{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T12:23:55Z","timestamp":1769603035298,"version":"3.49.0"},"reference-count":41,"publisher":"Rockefeller University Press","issue":"12","license":[{"start":{"date-parts":[[2018,10,24]],"date-time":"2018-10-24T00:00:00Z","timestamp":1540339200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/www.rupress.org\/terms\/"},{"start":{"date-parts":[[2019,6,3]],"date-time":"2019-06-03T00:00:00Z","timestamp":1559520000000},"content-version":"vor","delay-in-days":222,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DC009433"],"award-info":[{"award-number":["DC009433"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NS084190"],"award-info":[{"award-number":["NS084190"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["EY026817"],"award-info":[{"award-number":["EY026817"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["EY026477"],"award-info":[{"award-number":["EY026477"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Neuroscience Training Program","award":["T32 NS007421"],"award-info":[{"award-number":["T32 NS007421"]}]},{"name":"Carver Research Program of Excellence"},{"DOI":"10.13039\/100008893","name":"University of Iowa","doi-asserted-by":"publisher","award":["R25GM058939"],"award-info":[{"award-number":["R25GM058939"]}],"id":[{"id":"10.13039\/100008893","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2018,12,3]]},"abstract":"<jats:p>Ca2+ influx through Cav1.4 L-type Ca2+ channels supports the sustained release of glutamate from photoreceptor synaptic terminals in darkness, a process that is critical for vision. Consistent with this role, Cav1.4 exhibits weak Ca2+-dependent inactivation (CDI)\u2014a negative feedback regulation mediated by Ca2+-bound calmodulin (CaM). CaM binds to a conserved IQ domain in the proximal C-terminal domain of Cav channels, but in Cav1.4, a C-terminal modulatory domain (CTM) disrupts interactions with CaM. Exon 47 encodes a portion of the CTM and is deleted in a Cav1.4 splice variant (Cav1.4\u0394ex47) that is highly expressed in the human retina. Cav1.4\u0394ex47 exhibits CDI and enhanced voltage-dependent activation, similar to that caused by a mutation that is associated with congenital stationary night blindness type 2, in which the CTM is deleted (K1591X). The presence of CDI and very negative activation thresholds in a naturally occurring variant of Cav1.4 are perplexing considering that these properties are expected to be maladaptive for visual signaling and result in night blindness in the case of K1591X. Here we show that Cav1.4\u0394ex47 and K1591X exhibit fundamental differences in their regulation by CaM. In Cav1.4\u0394ex47, CDI requires both the N-terminal (N lobe) and C-terminal (C lobe) lobes of CaM to bind Ca2+, whereas CDI in K1591X is driven mainly by Ca2+ binding to the C lobe. Moreover, the CaM N lobe causes a Ca2+-dependent enhancement of activation of Cav1.4\u0394ex47 but not K1591X. We conclude that the residual CTM in Cav1.4\u0394ex47 enables a form of CaM N lobe regulation of activation and CDI that is absent in K1591X. Interaction with the N lobe of CaM, which is more sensitive to global elevations in cytosolic Ca2+ than the C lobe, may allow Cav1.4\u0394ex47 to be modulated by a wider range of synaptic Ca2+ concentrations than K1591X; this may distinguish the normal physiological function of Cav1.4\u0394ex47 from the pathological consequences of K1591X.<\/jats:p>","DOI":"10.1085\/jgp.201812140","type":"journal-article","created":{"date-parts":[[2018,10,24]],"date-time":"2018-10-24T13:29:34Z","timestamp":1540387774000},"page":"1676-1687","update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":14,"title":["Splicing of an automodulatory domain in Cav1.4 Ca2+ channels confers distinct regulation by calmodulin"],"prefix":"10.1085","volume":"150","author":[{"given":"Brittany","family":"Williams","sequence":"first","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA 1"},{"name":"Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, IA 2"},{"name":"Iowa Neuroscience Institute, University of Iowa, Iowa City, IA 3"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1887-1798","authenticated-orcid":true,"given":"Fran\u00e7oise","family":"Haeseleer","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, University of Washington, Seattle, WA 6"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8021-0443","authenticated-orcid":true,"given":"Amy","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA 1"},{"name":"Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, IA 2"},{"name":"Iowa Neuroscience Institute, University of Iowa, Iowa City, IA 3"},{"name":"Department of Otolaryngology Head-Neck Surgery, University of Iowa, Iowa City, IA 4"},{"name":"Department of Neurology, University of Iowa, Iowa City, IA 5"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"291","published-online":{"date-parts":[[2018,10,24]]},"reference":[{"key":"2023072705050353200_bib1","doi-asserted-by":"publisher","first-page":"110","DOI":"10.4161\/chan.3.2.7932","article-title":"Ca(V)2.1 P\/Q-type calcium channel alternative splicing affects the functional impact of familial hemiplegic migraine mutations: implications for calcium channelopathies","volume":"3","author":"Adams","year":"2009","journal-title":"Channels (Austin)."},{"key":"2023072705050353200_bib2","doi-asserted-by":"publisher","first-page":"608","DOI":"10.1016\/j.cell.2014.09.047","article-title":"Apocalmodulin itself promotes ion channel opening and Ca(2+) regulation","volume":"159","author":"Adams","year":"2014","journal-title":"Cell."},{"key":"2023072705050353200_bib3","doi-asserted-by":"publisher","first-page":"1249","DOI":"10.1038\/nn.2643","article-title":"Opioid inhibition of N-type Ca2+ channels and spinal analgesia couple to alternative splicing","volume":"13","author":"Andrade","year":"2010","journal-title":"Nat. Neurosci."},{"key":"2023072705050353200_bib4","doi-asserted-by":"publisher","first-page":"708","DOI":"10.1167\/iovs.03-0937","article-title":"Functional characterization of the L-type Ca2+ channel Cav1.4alpha1 from mouse retina","volume":"45","author":"Baumann","year":"2004","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"2023072705050353200_bib5","doi-asserted-by":"publisher","first-page":"1717","DOI":"10.1038\/ncomms2727","article-title":"Dynamic switching of calmodulin interactions underlies Ca2+ regulation of CaV1.3 channels","volume":"4","author":"Ben Johny","year":"2013","journal-title":"Nat. Commun."},{"key":"2023072705050353200_bib6","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1085\/jgp.201311153","article-title":"Calmodulin regulation (calmodulation) of voltage-gated calcium channels","volume":"143","author":"Ben-Johny","year":"2014","journal-title":"J. Gen. Physiol."},{"key":"2023072705050353200_bib7","doi-asserted-by":"publisher","first-page":"1530","DOI":"10.1016\/j.bbamem.2012.08.028","article-title":"Structure and function of the \u03b2 subunit of voltage-gated Ca2+ channels","volume":"1828","author":"Buraei","year":"2013","journal-title":"Biochim. Biophys. Acta."},{"key":"2023072705050353200_bib8","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1111\/j.1471-4159.2008.05286.x","article-title":"Ca(v)1 L-type Ca2+ channel signaling complexes in neurons","volume":"105","author":"Calin-Jageman","year":"2008","journal-title":"J. Neurochem."},{"key":"2023072705050353200_bib9","doi-asserted-by":"publisher","first-page":"6334","DOI":"10.1523\/JNEUROSCI.1712-04.2004","article-title":"Alternative splicing as a molecular switch for Ca2+\/calmodulin-dependent facilitation of P\/Q-type Ca2+ channels","volume":"24","author":"Chaudhuri","year":"2004","journal-title":"J. Neurosci."},{"key":"2023072705050353200_bib10","doi-asserted-by":"publisher","first-page":"8282","DOI":"10.1523\/JNEUROSCI.2253-05.2005","article-title":"Developmental activation of calmodulin-dependent facilitation of cerebellar P-type Ca2+ current","volume":"25","author":"Chaudhuri","year":"2005","journal-title":"J. Neurosci."},{"key":"2023072705050353200_bib11","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1085\/jgp.200709749","article-title":"Elementary mechanisms producing facilitation of Cav2.1 (P\/Q-type) channels","volume":"129","author":"Chaudhuri","year":"2007","journal-title":"J. Gen. Physiol."},{"key":"2023072705050353200_bib12","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1038\/35078091","article-title":"Calmodulin bifurcates the local Ca2+ signal that modulates P\/Q-type Ca2+ channels","volume":"411","author":"DeMaria","year":"2001","journal-title":"Nature."},{"key":"2023072705050353200_bib13","doi-asserted-by":"publisher","first-page":"830","DOI":"10.1038\/nature06529","article-title":"A modular switch for spatial Ca2+ selectivity in the calmodulin regulation of CaV channels","volume":"451","author":"Dick","year":"2008","journal-title":"Nature."},{"key":"2023072705050353200_bib14","doi-asserted-by":"publisher","first-page":"1541","DOI":"10.1016\/j.bbamem.2012.11.019","article-title":"The \u03b12\u03b4 subunits of voltage-gated calcium channels","volume":"1828","author":"Dolphin","year":"2013","journal-title":"Biochim. Biophys. Acta."},{"key":"2023072705050353200_bib15","doi-asserted-by":"publisher","first-page":"3217","DOI":"10.1016\/j.jmb.2013.06.024","article-title":"Apo states of calmodulin and CaBP1 control CaV1 voltage-gated calcium channel function through direct competition for the IQ domain","volume":"425","author":"Findeisen","year":"2013","journal-title":"J. Mol. Biol."},{"key":"2023072705050353200_bib16","doi-asserted-by":"publisher","first-page":"29809","DOI":"10.1074\/jbc.M109.048082","article-title":"Calmodulin is a functional regulator of Cav1.4 L-type Ca2+ channels","volume":"284","author":"Griessmeier","year":"2009","journal-title":"J. Biol. Chem."},{"key":"2023072705050353200_bib17","doi-asserted-by":"publisher","first-page":"1079","DOI":"10.1038\/nn1320","article-title":"Essential role of Ca2+-binding protein 4, a Cav1.4 channel regulator, in photoreceptor synaptic function","volume":"7","author":"Haeseleer","year":"2004","journal-title":"Nat. Neurosci."},{"key":"2023072705050353200_bib18","doi-asserted-by":"publisher","first-page":"15663","DOI":"10.1074\/jbc.M116.731737","article-title":"Characterization of C-terminal Splice Variants of Cav1.4 Ca2+ Channels in Human Retina","volume":"291","author":"Haeseleer","year":"2016","journal-title":"J. Biol. Chem."},{"key":"2023072705050353200_bib19","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1080\/19336950.2015.1051273","article-title":"Decalmodulation of Cav1 channels by CaBPs","volume":"10","author":"Hardie","year":"2016","journal-title":"Channels (Austin)."},{"key":"2023072705050353200_bib20","doi-asserted-by":"publisher","first-page":"16059","DOI":"10.1073\/pnas.2237000100","article-title":"Molecular determinants of Ca(2+)\/calmodulin-dependent regulation of Ca(v)2.1 channels","volume":"100","author":"Lee","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072705050353200_bib21","doi-asserted-by":"publisher","first-page":"1505","DOI":"10.1074\/jbc.M114.607465","article-title":"Characterization of Cav1.4 complexes (\u03b111.4, \u03b22, and \u03b12\u03b44) in HEK293T cells and in the retina","volume":"290","author":"Lee","year":"2015","journal-title":"J. Biol. Chem."},{"key":"2023072705050353200_bib22","doi-asserted-by":"publisher","first-page":"598","DOI":"10.1016\/j.tins.2013.06.008","article-title":"Control of neuronal voltage-gated calcium ion channels from RNA to protein","volume":"36","author":"Lipscombe","year":"2013","journal-title":"Trends Neurosci."},{"key":"2023072705050353200_bib23","doi-asserted-by":"publisher","first-page":"968","DOI":"10.1038\/nature08766","article-title":"Enzyme-inhibitor-like tuning of Ca(2+) channel connectivity with calmodulin","volume":"463","author":"Liu","year":"2010","journal-title":"Nature."},{"key":"2023072705050353200_bib24","doi-asserted-by":"publisher","first-page":"514","DOI":"10.4161\/chan.26376","article-title":"Dysregulation of Ca(v)1.4 channels disrupts the maturation of photoreceptor synaptic ribbons in congenital stationary night blindness type 2","volume":"7","author":"Liu","year":"2013","journal-title":"Channels (Austin)."},{"key":"2023072705050353200_bib25","doi-asserted-by":"publisher","first-page":"3035","DOI":"10.1093\/hmg\/ddi336","article-title":"Mutation of the calcium channel gene Cacna1f disrupts calcium signaling, synaptic transmission and cellular organization in mouse retina","volume":"14","author":"Mansergh","year":"2005","journal-title":"Hum. Mol. Genet."},{"key":"2023072705050353200_bib26","doi-asserted-by":"publisher","first-page":"1707","DOI":"10.1523\/JNEUROSCI.4846-03.2004","article-title":"The CACNA1F gene encodes an L-type calcium channel with unique biophysical properties and tissue distribution","volume":"24","author":"McRory","year":"2004","journal-title":"J. Neurosci."},{"key":"2023072705050353200_bib27","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1016\/S0896-6273(00)80709-6","article-title":"Calmodulin is the Ca2+ sensor for Ca2+ -dependent inactivation of L-type calcium channels","volume":"22","author":"Peterson","year":"1999","journal-title":"Neuron."},{"key":"2023072705050353200_bib28","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1038\/nn1848","article-title":"Alternative splicing controls G protein-dependent inhibition of N-type calcium channels in nociceptors","volume":"10","author":"Raingo","year":"2007","journal-title":"Nat. Neurosci."},{"key":"2023072705050353200_bib29","doi-asserted-by":"publisher","first-page":"36312","DOI":"10.1074\/jbc.M112.392811","article-title":"Complex regulation of voltage-dependent activation and inactivation properties of retinal voltage-gated Cav1.4 L-type Ca2+ channels by Ca2+-binding protein 4 (CaBP4)","volume":"287","author":"Shaltiel","year":"2012","journal-title":"J. Biol. Chem."},{"key":"2023072705050353200_bib30","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.neuron.2014.03.016","article-title":"Neuronal voltage-gated calcium channels: structure, function, and dysfunction","volume":"82","author":"Simms","year":"2014","journal-title":"Neuron."},{"key":"2023072705050353200_bib31","doi-asserted-by":"publisher","first-page":"1108","DOI":"10.1038\/nn1751","article-title":"C-terminal modulator controls Ca2+-dependent gating of Ca(v)1.4 L-type Ca2+ channels","volume":"9","author":"Singh","year":"2006","journal-title":"Nat. Neurosci."},{"key":"2023072705050353200_bib32","doi-asserted-by":"publisher","first-page":"20733","DOI":"10.1074\/jbc.M802254200","article-title":"Modulation of voltage- and Ca2+-dependent gating of CaV1.3 L-type calcium channels by alternative splicing of a C-terminal regulatory domain","volume":"283","author":"Singh","year":"2008","journal-title":"J. Biol. Chem."},{"key":"2023072705050353200_bib33","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1167\/iovs.08-2758","article-title":"Effects of presynaptic mutations on a postsynaptic Cacna1s calcium channel colocalized with mGluR6 at mouse photoreceptor ribbon synapses","volume":"50","author":"Specht","year":"2009","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"2023072705050353200_bib34","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1038\/940","article-title":"An L-type calcium-channel gene mutated in incomplete X-linked congenital stationary night blindness","volume":"19","author":"Strom","year":"1998","journal-title":"Nat. Genet."},{"key":"2023072705050353200_bib35","doi-asserted-by":"publisher","first-page":"832","DOI":"10.1074\/jbc.M111.268722","article-title":"Alternative splicing at C terminus of Ca(V)1.4 calcium channel modulates calcium-dependent inactivation, activation potential, and current density","volume":"287","author":"Tan","year":"2012","journal-title":"J. Biol. Chem."},{"key":"2023072705050353200_bib36","doi-asserted-by":"publisher","first-page":"1108","DOI":"10.1038\/nsmb1027","article-title":"Insights into voltage-gated calcium channel regulation from the structure of the CaV1.2 IQ domain-Ca2+\/calmodulin complex","volume":"12","author":"Van Petegem","year":"2005","journal-title":"Nat. Struct. Mol. Biol."},{"key":"2023072705050353200_bib37","doi-asserted-by":"publisher","first-page":"15657","DOI":"10.1073\/pnas.0604621103","article-title":"Switching off calcium-dependent inactivation in L-type calcium channels by an autoinhibitory domain","volume":"103","author":"Wahl-Schott","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072705050353200_bib38","doi-asserted-by":"publisher","first-page":"10677","DOI":"10.1523\/JNEUROSCI.3236-06.2006","article-title":"Switching of Ca2+-dependent inactivation of Ca(v)1.3 channels by calcium binding proteins of auditory hair cells","volume":"26","author":"Yang","year":"2006","journal-title":"J. Neurosci."},{"key":"2023072705050353200_bib39","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1038\/nchembio.1436","article-title":"Allostery in Ca2+ channel modulation by calcium-binding proteins","volume":"10","author":"Yang","year":"2014","journal-title":"Nat. Chem. Biol."},{"key":"2023072705050353200_bib40","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1124\/pr.57.4.13","article-title":"Overview of molecular relationships in the voltage-gated ion channel superfamily","volume":"57","author":"Yu","year":"2005","journal-title":"Pharmacol. Rev."},{"key":"2023072705050353200_bib41","doi-asserted-by":"publisher","first-page":"29612","DOI":"10.1074\/jbc.M504167200","article-title":"Molecular mechanism for divergent regulation of Cav1.2 Ca2+ channels by calmodulin and Ca2+-binding protein-1","volume":"280","author":"Zhou","year":"2005","journal-title":"J. Biol. Chem."}],"container-title":["Journal of General Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jgp\/article-pdf\/150\/12\/1676\/1797861\/jgp_201812140.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jgp\/article-pdf\/150\/12\/1676\/1797861\/jgp_201812140.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,27]],"date-time":"2023-07-27T05:05:30Z","timestamp":1690434330000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jgp\/article\/150\/12\/1676\/43697\/Splicing-of-an-automodulatory-domain-in-Cav1-4-Ca2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,10,24]]},"references-count":41,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2018,12,3]]}},"URL":"https:\/\/doi.org\/10.1085\/jgp.201812140","relation":{},"ISSN":["0022-1295","1540-7748"],"issn-type":[{"value":"0022-1295","type":"print"},{"value":"1540-7748","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,10,24]]}}}