{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T06:09:41Z","timestamp":1791353381407,"version":"4.3.1"},"reference-count":56,"publisher":"Wiley","issue":"13","license":[{"start":{"date-parts":[[2013,5,29]],"date-time":"2013-05-29T00:00:00Z","timestamp":1369785600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2013,7]]},"abstract":"<jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"explicit-label\">\n<jats:list-item><jats:p>Ca<jats:sub>v<\/jats:sub>1.3 Ca<jats:sup>2+<\/jats:sup> channels mediate sound transmission by triggering presynaptic exocytosis of glutamate from cochlear inner hair cells (IHCs).<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Harmonin is a PDZ\u2010domain\u2010containing protein in IHCs that is altered in Usher syndrome, a form of deaf\u2013blindness in humans.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We show that harmonin enhances Ca<jats:sub>v<\/jats:sub>1.3 voltage\u2010dependent facilitation (VDF) in transfected HEK293T cells in a manner that depends on the identity of the auxiliary Ca<jats:sup>2+<\/jats:sup> channel \u03b2 subunit.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Ca<jats:sub>v<\/jats:sub>1.3 VDF is impaired, and synchronous exocytosis and the Ca<jats:sup>2+<\/jats:sup> efficiency of exocytosis are reduced, in IHCs from deaf\u2010circler mice expressing a mutant form of harmonin (<jats:italic>dfcr<\/jats:italic>) that cannot interact with Ca<jats:sub>v<\/jats:sub>1.3.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We conclude that harmonin regulates presynaptic function in mouse IHCs, which adds to our understanding of the factors that may influence hearing impairment in Usher syndrome.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><jats:p><jats:bold>Abstract\u2002<\/jats:bold> Ca<jats:sub>v<\/jats:sub>1.3 channels mediate Ca<jats:sup>2+<\/jats:sup> influx that triggers exocytosis of glutamate at cochlear inner hair cell (IHC) synapses. Harmonin is a PDZ\u2010domain\u2010containing protein that interacts with the C\u2010terminus of the Ca<jats:sub>v<\/jats:sub>1.3 \u03b1<jats:sub>1<\/jats:sub> subunit (\u03b1<jats:sub>1<\/jats:sub>1.3) and controls cell surface Ca<jats:sub>v<\/jats:sub>1.3 levels by promoting ubiquitin\u2010dependent proteosomal degradation. However, PDZ\u2010domain\u2010containing proteins have diverse functions and regulate other Ca<jats:sub>v<\/jats:sub>1.3 properties, which could collectively influence presynaptic transmitter release. Here, we report that harmonin binding to the \u03b1<jats:sub>1<\/jats:sub>1.3 distal C\u2010terminus (dCT) enhances voltage\u2010dependent facilitation (VDF) of Ca<jats:sub>v<\/jats:sub>1.3 currents both in transfected HEK293T cells and in mouse inner hair cells. In HEK293T cells, this effect of harmonin was greater for Ca<jats:sub>v<\/jats:sub>1.3 channels containing the auxiliary Ca<jats:sub>v<\/jats:sub>\u03b2<jats:sub>1<\/jats:sub> than with the \u03b2<jats:sub>2<\/jats:sub> auxiliary subunit. Ca<jats:sub>v<\/jats:sub>1.3 channels lacking the \u03b1<jats:sub>1<\/jats:sub>1.3 dCT were insensitive to harmonin modulation. Moreover, the \u2018deaf\u2010circler\u2019<jats:italic>dfcr<\/jats:italic> mutant form of harmonin, which does not interact with the \u03b1<jats:sub>1<\/jats:sub>1.3 dCT, did not promote VDF. In mature IHCs from mice expressing the <jats:italic>dfcr<\/jats:italic> harmonin mutant, Ca<jats:sub>v<\/jats:sub>1.3 VDF was less than in control IHCs. This difference was not observed between control and <jats:italic>dfcr<\/jats:italic> IHCs prior to hearing onset. Membrane capacitance recordings from <jats:italic>dfcr<\/jats:italic> IHCs revealed a role for harmonin in synchronous exocytosis and in increasing the efficiency of Ca<jats:sup>2+<\/jats:sup> influx for triggering exocytosis. Collectively, our results indicate a multifaceted presynaptic role of harmonin in IHCs in regulating Ca<jats:sub>v<\/jats:sub>1.3 Ca<jats:sup>2+<\/jats:sup> channels and exocytosis.<\/jats:p>","DOI":"10.1113\/jphysiol.2013.254367","type":"journal-article","created":{"date-parts":[[2013,4,24]],"date-time":"2013-04-24T00:35:34Z","timestamp":1366763734000},"page":"3253-3269","source":"Crossref","is-referenced-by-count":43,"title":["Harmonin enhances voltage\u2010dependent facilitation of Ca<sub>v<\/sub>1.3 channels and synchronous exocytosis in mouse inner hair cells"],"prefix":"10.1113","volume":"591","author":[{"given":"Frederick D.","family":"Gregory","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tina","family":"Pangr\u0161i\u010d","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina 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