{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T15:56:57Z","timestamp":1790870217350,"version":"4.1.0"},"posted":{"date-parts":[[2026,9,28]]},"group-title":"Physiology","reference-count":42,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"NIH","award":["R01HL161070"],"award-info":[{"award-number":["R01HL161070"]}]},{"name":"NIH","award":["R01HL167195"],"award-info":[{"award-number":["R01HL167195"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,28]]},"abstract":"<jats:title>Intro<\/jats:title>\n                <jats:p>\n                  The adrenergic response is a fundamental mechanism that regulates heart rate (chronotropy), cardiac contractility (inotropy) and relaxation (lusitropy).\n                  <jats:sup>1<\/jats:sup>\n                  Adrenergic stress is also a recognized trigger of arrhythmia in disease.\n                  <jats:sup>2<\/jats:sup>\n                  Yet, our understanding of the underlying molecular basis remains incomplete. Protein kinase A (PKA) and the Ca\n                  <jats:sup>2+<\/jats:sup>\n                  \/calmodulin-dependent kinase II (CaMKII) phosphorylate multiple targets proposed to participate in the adrenergic response, including the GTP-binding protein Rad, phospholamban (PLB) and ryanodine receptor 2 (RyR2).\n                  <jats:sup>1, 3\u20135<\/jats:sup>\n                  Here we demonstrate that phosphorylation of both Rad and PLB is necessary for inotropy and lusitropy. We show that changes in cardiac contractility and relaxation are primarily dependent on intracellular Ca\n                  <jats:sup>2+<\/jats:sup>\n                  handling. Finally, we report that Rad and PLB control stress-induced arrhythmogenesis, despite the phosphorylation of other pro-arrhythmic targets. We have identified the essential molecular components of the adrenergic response, resolving a long-standing debate in cardiac excitation-contraction coupling and refining current models of sympathetic regulation in health and disease.\n                <\/jats:p>","DOI":"10.64898\/2026.09.22.747614","type":"posted-content","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T15:25:22Z","timestamp":1790609122000},"source":"Crossref","is-referenced-by-count":0,"title":["Rad and Phospholamban are Key Drivers of the Ventricular Adrenergic Response and Stress-Induced Arrhythmia"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-1364-0387","authenticated-orcid":false,"given":"Achal M.","family":"Gowda","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Cardiovascular Medicine, Cardiovascular Research Center, University of Wisconsin School of Medicine and Public Health. Madison, Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2246-9112","authenticated-orcid":false,"given":"Erick B.","family":"R\u00edos P\u00e9rez","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiovascular Medicine, Cardiovascular Research Center, University of Wisconsin School of Medicine and Public Health. Madison, Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7413-5325","authenticated-orcid":false,"given":"Daniela","family":"Ponce-Balbuena","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiovascular Medicine, Cardiovascular Research Center, University of Wisconsin School of Medicine and Public Health. Madison, Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3001-9450","authenticated-orcid":false,"given":"Samuel L.","family":"Shenkenberg","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiovascular Medicine, Cardiovascular Research Center, University of Wisconsin School of Medicine and Public Health. Madison, Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0552-9029","authenticated-orcid":false,"given":"Francisco J.","family":"Alvarado","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiovascular Medicine, Cardiovascular Research Center, University of Wisconsin School of Medicine and Public Health. Madison, Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026100108050732000_2026.09.22.747614v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/415198a"},{"key":"2026100108050732000_2026.09.22.747614v1.2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.113.300308"},{"key":"2026100108050732000_2026.09.22.747614v1.3","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000066661.49920.59"},{"key":"2026100108050732000_2026.09.22.747614v1.4","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1038\/s44161-022-00157-y","article-title":"Rad regulation of Ca(V)1.2 channels controls cardiac fight-or-flight response","volume":"1","year":"2022","journal-title":"Nat Cardiovasc Res"},{"key":"2026100108050732000_2026.09.22.747614v1.5","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.yjmcc.2026.05.001","article-title":"Loss of phospholamban phosphorylation blunts Ca(2+) handling during the cellular adrenergic response","volume":"216","year":"2026","journal-title":"J Mol Cell Cardiol"},{"key":"2026100108050732000_2026.09.22.747614v1.6","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00018.2007"},{"key":"2026100108050732000_2026.09.22.747614v1.7","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.109.206078"},{"key":"2026100108050732000_2026.09.22.747614v1.8","doi-asserted-by":"publisher","DOI":"10.1172\/JCI32726"},{"key":"2026100108050732000_2026.09.22.747614v1.9","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201812155"},{"key":"2026100108050732000_2026.09.22.747614v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2015.06.007"},{"key":"2026100108050732000_2026.09.22.747614v1.11","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1038\/s44161-025-00693-3","article-title":"Preventing the phosphorylation of RyR2 at canonical sites reduces Ca(2+) leak and promotes arrhythmia by reactivating the I(Na) current","volume":"4","year":"2025","journal-title":"Nat Cardiovasc Res"},{"key":"2026100108050732000_2026.09.22.747614v1.12","doi-asserted-by":"crossref","unstructured":"Janicek R , et al. 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How does CaMKIIdelta phosphorylation of the cardiac ryanodine receptor contribute to inotropy? 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