{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T12:15:05Z","timestamp":1783426505270,"version":"3.54.6"},"posted":{"date-parts":[[2026,7,3]]},"group-title":"Physiology","reference-count":49,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T00:00:00Z","timestamp":1783036800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"crossref","award":["24POST1199293"],"award-info":[{"award-number":["24POST1199293"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000050","name":"National Heart Lung and Blood Institute","doi-asserted-by":"crossref","award":["R01HL144615"],"award-info":[{"award-number":["R01HL144615"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  The cardiac sodium channel Na\n                  <jats:sub>V<\/jats:sub>\n                  1.5 initiates each heartbeat by generating the rapid depolarizing upstroke of the action potential. Dysregulation of Na\n                  <jats:sub>V<\/jats:sub>\n                  1.5 gating can produce cardiac arrhythmias by slowing inactivation, increasing late sodium current (I\n                  <jats:sub>Na,L<\/jats:sub>\n                  ), and impairing electrical stability. Here, we show that phosphatidylinositol-4,5-bisphosphate (PIP\n                  <jats:sub>2<\/jats:sub>\n                  ) is a critical membrane cofactor that stabilizes Na\n                  <jats:sub>V<\/jats:sub>\n                  1.5 gating. Acute PIP\n                  <jats:sub>2<\/jats:sub>\n                  depletion in human iPSC-derived cardiomyocytes, produced by activation of endogenous AT1 receptors, activation of an engineered M3q-DREADD, or optogenetic recruitment of CRY2-pseudojanin, shifted voltage dependence, slowed fast inactivation, and increased I\n                  <jats:sub>Na,L<\/jats:sub>\n                  . These effects were prevented by augmenting intracellular PIP\n                  <jats:sub>2<\/jats:sub>\n                  , required PLC activity when driven by Gq-coupled receptors, and were independent of downstream Ca\u00b2 or PKC signaling. Unlike the skeletal-muscle isoform Na\n                  <jats:sub>V<\/jats:sub>\n                  1.4, Na\n                  <jats:sub>V<\/jats:sub>\n                  1.5 displayed PIP\n                  <jats:sub>2<\/jats:sub>\n                  -dependent shifts in both activation and steady-state inactivation, indicating isoform-specific lipid coupling. Induced-fit docking and molecular dynamics simulations identified a PIP\n                  <jats:sub>2<\/jats:sub>\n                  -interaction interface between the domain IV voltage sensor and pore that contains disease-linked residues. The disease-reported variant R1644C weakened and redistributed the predicted PIP\n                  <jats:sub>2<\/jats:sub>\n                  -contact network, produced elevated basal I\n                  <jats:sub>Na,L<\/jats:sub>\n                  , showed enhanced sensitivity to PIP\n                  <jats:sub>2<\/jats:sub>\n                  depletion, and caused an approximately 30-fold reduction in apparent functional PIP\n                  <jats:sub>2<\/jats:sub>\n                  sensitivity in excised patches. These findings define a lipid-dependent mechanism that stabilizes Na\n                  <jats:sub>V<\/jats:sub>\n                  1.5 gating and reveal how physiological Gq signaling and inherited channel variants can converge on the channel-PIP\n                  <jats:sub>2<\/jats:sub>\n                  axis to promote proarrhythmic late sodium current.\n                <\/jats:p>","DOI":"10.64898\/2026.06.29.735321","type":"posted-content","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T10:10:16Z","timestamp":1783073416000},"source":"Crossref","is-referenced-by-count":0,"title":["PIP\n                  <sub>2<\/sub>\n                  stabilizes Na\n                  <sub>V<\/sub>\n                  1.5 gating and links receptor signaling to cardiac late sodium current"],"prefix":"10.64898","author":[{"given":"Kirin D.","family":"Gada","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical and Biomedical Sciences, School of Pharmacy and Pharmaceutical 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