{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T07:47:04Z","timestamp":1792568824253,"version":"4.5.0"},"reference-count":42,"publisher":"National Academy of Sciences","issue":"1","license":[{"start":{"date-parts":[[2022,12,30]],"date-time":"2022-12-30T00:00:00Z","timestamp":1672358400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01-HL59949-23"],"award-info":[{"award-number":["R01-HL59949-23"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,1,3]]},"abstract":"<jats:p>\n                    G-protein-gated inwardly rectifying potassium (GIRK) channel activity is regulated by the membrane phospholipid, phosphatidylinositol-4,5-bisphosphate (PI 4,5P\n                    <jats:sub>2<\/jats:sub>\n                    ). Constitutive activity of cardiac GIRK channels in atrial myocytes, that is implicated in atrial fibrillation (AF), is mediated via a protein kinase C-\u03b5 (PKC\u03b5)-dependent mechanism. The novel PKC isoform, PKC\u03b5, is reported to enhance the activity of cardiac GIRK channels. Here, we report that PKC\u03b5 stimulation leads to activation of GIRK channels in mouse atria and in human stem cell-derived atrial cardiomyocytes (iPSCs). We identified residue GIRK4(S418) which when mutated to Ala abolished, or to Glu, mimicked the effects of PKC\u03b5 on GIRK currents. PKC\u03b5 strengthened the interactions of the cardiac GIRK isoforms, GIRK4 and GIRK1\/4 with PIP\n                    <jats:sub>2<\/jats:sub>\n                    , an effect that was reversed in the GIRK4(S418A) mutant. This mechanistic insight into the PKC\u03b5-mediated increase in channel activity because of GIRK4(S418) phosphorylation, provides a precise druggable target to reverse AF-related pathologies due to GIRK overactivity.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2212325120","type":"journal-article","created":{"date-parts":[[2022,12,30]],"date-time":"2022-12-30T15:14:01Z","timestamp":1672413241000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":11,"title":["Mechanism of PKC\u03b5 regulation of cardiac GIRK channel gating"],"prefix":"10.1073","volume":"120","author":[{"given":"Kirin D.","family":"Gada","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, Bouv\u00e9 College of Health Sciences and College of Science, Northeastern University, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengmeng","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL 33602"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aishwarya","family":"Chandrashekar","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Bouv\u00e9 College of Health Sciences and College of Science, Northeastern University, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1622-1655","authenticated-orcid":false,"given":"Leigh D.","family":"Plant","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Bouv\u00e9 College of Health Sciences and College of Science, Northeastern University, Boston, MA 02115"},{"name":"Center for Drug Discovery, Bouv\u00e9 College of Health Sciences and College of Science, Northeastern University, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sami F.","family":"Noujaim","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL 33602"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0576-884X","authenticated-orcid":false,"given":"Diomedes E.","family":"Logothetis","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Bouv\u00e9 College of Health Sciences and College of Science, Northeastern University, Boston, MA 02115"},{"name":"Center for Drug Discovery, Bouv\u00e9 College of Health Sciences and College of Science, Northeastern University, Boston, MA 02115"},{"name":"Department of Chemistry and Chemical Biology, Bouv\u00e9 College of Health Sciences and College of Science, Northeastern University, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2022,12,30]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2112"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/325321a0"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(01)01304-3"},{"key":"e_1_3_4_4_2","unstructured":"D. Dobrev \u201cThe selective IK (ACh) blocker tertiapin unmasks constitutively active IK I-ACh in chronic human atrial fibrillation\u201d in Circulation (Lippincott Williams & Wilkins Philadelphia PA 19106-3621 2003)."},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2007.145912"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M004989200"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.111.253120"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-008-0628-9"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1415-15.2015"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.4161\/chan.4321"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2022.101893"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2007.02.009"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M500329-JLR200"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.50.31553"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.107.3.381"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.24.14193"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M700574-MCP200"},{"key":"e_1_3_4_18_2","unstructured":"L. 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