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A cardiac dihydropyridine receptor II–III loop peptide inhibits resting Ca2+ sparks in ferret ventricular myocytes

By Yanxia Li and Donald M Bers


We studied the effect of a peptide (Ac-10C) on cardiac ryanodine receptor (RyR) opening. This decapeptide (KKERKLARTA) is a fragment of the cardiac dihydropyridine receptor (DHPR) from the cytosolic loop between the second and third transmembrane domains (II–III loop). Studies were carried out in ferret ventricular myocytes by simultaneously applying ruptured-patch voltage clamp and line-scan confocal microscopy with fluo-3 to measure intracellular [Ca2+] ([Ca2+]i) and Ca2+ sparks.Inclusion of Ac-10C in the dialysing pipette solution inhibited resting Ca2+ spark frequency (due to diastolic RyR openings) by > 50 %. This occurred without changing sarcoplasmic reticulum (SR) Ca2+ content, which was measured via the caffeine-induced Ca2+ transient amplitude and the caffeine-induced Na+–Ca2+ exchange current (INCX) integral. Ac-10C also reduced slightly the size of Ca2+ sparks.Ac-10C did not alter either resting [Ca2+]i (assessed by indo-1 fluorescence) or DHPR gating (measured as L-type Ca2+ current).The SR Ca2+ fractional release was depressed by Ac-10C at relatively low SR Ca2+ content, but not at higher SR Ca2+ content.A control scrambled peptide (Ac-10CS) did not alter any of the measured parameters (notably Ca2+ spark frequency or SR Ca2+ fractional release). Thus, the Ac-10C effects may be sequence or charge distribution specific.Our results suggest an inhibitory regulation of RyRs at rest via the cardiac DHPR II–III loop N-terminus region. The mechanism of the effect and whether this interaction is important in cardiac excitation-contraction coupling (E–C coupling) per se, requires further investigation

Topics: Original Articles
Publisher: Blackwell Science Inc
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Provided by: PubMed Central
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