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

Yanxia Li and Donald M. Bers

1. 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.
2. 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 (I_NCX) integral. Ac-10C also reduced slightly the size of Ca²⁺ sparks.
3. Ac-10C did not alter either resting [Ca²⁺]_i (assessed by indo-1 fluorescence) or DHPR gating (measured as L-type Ca²⁺ current).
4. The SR Ca²⁺ fractional release was depressed by Ac-10C at relatively low SR Ca²⁺ content, but not at higher SR Ca²⁺ content.
5. 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.
6. 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.

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