{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:13:05Z","timestamp":1785413585914,"version":"3.56.0"},"posted":{"date-parts":[[2026,5,21]]},"group-title":"Physiology","reference-count":46,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T00:00:00Z","timestamp":1779321600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["R01 HL14616"],"award-info":[{"award-number":["R01 HL14616"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Dorothy and E. Philip Lyon Chair in Laser Research"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,21]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>BACKGROUND<\/jats:title>\n                  <jats:p>In addition to lethal ventricular arrhythmias, arrhythmogenic cardiomyopathy (ACM) is associated with conduction abnormalities, bradycardias, and reduced expression of the scaffolding junctional protein zonula occludens-1 (ZO-1). Reduced ZO-1 expression is also seen in dilated cardiomyopathy, which is far more common than ACM. Conduction abnormalities are likewise a feature of ZO-1 cardiac-specific knockout (ZO-1cKO) mice. However, the role of ZO-1 in sinoatrial node (SAN) automaticity has not been studied.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>OBJECTIVE<\/jats:title>\n                  <jats:p>To investigate the role of ZO-1 in SAN automaticity and elucidate the mechanisms by which ZO-1 deficiency leads to SAN dysfunction.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>METHODS<\/jats:title>\n                  <jats:p>ZO-1 cardiac-specific knockout (ZO-1cKO) mice were generated by crossing ZO-1 floxed mice with \u03b1MHC-nuclear Cre mice. SAN\/atrial tissue and isolated SAN cells were examined using optical mapping, single-cell patch clamp, and quantitative PCR techniques to assess functional alterations caused by ZO-1 loss.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>RESULTS<\/jats:title>\n                  <jats:p>\n                    ZO-1cKO mice exhibited enlarged atria and SAN area compared to control mice, with normal left ventricular function. Electrocardiograms showed sinus bradycardia, sinus pauses and atrioventricular block. Optical mapping revealed a caudal shift in the SAN leading region and reduced intra-atrial conduction velocity in ZO-1cKO mice. Patch-clamp recordings from isolated SAN cells showed reduced spontaneous action potential frequency and diastolic depolarization rate, while voltage-clamp revealed a marked reduction in pacemaker current (I\n                    <jats:sub>f<\/jats:sub>\n                    ).\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>CONCLUSION<\/jats:title>\n                  <jats:p>ZO-1 expression is essential for SAN automaticity. Its loss impairs SAN impulse generation by reducing pacemaker current and hampering atrial conduction, leading to bradyarrhythmia, conduction delay and block. These findings help explain impulse generation and conduction abnormalities in ACM and other cardiomyopathies.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.05.19.726291","type":"posted-content","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T03:40:21Z","timestamp":1779421221000},"source":"Crossref","is-referenced-by-count":0,"title":["Regulation of Pacemaker Current in the Sinoatrial Node by Zonula Occludens-1"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1893-0647","authenticated-orcid":false,"given":"Rui","family":"Zhang","sequence":"first","affiliation":[{"name":"Smidt Heart Institute, Cedars-Sinai Health Sciences University, Los Angeles, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Teboull","sequence":"additional","affiliation":[{"name":"Smidt Heart Institute, Cedars-Sinai Health Sciences University, Los Angeles, 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