.
MedLine Citation:
PMID:  22711817     Owner:  NLM     Status:  MEDLINE    
Extracellular Ca(2+) (Ca(2+)(o)) plays important roles in physiology. Changes of Ca(2+)(o) concentration ([Ca(2+)](o)) have been observed to modulate neuronal excitability in various physiological and pathophysiological settings, but the mechanisms by which neurons detect [Ca(2+)](o) are not fully understood. Calcium homeostasis modulator 1 (CALHM1) expression was shown to induce cation currents in cells and elevate cytoplasmic Ca(2+) concentration ([Ca(2+)](i)) in response to removal of Ca(2+)(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 Ca(2+)-permeable ion channel with distinct ion permeability properties and unique coupled allosteric gating regulation by voltage and [Ca(2+)](o). Furthermore, we show that CALHM1 is expressed in mouse cortical neurons that respond to reducing [Ca(2+)](o) with enhanced conductance and action potential firing and strongly elevated [Ca(2+)](i) upon 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 Ca(2+) levels and plays a role in cortical neuronal excitability and Ca(2+) homeostasis, particularly in response to lowering [Ca(2+)](o) and its restoration to normal levels.
Zhongming Ma; Adam P Siebert; King-Ho Cheung; Robert J Lee; Brian Johnson; Akiva S Cohen; Valérie Vingtdeux; Philippe Marambaud; J Kevin Foskett
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-06-18
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  109     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-07-11     Completed Date:  2012-10-05     Revised Date:  2013-07-12    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  E1963-71     Citation Subset:  IM    
Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
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MeSH Terms
Alzheimer Disease / genetics
Binding Sites
Calcium / chemistry,  metabolism*
Calcium Channels / genetics,  metabolism*
Cell Membrane / metabolism*
Electrophysiology / methods
Gene Deletion
Gene Expression Regulation, Developmental
Mice, Inbred C57BL
Models, Biological
Neurodegenerative Diseases / genetics
Neurons / metabolism*
Oocytes / cytology,  metabolism
Polymorphism, Genetic
Time Factors
Grant Support
Reg. No./Substance:
0/CALHM1 protein, mouse; 0/Calcium Channels; 0/Ions; 7440-70-2/Calcium

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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