{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T04:26:18Z","timestamp":1768278378458,"version":"3.49.0"},"reference-count":28,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2021,4,15]],"date-time":"2021-04-15T00:00:00Z","timestamp":1618444800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Grants-in-Aid for Scientific Research from JSPS","award":["25460293, 17K08527, and 17H04319"],"award-info":[{"award-number":["25460293, 17K08527, and 17H04319"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>In the present study, we examined the importance of Ca<jats:sup>2+<\/jats:sup>\/calmodulin-dependent protein kinase IV (CaMKIV) in the regulation of cardiac function using genetically modified CaMKIV-null mice. RT-PCR analysis revealed decreased expression of voltage-dependent calcium channels in the cardiac myocytes of CaMKIV-null mice compared with wild-type mice. CaMKIV-null mice showed shortened QT time on electrocardiograms. Pharmacological analysis revealed decreased responsiveness to the \u03b2-adrenergic blocker propranolol in CaMKIV-null mice, whereas the plasma norepinephrine level was not affected. CaMKIV-null mice showed decreased baroreflex on electrocardiograms. Heart rate variability analysis showed unstable R-R intervals, a decreased low frequency power\/high frequency power (LF\/HF) ratio, and increased standard deviation of the normal to normal R-R intervals (SDNN) in CaMKIV-null mice, suggesting decreased responsiveness to \u03b2-adrenergic stimulation in CaMKIV-null mice. Atrial contraction analysis and cardiac action potential recording showed a decreased response to the \u03b2-adrenoceptor agonist isoproterenol in CaMKIV-null mice. Furthermore, fluorescence imaging in a CRE-hrGFP assay revealed a decreased response to isoproterenol in CaMKIV-null cardiac myocytes. Taken together, our data strongly suggest a significant effect of CaMKIV gene ablation on cardiac \u03b2-adrenergic signal transduction.<\/jats:p>","DOI":"10.1371\/journal.pone.0249932","type":"journal-article","created":{"date-parts":[[2021,4,15]],"date-time":"2021-04-15T20:35:11Z","timestamp":1618518911000},"page":"e0249932","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Attenuated \u03b2-adrenergic response in calcium\/calmodulin-dependent protein kinase IV-knockout mice"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6704-1796","authenticated-orcid":true,"given":"Manabu","family":"Murakami","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Agnieszka M.","family":"Murakami","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasushi","family":"Matsuzaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daisuke","family":"Sawamura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takayoshi","family":"Ohba","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ichirou","family":"Miyoshi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shirou","family":"Itagaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroyuki","family":"Sakagami","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,4,15]]},"reference":[{"key":"pone.0249932.ref001","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1172\/JCI8551","article-title":"CaM kinase signaling induces cardiac hypertrophy and activates the MEF2 transcription factor in vivo","volume":"105","author":"R Passier","year":"2000","journal-title":"J Clin Invest"},{"key":"pone.0249932.ref002","doi-asserted-by":"crossref","first-page":"5866","DOI":"10.1016\/S0021-9258(18)83630-4","article-title":"Ca2+\/calmodulin-dependent protein kinase enriched in cerebellar granule cells. 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