| Calcium homeostasis modulator 1 (CALHM1) is the pore-forming subunit of an ion channel that mediates extracellular Ca2+ regulation of neuronal excitability. | |
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MedLine Citation:
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PMID: 22711817 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2012-06-18 |
Journal Detail:
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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:
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Created Date: 2012-07-11 Completed Date: 2012-10-05 Revised Date: 2013-02-21 |
Medline Journal Info:
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Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: United States |
Other Details:
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Languages: eng Pagination: E1963-71 Citation Subset: IM |
Affiliation:
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Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Alzheimer Disease
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genetics Animals Binding Sites Calcium / chemistry, metabolism* Calcium Channels / genetics, metabolism* Cell Membrane / metabolism* Electrophysiology / methods Female Gene Deletion Gene Expression Regulation, Developmental Ions Male Mice Mice, Inbred C57BL Models, Biological Mutagenesis Neurodegenerative Diseases / genetics Neurons / metabolism* Oocytes / cytology, metabolism Polymorphism, Genetic Time Factors Xenopus |
| Grant Support | |
ID/Acronym/Agency:
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HD059288/HD/NICHD NIH HHS; MH059937/MH/NIMH NIH HHS; NS069629/NS/NINDS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/CALHM1 protein, mouse; 0/Calcium Channels; 0/Ions; 7440-70-2/Calcium |
| Comments/Corrections | |
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