title: Calcium homeostasis modulator (CALHM) ion channels.
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 Ca(2+) concentration ([Ca(2+)]o). In the presence of physiological [Ca(2+)]o (∼1.5 mM), CALHM1 and CLHM-1 are closed at resting membrane potentials but can be opened by strong depolarizations. Reducing [Ca(2+)]o increases channel open probability, enabling channel activation at negative membrane potentials. Together, voltage and Ca(2+) 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 Ca(2+) 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 [Ca(2+)]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 Ca(2+) o-gated ion channel, permeable to large cations and anions, that plays important roles in physiology.
authors.affiliation: Department of Physiology, Perelman School of Medicine, University of Pennsylvania, 720 Clinical Research Bldg., 415 Curie Blvd., Philadelphia, PA, 19104, USA. zma@mail.med.upenn.edu.
authors.forename: Zhongming
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Department of Physiology, Perelman School of Medicine, University of Pennsylvania, 720 Clinical Research Bldg., 415 Curie Blvd., Philadelphia, PA, 19104, USA.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Tanis
authors.affiliation: Department of Molecular Cell Physiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan.
authors.forename: Akiyuki
authors.initials: A
authors.lastname: Taruno
authors.affiliation: Department of Physiology, Perelman School of Medicine, University of Pennsylvania, 720 Clinical Research Bldg., 415 Curie Blvd., Philadelphia, PA, 19104, USA. foskett@mail.med.upenn.edu.|Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. foskett@mail.med.upenn.edu.
authors.forename: J Kevin
authors.initials: JK
authors.lastname: Foskett
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017630:Connexins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015640:Ion Channel Gating; D007473:Ion Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction
chemical_list: C530077:CALHM1 protein, human; D015220:Calcium Channels; D017630:Connexins; D007473:Ion Channels; D008562:Membrane Glycoproteins; D002118:Calcium
keywords: ATP; Connexin; Extracellular calcium; Pannexin; Taste; Voltage gated