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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,2,4]]},"abstract":"<jats:p>\n                    The L-type Ca\n                    <jats:sup>2+<\/jats:sup>\n                    channel (Ca\n                    <jats:sub>V<\/jats:sub>\n                    1.2) is essential for cardiac excitation\u2013contraction coupling. To contribute to the inward Ca\n                    <jats:sup>2+<\/jats:sup>\n                    flux that drives Ca\n                    <jats:sup>2+<\/jats:sup>\n                    -induced-Ca\n                    <jats:sup>2+<\/jats:sup>\n                    -release, Ca\n                    <jats:sub>V<\/jats:sub>\n                    1.2 channels must be expressed on the sarcolemma; thus the regulatory mechanisms that tune Ca\n                    <jats:sub>V<\/jats:sub>\n                    1.2 expression to meet contractile demand are an emerging area of research. A ubiquitously expressed protein called 14-3-3 has been proposed to affect Ca\n                    <jats:sup>2+<\/jats:sup>\n                    channel trafficking in nonmyocytes; however, whether 14-3-3 has similar effects on Ca\n                    <jats:sub>V<\/jats:sub>\n                    1.2 in cardiomyocytes is unknown. 14-3-3 preferentially binds phospho-serine\/threonine residues to affect many cellular processes and is known to regulate cardiac ion channels including Na\n                    <jats:sub>V<\/jats:sub>\n                    1.5 and the human ether-\u00e0-go-go\u2013related gene (hERG) potassium channel. Altered 14-3-3 expression and function have been implicated in cardiac pathologies including hypertrophy. Accordingly, we tested the hypothesis that 14-3-3 interacts with Ca\n                    <jats:sub>V<\/jats:sub>\n                    1.2 in a phosphorylation-dependent manner and regulates cardiac Ca\n                    <jats:sub>V<\/jats:sub>\n                    1.2 trafficking and recycling. Confocal imaging, proximity ligation assays, superresolution imaging, and coimmunoprecipitation revealed a population of 14-3-3 colocalized and closely associated with Ca\n                    <jats:sub>V<\/jats:sub>\n                    1.2. The degree of 14-3-3\/Ca\n                    <jats:sub>V<\/jats:sub>\n                    1.2 colocalization increased upon stimulation of\n                    <jats:italic>\u03b2<\/jats:italic>\n                    -adrenergic receptors with isoproterenol. Notably, only the 14-3-3-associated Ca\n                    <jats:sub>V<\/jats:sub>\n                    1.2 population displayed increased cluster size with isoproterenol, revealing a role for 14-3-3 as a nucleation factor that directs Ca\n                    <jats:sub>V<\/jats:sub>\n                    1.2 superclustering. Isoproterenol-stimulated augmentation of sarcolemmal Ca\n                    <jats:sub>V<\/jats:sub>\n                    1.2 expression, Ca\n                    <jats:sup>2+<\/jats:sup>\n                    currents, and Ca\n                    <jats:sup>2+<\/jats:sup>\n                    transients in ventricular myocytes were strengthened by 14-3-3 overexpression and attenuated by 14-3-3 inhibition. These data support a model where 14-3-3 interacts with Ca\n                    <jats:sub>V<\/jats:sub>\n                    1.2 in a phosphorylation-dependent manner to promote enhanced trafficking\/recycling, clustering, and activity during\n                    <jats:italic>\u03b2<\/jats:italic>\n                    -adrenergic stimulation.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2413308122","type":"journal-article","created":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T15:09:11Z","timestamp":1737990551000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":6,"title":["14-3-3 promotes sarcolemmal expression of cardiac Ca\n                    <sub>V<\/sub>\n                    1.2 and nucleates isoproterenol-triggered channel superclustering"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0873-8021","authenticated-orcid":false,"given":"Heather 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Davis","place":["Davis"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3235-442X","authenticated-orcid":false,"given":"Adriana","family":"Hern\u00e1ndez-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Department of Physiology and Membrane Biology, University of California Davis","place":["Davis"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Husna","family":"Ibrahimkhail","sequence":"additional","affiliation":[{"name":"Department of Physiology and Membrane Biology, University of California Davis","place":["Davis"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2325-4834","authenticated-orcid":false,"given":"Vladimir","family":"Yarov-Yarovoy","sequence":"additional","affiliation":[{"name":"Department of Physiology and Membrane Biology, University of California Davis","place":["Davis"]},{"name":"Department of Anesthesiology and Pain Medicine, University of California Davis","place":["Davis"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2799-3212","authenticated-orcid":false,"given":"Mary C.","family":"Horne","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of California Davis","place":["Davis"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8619-7630","authenticated-orcid":false,"given":"Eamonn J.","family":"Dickson","sequence":"additional","affiliation":[{"name":"Department of Physiology and Membrane Biology, University of California Davis","place":["Davis"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0655-690X","authenticated-orcid":false,"given":"Rose E.","family":"Dixon","sequence":"additional","affiliation":[{"name":"Department of Physiology and Membrane Biology, University of California 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