{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T12:08:46Z","timestamp":1790251726454,"version":"4.1.0"},"reference-count":48,"publisher":"American Physiological Society","issue":"3","funder":[{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science, and Technology (MEXT)","doi-asserted-by":"publisher","award":["23390057"],"award-info":[{"award-number":["23390057"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science, and Technology (MEXT)","doi-asserted-by":"publisher","award":["26293054"],"award-info":[{"award-number":["26293054"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005865","name":"Mochida Memorial Foundation for Medical and Pharmaceutical Research","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100005865","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"published-print":{"date-parts":[[2017,3,1]]},"abstract":"<jats:p>Activation of CaMKII induces a myriad of biological processes and plays dominant roles in cardiac hypertrophy. Caveolar microdomain contains many calcium\/calmodulin-dependent kinase II (CaMKII) targets, including L-type Ca<jats:sup>2+<\/jats:sup>channel (LTCC) complex, and serves as a signaling platform. The location of CaMKII activation is thought to be critical; however, the roles of CaMKII in caveolae are still elusive due to lack of methodology for the assessment of caveolae-specific activation. Our aim was to develop a novel tool for the specific analysis of CaMKII activation in caveolae and to determine the functional role of caveolar CaMKII in cardiac hypertrophy. To assess the caveolae-specific activation of CaMKII, we generated a fusion protein composed of phospholamban and caveolin-3 (cPLN-Cav3) and GFP fusion protein with caveolin-binding domain fused to CaMKII inhibitory peptide (CBD-GFP-AIP), which inhibits CaMKII activation specifically in caveolae. Caveolae-specific activation of CaMKII was detected using phosphospecific antibody for PLN (Thr<jats:sup>17<\/jats:sup>). Furthermore, adenoviral overexpression of LTCC \u03b2<jats:sub>2a<\/jats:sub>-subunit (\u03b2<jats:sub>2a<\/jats:sub>) in NRCMs showed its constitutive phosphorylation by CaMKII, which induces hypertrophy, and that both phosphorylation and hypertrophy are abolished by CBD-GFP-AIP expression, indicating that \u03b2<jats:sub>2a<\/jats:sub>phosphorylation occurs specifically in caveolae. Finally, \u03b2<jats:sub>2a<\/jats:sub>phosphorylation was observed after phenylephrine stimulation in \u03b2<jats:sub>2a<\/jats:sub>-overexpressing mice, and attenuation of cardiac hypertrophy after chronic phenylephrine stimulation was observed in nonphosphorylated mutant of \u03b2<jats:sub>2a<\/jats:sub>-overexpressing mice. We developed novel tools for the evaluation and inhibition of caveolae-specific activation of CaMKII. We demonstrated that phosphorylated \u03b2<jats:sub>2a<\/jats:sub>dominantly localizes to caveolae and induces cardiac hypertrophy after \u03b1<jats:sub>1<\/jats:sub>-adrenergic stimulation in mice.<\/jats:p><jats:p>NEW &amp; NOTEWORTHY While signaling in caveolae is thought to be important in cardiac hypertrophy, direct evidence is missing due to lack of tools to assess caveolae-specific signaling. This is the first study to demonstrate caveolae-specific activation of CaMKII signaling in cardiac hypertrophy induced by \u03b1<jats:sub>1<\/jats:sub>-adrenergic stimulation using an originally developed tool.<\/jats:p>","DOI":"10.1152\/ajpheart.00601.2016","type":"journal-article","created":{"date-parts":[[2016,12,31]],"date-time":"2016-12-31T02:45:13Z","timestamp":1483152313000},"page":"H501-H514","source":"Crossref","is-referenced-by-count":22,"title":["Caveolae-specific activation loop between CaMKII and L-type Ca<sup>2+<\/sup>channel aggravates cardiac hypertrophy in \u03b1<sub>1<\/sub>-adrenergic stimulation"],"prefix":"10.1152","volume":"312","author":[{"given":"Kota","family":"Tonegawa","sequence":"first","affiliation":[{"name":"Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmacological Sciences, Osaka University, Suita, Osaka, 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