Published online before print September 23, 2004, doi: 10.1161/01.RES.0000146029.80463.7d
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Submitted on March 25, 2004
Revised on September 13, 2004
Accepted on September 13, 2004
Sarcoplasmic Reticulum Ca2+ Refilling Controls Recovery From Ca2+-Induced Ca2+ Release Refractoriness in Heart Muscle
Peter Szentesi ;
From the Department of Physiology (P.S., C.P., M.E., E.N.), University of Bern, Bern, Switzerland; the Department of Physiology (P.S.), Medical and Health Science Center, University of Debrecen, Debrecen, Hungary; and the Department of Pharmacology and Cell Biophysics (E.G.K.), University of Cincinnati, Cincinnati, Ohio.
* To whom correspondence should be addressed. E-mail: niggli{at}pyl.unibe.ch.
In cardiac muscle Ca2+-induced Ca2+ release (CICR) from the sarcoplasmic reticulum (SR) is initiated by Ca2+ influx via L-type Ca2+ channels. At present, the mechanisms underlying termination of SR Ca2+ release, which are required to ensure stable excitation-contraction coupling cycles, are not precisely known. However, the same mechanism leading to refractoriness of SR Ca2+ release could also be responsible for the termination of CICR. To examine the refractoriness of SR Ca2+ release, we analyzed Na+-Ca2+ exchange currents reflecting cytosolic Ca2+ signals induced by UV-laser flash-photolysis of caged Ca2+. Pairs of UV flashes were applied at various intervals to examine the time course of recovery from CICR refractoriness. In cardiomyocytes isolated from guinea-pigs and mice, 
-adrenergic stimulation with isoproterenol-accelerated recovery from refractoriness by 
2-fold. Application of cyclopiazonic acid at moderate concentrations (<10 mmol/L) slowed down recovery from refractoriness in a dose-dependent manner. Compared with cells from wild-type littermates, those from phospholamban knockout (PLB-KO) mice exhibited almost 5-fold accelerated recovery from refractoriness. Our results suggest that SR Ca2+ refilling mediated by the SR Ca2+-pump corresponds to the rate-limiting step for recovery from CICR refractoriness. Thus, the Ca2+ sensitivity of CICR appears to be regulated by SR Ca2+ content, possibly resulting from a change in the steady-state Ca2+ sensitivity and in the gating kinetics of the SR Ca2+ release channels (ryanodine receptors). During Ca2+ release, the concomitant reduction in Ca2+ sensitivity of the ryanodine receptors might also underlie Ca2+ spark termination by deactivation.
Key words: calcium-induced calcium release • excitation-contraction coupling • cardiac myocyte • heart • sarcoplasmic reticulum • calcium content • photolysis of caged calcium
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