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

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.

• Authors: L R Jones, Y J Suzuki, W Wang, Y M Kobayashi, V Ramesh, C Franzini-Armstrong, L Cleemann, M Morad
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 101 Issue 7 Pg. 1385-93 (Apr 01 1998) ISSN: 0021-9738 [Print] United States
• PMID: 9525981 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Calcium Channels
• Calcium-Binding Proteins
• Calsequestrin
• Carrier Proteins
• Intracellular Signaling Peptides and Proteins
• Membrane Proteins
• Muscle Proteins
• Ryanodine Receptor Calcium Release Channel
• Sodium-Calcium Exchanger
• TRDN protein, human
• Trdn protein, mouse
• triadin
• Caffeine
• Asph protein, mouse
• Mixed Function Oxygenases
• Calcium

Topics

• Animals
• Caffeine (pharmacology)
• Calcium (physiology)
• Calcium Channels (physiology)
• Calcium-Binding Proteins
• Calsequestrin (physiology)
• Cardiomegaly (genetics)
• Carrier Proteins (metabolism)
• Cell Compartmentation (drug effects)
• Gene Expression Regulation
• Intracellular Membranes (ultrastructure)
• Intracellular Signaling Peptides and Proteins
• Ion Channel Gating
• Membrane Proteins
• Mice
• Mice, Transgenic
• Microscopy, Confocal
• Microscopy, Electron
• Mixed Function Oxygenases
• Muscle Proteins (genetics, metabolism)
• Myocardial Contraction
• Myocardium (metabolism, ultrastructure)
• Ryanodine Receptor Calcium Release Channel (metabolism)
• Sarcoplasmic Reticulum (metabolism)
• Signal Transduction
• Sodium-Calcium Exchanger (metabolism)