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The RyR2 central domain peptide DPc10 lowers the threshold for spontaneous Ca2+ release in permeabilized cardiomyocytes
The RyR2 central domain peptide DPc10 lowers the threshold for spontaneous Ca2+ release in permeabilized cardiomyocytes
- Source :
- Cardiovascular Research. 70:475-485
- Publication Year :
- 2006
- Publisher :
- Oxford University Press (OUP), 2006.
-
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 active cells increased. Caffeine induced a similar, transient increase in spark frequency and a reduction in the [Ca(2+)] threshold for SPCR. However, unlike DPc10, caffeine increased SPCR frequency and had no sustained effect on resting [Ca(2+)]. These results suggest that the net effect of DPc10 (and CPVT mutations) on RyR2 function in situ is not only to increase the sensitivity to CICR as caffeine does, but also to potentiate Ca(2+) leakage from the SR. As SPCR can trigger delayed after-depolarisations, the decrease in [Ca(2+)] threshold may contribute to arrhythmias in CPVT patients during exercise or stress.
- Subjects :
- medicine.medical_specialty
Phosphodiesterase Inhibitors
Physiology
Biology
Catecholaminergic polymorphic ventricular tachycardia
Ryanodine receptor 2
chemistry.chemical_compound
Caffeine
Physiology (medical)
Internal medicine
medicine
Animals
Myocyte
Myocytes, Cardiac
Rats, Wistar
Cells, Cultured
Microscopy, Confocal
Ryanodine receptor
Endoplasmic reticulum
Ryanodine Receptor Calcium Release Channel
medicine.disease
Peptide Fragments
Rats
Sarcoplasmic Reticulum
Endocrinology
chemistry
cardiovascular system
Biophysics
Liberation
Calcium
Cardiology and Cardiovascular Medicine
Intracellular
Subjects
Details
- ISSN :
- 00086363
- Volume :
- 70
- Database :
- OpenAIRE
- Journal :
- Cardiovascular Research
- Accession number :
- edsair.doi.dedup.....0062038e948b7a52e8d25bc1f5ab8fd0
- Full Text :
- https://doi.org/10.1016/j.cardiores.2006.03.001