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Calcium homeostasis modulator (CALHM) ion channels

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Abstract

Calcium homeostasis modulator 1 (CALHM1), formerly known as FAM26C, was recently identified as a physiologically important plasma membrane ion channel. CALHM1 and its Caenorhabditis elegans homolog, CLHM-1, are regulated by membrane voltage and extracellular Ca2+ concentration ([Ca2+]o). In the presence of physiological [Ca2+]o (∼1.5 mM), CALHM1 and CLHM-1 are closed at resting membrane potentials but can be opened by strong depolarizations. Reducing [Ca2+]o increases channel open probability, enabling channel activation at negative membrane potentials. Together, voltage and Ca2+ o allosterically regulate CALHM channel gating. Through convergent evolution, CALHM has structural features that are reminiscent of connexins and pannexins/innexins/LRRC8 (volume-regulated anion channel (VRAC)) gene families, including four transmembrane helices with cytoplasmic amino and carboxyl termini. A CALHM1 channel is a hexamer of CALHM1 monomers with a functional pore diameter of ∼14 Å. CALHM channels discriminate poorly among cations and anions, with signaling molecules including Ca2+ and ATP able to permeate through its pore. CALHM1 is expressed in the brain where it plays an important role in cortical neuron excitability induced by low [Ca2+]o and in type II taste bud cells in the tongue that sense sweet, bitter, and umami tastes where it functions as an essential ATP release channel to mediate nonsynaptic neurotransmitter release. CLHM-1 is expressed in C. elegans sensory neurons and body wall muscles, and its genetic deletion causes locomotion defects. Thus, CALHM is a voltage- and Ca2+ o-gated ion channel, permeable to large cations and anions, that plays important roles in physiology.

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Acknowledgments

This work was supported by National Institutes of Health (NIH) Grants R01DC012538 (J.K.F. and Z.M.) and R03DC014328 (J.E.T.), an American Heart Postdoctoral fellowship 12POST11940054 (J.E.T.), JSPS KAKENHI Grants (25893201 and 26713008) (A.T.), The Salt Science Research Foundation (1429 and 1542) (A.T.), Society for Research on Umami Taste, Nestlé Nutrition Council, Japan (A.T.), and Kyoto Prefectural Public University Corporation (A.T.).

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Authors and Affiliations

  1. Department of Physiology, Perelman School of Medicine, University of Pennsylvania, 720 Clinical Research Bldg., 415 Curie Blvd., Philadelphia, PA, 19104, USA

    Zhongming Ma, Jessica E. Tanis & J. Kevin Foskett

  2. Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    J. Kevin Foskett

  3. Department of Molecular Cell Physiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan

    Akiyuki Taruno

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  1. Zhongming Ma
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Correspondence to Zhongming Ma or J. Kevin Foskett.

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Ma, Z., Tanis, J.E., Taruno, A. et al. Calcium homeostasis modulator (CALHM) ion channels. Pflugers Arch - Eur J Physiol 468, 395–403 (2016). https://doi.org/10.1007/s00424-015-1757-6

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