Regulation of Ca2+ signaling in transgenic mouse cardiac myocytes overexpressing calsequestrin.

L. R. Jones, Y. J. Suzuki, W. Wang, Y. M. Kobayashi, V. Ramesh, C. Franzini-Armstrong, L. Cleemann, M. Morad

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235 Scopus citations

Abstract

To probe the physiological role of calsequestrin in excitation-contraction coupling, transgenic mice overexpressing cardiac calsequestrin were developed. Transgenic mice exhibited 10-fold higher levels of calsequestrin in myocardium and survived into adulthood, but had severe cardiac hypertrophy, with a twofold increase in heart mass and cell size. In whole cell-clamped transgenic myocytes, Ca2+ channel- gated Ca2+ release from the sarcoplasmic reticulum was strongly suppressed, the frequency of occurrence of spontaneous or Ca2+ current-triggered "Ca2+ sparks" was reduced, and the spark perimeter was less defined. In sharp contrast, caffeine-induced Ca2+ transients and the resultant Na+-Ca2+ exchanger currents were increased 10-fold in transgenic myocytes, directly implicating calsequestrin as the source of the contractile-dependent pool of Ca2+. Interestingly, the proteins involved in the Ca2+-release cascade (ryanodine receptor, junctin, and triadin) were downregulated, whereas Ca2+-uptake proteins (Ca2+-ATPase and phospholamban) were unchanged or slightly increased. The parallel increase in the pool of releasable Ca2+ with overexpression of calsequestrin and subsequent impairment of physiological Ca2+ release mechanism show for the first time that calsequestrin is both a storage and a regulatory protein in the cardiac muscle Ca2+-signaling cascade. Cardiac hypertrophy in these mice may provide a novel model to investigate the molecular determinants of heart failure.

Original languageEnglish (US)
Pages (from-to)1385-1393
Number of pages9
JournalThe Journal of clinical investigation
Volume101
Issue number7
DOIs
StatePublished - Apr 1 1998

ASJC Scopus subject areas

  • Medicine(all)

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    Jones, L. R., Suzuki, Y. J., Wang, W., Kobayashi, Y. M., Ramesh, V., Franzini-Armstrong, C., Cleemann, L., & Morad, M. (1998). Regulation of Ca2+ signaling in transgenic mouse cardiac myocytes overexpressing calsequestrin. The Journal of clinical investigation, 101(7), 1385-1393. https://doi.org/10.1172/JCI1362