The RyR2 central domain peptide DPc10 lowers the threshold for spontaneous Ca2+ release in permeabilized cardiomyocytes

Cardiovascular Research
Zhaokang YangDerek S Steele

Abstract

In vitro experiments have shown that the ryanodine receptor-2 (RyR2) central domain peptide DPc10 (Gly(2460)-Pro(2495)) mimics channel dysfunction associated with catecholaminergic polymorphic ventricular tachycardia (CPVT) by acting competitively to reduce stabilizing interactions between the N-terminal and central domains. In the present study, DPc10 was used as a tool to establish an adult cell model of the disease and to analyse the underlying mechanisms. Rat ventricular myocytes were permeabilized with saponin and perfused with solutions approximating the intracellular milieu containing fluo-3. Sarcoplasmic reticulum (SR) Ca(2+) release was detected using confocal microscopy. DPc10 (10 or 50 microM) was compared with 0.2 mM caffeine, which is known to activate RyR2 and to facilitate Ca(2+)-induced Ca(2+) release (CICR). Introduction of DPc10 induced a transient increase in spark frequency and a sustained rise in resting [Ca(2+)]. Under conditions causing initial Ca(2+) overload of the SR, DPc10 reduced the frequency and amplitude of spontaneous, propagated Ca(2+) release (SPCR). Following equilibration with 10microM DPc10, the cytosolic [Ca(2+)] threshold for SPCR was markedly reduced and the proportion of spontaneously ac...Continue Reading

Citations

Mar 20, 2012·American Journal of Physiology. Heart and Circulatory Physiology·David BenoistEd White
Jun 9, 2007·Heart Rhythm : the Official Journal of the Heart Rhythm Society·Xander H T Wehrens
May 27, 2015·Biochemical Society Transactions·Monika SeidelSpyros Zissimopoulos
Sep 11, 2012·Biochimica Et Biophysica Acta·Ernst NiggliNatalia Shirokova
Nov 4, 2006·Journal of Molecular and Cellular Cardiology·Christopher H GeorgeF Anthony Lai
Oct 21, 2006·Biochemical Society Transactions·N L ThomasF A Lai

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