{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T14:11:37Z","timestamp":1791209497978,"version":"4.1.0"},"reference-count":33,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2000,10,27]]},"abstract":"<jats:p><jats:italic>Abstract<\/jats:italic>\u2014Cardiac beating arises from the spontaneous rhythmic excitation of sinoatrial (SA) node cells. Here we report that SA node pacemaker activity is critically dependent on Ca<jats:sup>2+<\/jats:sup>\/calmodulin-dependent protein kinase II (CaMKII). In freshly dissociated rabbit single SA node cells, inhibition of CaMKII by a specific peptide inhibitor, autocamtide-2 inhibitory peptide (AIP, 10 \u03bcmol\/L), or by KN-93 (0.1 to 3.0 \u03bcmol\/L), but not its inactive analog, KN-92, depressed the rate and amplitude of spontaneous action potentials (APs) in a dose-dependent manner. Strikingly, 10 \u03bcmol\/L AIP and 3 \u03bcmol\/L KN-93 completely arrested SA node cells, which indicates that basal CaMKII activation is obligatory to the genesis of pacemaker AP. To understand the ionic mechanisms of the CaMKII effects, we measured L-type Ca<jats:sup>2+<\/jats:sup>current (<jats:italic>I<\/jats:italic><jats:sub>Ca, L<\/jats:sub>), which contributes both to AP upstroke and to pacemaker depolarization. KN-93 (1 \u03bcmol\/L), but not its inactive analog, KN-92, decreased<jats:italic>I<\/jats:italic><jats:sub>Ca, L<\/jats:sub>amplitude from 12\u00b12 to 6\u00b11 pA\/pF without altering the shape of the current-voltage relationship. Both AIP and KN-93 shifted the midpoint of the steady-state inactivation curve leftward and markedly slowed the recovery of<jats:italic>I<\/jats:italic><jats:sub>Ca, L<\/jats:sub>from inactivation. Similar results were observed using the fast Ca<jats:sup>2+<\/jats:sup>chelator BAPTA, whereas the slow Ca<jats:sup>2+<\/jats:sup>chelator EGTA had no significant effect, which suggests that CaMKII activity is preferentially regulated by local Ca<jats:sup>2+<\/jats:sup>transients. Indeed, confocal immunocytochemical imaging showed that active CaMKII is highly localized beneath the surface membrane in the vicinity of L-type channels and that AIP and KN-93 significantly reduced CaMKII activity. Thus, we conclude that CaMKII plays a vital role in regulating cardiac pacemaker activity mainly via modulating<jats:italic>I<\/jats:italic><jats:sub>Ca, L<\/jats:sub>inactivation and reactivation, and local Ca<jats:sup>2+<\/jats:sup>is critically involved in these processes.<\/jats:p>","DOI":"10.1161\/01.res.87.9.760","type":"journal-article","created":{"date-parts":[[2012,6,12]],"date-time":"2012-06-12T00:52:16Z","timestamp":1339462336000},"page":"760-767","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":166,"title":["Sinoatrial Node Pacemaker Activity Requires Ca<sup>2+<\/sup>\/Calmodulin-Dependent Protein Kinase II Activation"],"prefix":"10.1161","volume":"87","author":[{"given":"Tatiana M.","family":"Vinogradova","sequence":"first","affiliation":[{"name":"From the Laboratory of Cardiovascular Sciences (T.M.V., Y.-Y.Z., K.Y.B., D.Y., M.K., H.C., R.-P.X.), National Institute of Aging, Gerontology Research Center, Baltimore, Md, and National Laboratory of Biomembrane and Membrane Biotechnology (D.Y., H.C.), College of Life Sciences, Beijing University, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying-Ying","family":"Zhou","sequence":"additional","affiliation":[{"name":"From the Laboratory of Cardiovascular Sciences (T.M.V., Y.-Y.Z., K.Y.B., D.Y., M.K., H.C., R.-P.X.), National Institute of Aging, Gerontology Research Center, Baltimore, Md, and National Laboratory of Biomembrane and Membrane Biotechnology (D.Y., H.C.), College of Life Sciences, Beijing University, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantin Y.","family":"Bogdanov","sequence":"additional","affiliation":[{"name":"From the Laboratory of Cardiovascular Sciences (T.M.V., Y.-Y.Z., K.Y.B., D.Y., M.K., H.C., R.-P.X.), National Institute of Aging, Gerontology Research Center, Baltimore, Md, and National Laboratory of Biomembrane and Membrane Biotechnology (D.Y., H.C.), College of Life Sciences, Beijing University, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongmei","family":"Yang","sequence":"additional","affiliation":[{"name":"From the Laboratory of Cardiovascular Sciences (T.M.V., Y.-Y.Z., K.Y.B., D.Y., M.K., H.C., R.-P.X.), National Institute of Aging, Gerontology Research Center, Baltimore, Md, and National Laboratory of Biomembrane and Membrane Biotechnology (D.Y., H.C.), College of Life Sciences, Beijing University, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meike","family":"Kuschel","sequence":"additional","affiliation":[{"name":"From the Laboratory of Cardiovascular Sciences (T.M.V., Y.-Y.Z., K.Y.B., D.Y., M.K., H.C., R.-P.X.), National Institute of Aging, Gerontology Research Center, Baltimore, Md, and National Laboratory of Biomembrane and Membrane Biotechnology (D.Y., H.C.), College of Life Sciences, Beijing University, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heping","family":"Cheng","sequence":"additional","affiliation":[{"name":"From the Laboratory of Cardiovascular Sciences (T.M.V., Y.-Y.Z., K.Y.B., D.Y., M.K., H.C., R.-P.X.), National Institute of Aging, Gerontology Research Center, Baltimore, Md, and National Laboratory of Biomembrane and Membrane Biotechnology (D.Y., H.C.), College of Life Sciences, Beijing University, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui-Ping","family":"Xiao","sequence":"additional","affiliation":[{"name":"From the Laboratory of Cardiovascular Sciences (T.M.V., Y.-Y.Z., K.Y.B., D.Y., M.K., H.C., R.-P.X.), National Institute of Aging, Gerontology Research Center, Baltimore, Md, and National Laboratory of Biomembrane and Membrane Biotechnology (D.Y., H.C.), College of Life Sciences, Beijing University, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2828(84)80714-2"},{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/res.46.1.7349910"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1536\/ihj.37.673"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.1993.73.1.197"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00581808"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.1999.276.3.H1064"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.ph.57.030195.002221"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)60487-9"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C000253200"},{"key":"e_1_3_2_10_2","first-page":"9659","volume":"91","year":"1994","unstructured":"Xiao R-P, Cheng P, Lederer WJ, Suzuki T, Lakatta EG. 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