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L.R. Jones; Y.J. Suzuki; W. Wang; Y.M. Kobayashi; V. Ramesh; C. Franzini-Armstrong; L. Cleemann; M. Morad (Profiled Author: Larry R. Jones)
The Journal of clinical investigation. 1998;101(7):1385-1393.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.
PMID: 9525981 PMCID: PMC508716
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Uwe Kirchhefer; Hideo A. Baba; Yvonne M. Kobayashi; Larry R. Jones; Wilhelm Schmitz; Joachim NeumannAmerican Journal of Physiology - Heart and Circulatory Physiology. 2002;283(4 52-4):H1334-H1343.
Uwe Kirchhefer; Joachim Neumann; Donald M. Bers; Igor B. Buchwalow; Larissa Fabritz; Gabriela Hanske; Isabel Justus; Burkhard Riemann; Wilhelm Schmitz; et al.Cardiovascular Research. 2003;59(2):369-379.
Pierre Tijskens; Larry R. Jones; Clara Franzini-ArmstrongJournal of Molecular and Cellular Cardiology. 2003;35(8):961-974.
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