{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T07:15:01Z","timestamp":1791270901866,"version":"4.1.0"},"reference-count":64,"publisher":"Rockefeller University Press","issue":"1","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2010,7,1]]},"abstract":"<jats:p>Mutations in GJB2, which encodes Cx26, are one of the most common causes of inherited deafness in humans. More than 100 mutations have been identified scattered throughout the Cx26 protein, most of which cause nonsyndromic sensorineural deafness. In a subset of mutations, deafness is accompanied by hyperkeratotic skin disorders, which are typically severe and sometimes fatal. Many of these syndromic deafness mutations localize to the amino-terminal and first extracellular loop (E1) domains. Here, we examined two such mutations, A40V and G45E, which are positioned near the TM1\/E1 boundary and are associated with keratitis ichthyosis deafness (KID) syndrome. Both of these mutants have been reported to form hemichannels that open aberrantly, leading to \u201cleaky\u201d cell membranes. Here, we quantified the Ca2+ sensitivities and examined the biophysical properties of these mutants at macroscopic and single-channel levels. We find that A40V hemichannels show significantly impaired regulation by extracellular Ca2+, increasing the likelihood of aberrant hemichannel opening as previously suggested. However, G45E hemichannels show only modest impairment in regulation by Ca2+ and instead exhibit a substantial increase in permeability to Ca2+. Using cysteine substitution and examination of accessibility to thiol-modifying reagents, we demonstrate that G45, but not A40, is a pore-lining residue. Both mutants function as cell\u2013cell channels. The data suggest that G45E and A40V are hemichannel gain-of-function mutants that produce similar phenotypes, but by different underlying mechanisms. A40V produces leaky hemichannels, whereas G45E provides a route for excessive entry of Ca2+. These aberrant properties, alone or in combination, can severely compromise cell integrity and lead to increased cell death.<\/jats:p>","DOI":"10.1085\/jgp.201010433","type":"journal-article","created":{"date-parts":[[2010,6,28]],"date-time":"2010-06-28T14:23:31Z","timestamp":1277735011000},"page":"47-62","update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":128,"title":["Differentially altered Ca2+ regulation and Ca2+ permeability in Cx26 hemichannels formed by the A40V and G45E mutations that cause keratitis ichthyosis deafness syndrome"],"prefix":"10.1085","volume":"136","author":[{"given":"Helmuth A.","family":"S\u00e1nchez","sequence":"first","affiliation":[{"name":"Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00fclistan","family":"Me\u015fe","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Stony Brook University Medical Center, Stony Brook, NY 11794 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miduturu","family":"Srinivas","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, State University of New York College of Optometry, New York, NY 10036 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas W.","family":"White","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Stony Brook University Medical Center, Stony Brook, NY 11794 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vytas K.","family":"Verselis","sequence":"additional","affiliation":[{"name":"Dominick P. 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