{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T22:20:16Z","timestamp":1758925216918},"reference-count":43,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2006,1,12]],"date-time":"2006-01-12T00:00:00Z","timestamp":1137024000000},"content-version":"vor","delay-in-days":621,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of the New York Academy of Sciences"],"published-print":{"date-parts":[[2004,5]]},"abstract":"<jats:p><jats:bold>A<jats:sc>bstract<\/jats:sc>: <\/jats:bold> Genetic engineering has already provided critical data on the Ca\u2010induced Ca<jats:sup>2+<\/jats:sup> release (CICR) hypothesis issues and promises even greater future insights. The two approaches employed thus far are (1) the construction of transgenic animal models with deletion or overexpression of Ca<jats:sup>2+<\/jats:sup> signaling proteins, and (2) direct structure\u2010function studies of these proteins in artificial systems. In our laboratory both approaches have provided some insight into molecular modulation of CICR and the pathophysiology arising from the deletion or overactivity of these proteins. Probing the cytoplasmic segments of the carboxyl c\u2010terminal tail of Ca<jats:sup>2+<\/jats:sup> channel, we identified two calcium sensing and calmodulin binding domains (LA and K) that have been implicated in Ca<jats:sup>2+<\/jats:sup>\u2010induced inactivation of Ca<jats:sup>2+<\/jats:sup> channels. Introducing these peptides into atrial myocytes, where a large fraction of Ca<jats:sup>2+<\/jats:sup> release sites are unassociated with the dihydropyridine receptors (DHPRs) (no t\u2010tubules), suggests that LA, but not K motif, increases the sensitivity of RyRs to Ca<jats:sup>2+<\/jats:sup>, is responsible for the higher frequency of Ca<jats:sup>2+<\/jats:sup> sparks in the peripheral sites, and provides for the voltage dependence of CICR. Genetic overexpression or deletion of the primary proteins of the Ca<jats:sup>2+<\/jats:sup> signaling cascade also provides supportive evidence for the Ca<jats:sup>2+<\/jats:sup> current (I<jats:sub>Ca<\/jats:sub>)\u2010gated CICR mechanism, generates some novel and unexpected cardiac phenotypes in transgenic mice, and suggests that Ca<jats:sup>2+<\/jats:sup> signaling defects can trigger compensatory molecular mechanisms that underlie the observed cardiac phenotype and pathophysiology.<\/jats:p>","DOI":"10.1196\/annals.1302.001","type":"journal-article","created":{"date-parts":[[2004,6,16]],"date-time":"2004-06-16T22:38:16Z","timestamp":1087425496000},"page":"1-15","source":"Crossref","is-referenced-by-count":6,"title":["Learning about Cardiac Calcium Signaling from Genetic Engineering"],"prefix":"10.1111","volume":"1015","author":[{"given":"MARTIN","family":"MORAD","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"MY","family":"CHAU","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2009,7,8]]},"reference":[{"key":"e_1_2_9_2_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.18.10984"},{"key":"e_1_2_9_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.8235594"},{"key":"e_1_2_9_4_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1975.sp011026"},{"key":"e_1_2_9_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.1.121"},{"key":"e_1_2_9_6_2","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.108.5.435"},{"key":"e_1_2_9_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/0079-6107(73)90008-4"},{"key":"e_1_2_9_8_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1991.sp018385"},{"key":"e_1_2_9_9_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.2543067"},{"key":"e_1_2_9_10_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.2173135"},{"key":"e_1_2_9_11_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1990.258.1.C189"},{"key":"e_1_2_9_12_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1994.sp020337"},{"key":"e_1_2_9_13_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.78.1.166"},{"key":"e_1_2_9_14_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.1999.276.4.H1178"},{"key":"e_1_2_9_15_2","first-page":"957","article-title":"Molecular determinants of L\u2010type Ca2+ channel inactivation","volume":"273","author":"Soldatov N.M.","year":"1998","journal-title":"Segment exchange analysis of the carboxyl-terminal cytoplasmic motif encoded by exons 40\u201342 of the human alpha1C subunit gene. 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