{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:57:58Z","timestamp":1785437878611,"version":"3.56.0"},"reference-count":79,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T00:00:00Z","timestamp":1785456000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2026,7,31]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Every heartbeat is initiated by a spontaneous electrical signal generated inside the cardiac pacemaker. This signal depends on the coordinated activity of ion channels, where voltage-gated L-type calcium channels play a central role. All mammals experience a progressive decline in pacemaker rate with age, which in humans can become pathological and drive the need for artificial pacemaker implantation. Yet the mechanisms underlying this age-associated slowdown remain incompletely understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>We combined patch-clamp electrophysiology, single-channel recording, calcium imaging, immunocytochemistry, and super-resolution microscopy to investigate L-type calcium channel density, organization, and function in sinoatrial node pacemaker cells from young and old mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>Aging reduced L-type calcium channel density at the plasma membrane, disrupted channel clustering, and decreased open probability, collectively diminishing calcium current density by 50%. Pharmacological enhancement of channel open probability with Bay K 8644 was sufficient to accelerate diastolic depolarization and restore pacemaker rate in old cells to young levels. These channel alterations were paralleled by a decline in caveolin-3 expression. Disrupting caveolae in young cells recapitulated the loss of channel clustering, pointing to caveolae as a structural basis for the age-associated channel alterations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Aging impairs L-type calcium channel organization and function in cardiac pacemaker cells. This impairment is mediated by an age-associated reduction of caveolae, key membrane microdomains for channel organization. The resulting decline in L-type calcium channel density and activity is an important driver of the age-associated slowdown of the cardiac pacemaker.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.125.327894","type":"journal-article","created":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T09:00:56Z","timestamp":1781859656000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Aging Disrupts L-type Ca\n                    <sup>2+<\/sup>\n                    Channel Organization and Function in Pacemaker Cells"],"prefix":"10.1161","volume":"139","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0964-385X","authenticated-orcid":true,"given":"Oscar","family":"Vivas","sequence":"first","affiliation":[{"name":"Department of Pharmacology (O.V., R.P.), University of Washington, Seattle."},{"name":"Department of Neurobiology and Biophysics (O.V., M.B., R.M., W.L.P.-T., M.S.H., S.C., C.M.M.), University of Washington, Seattle."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8725-3048","authenticated-orcid":true,"given":"Matthias","family":"Baudot","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Biophysics (O.V., M.B., R.M., W.L.P.-T., M.S.H., S.C., C.M.M.), University of Washington, Seattle."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roxanne","family":"Madden","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Biophysics (O.V., M.B., R.M., W.L.P.-T., M.S.H., S.C., C.M.M.), University of Washington, Seattle."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1907-8401","authenticated-orcid":true,"given":"Wendy L.","family":"Pi\u00f1on-Teal","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Biophysics (O.V., M.B., R.M., W.L.P.-T., M.S.H., S.C., C.M.M.), University of Washington, Seattle."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8776-7179","authenticated-orcid":true,"given":"Martina S.","family":"Hunt","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Biophysics (O.V., M.B., R.M., W.L.P.-T., M.S.H., S.C., C.M.M.), University of Washington, Seattle."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-8140-1592","authenticated-orcid":true,"given":"Sabrina","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Biophysics (O.V., M.B., R.M., W.L.P.-T., M.S.H., S.C., C.M.M.), University of Washington, Seattle."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roya","family":"Pournejati","sequence":"additional","affiliation":[{"name":"Department of Pharmacology (O.V., R.P.), University of Washington, Seattle."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8369-9192","authenticated-orcid":true,"given":"Victor A.","family":"Flores-Tamez","sequence":"additional","affiliation":[{"name":"Department of Pharmacology (V.A.F.-T), University of California, Davis."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4297-8029","authenticated-orcid":true,"given":"L. 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