Key result
Peptide fragments of the dihydropyridine receptor II-III loop activated cardiac ryanodine receptor channels at sub-activating cytoplasmic Ca2+ concentrations (100 nM) but inhibited them at activating concentrations (10-100 µM).
Peptide fragments of the dihydropyridine receptor II-III loop can specifically modulate cardiac ryanodine receptor channel activity and sarcoplasmic reticulum Ca2+ release in a Ca2+-dependent manner.
May modulate cardiac Ca2+ release experimentally; hypothesis-generating and leaves open in vivo relevance or therapeutic implications.
We show that peptide fragments of the dihydropyridine receptor II-III loop alter cardiac RyR (ryanodine receptor) channel activity in a cytoplasmic Ca2+-dependent manner. The peptides were AC (Thr-793-Ala-812 of the cardiac dihydropyridine receptor), AS (Thr-671-Leu-690 of the skeletal dihydropyridine receptor), and a modified AS peptide [AS(D-R18)], with an extended helical structure. The peptides added to the cytoplasmic side of channels in lipid bilayers at > or = 10 nM activated channels when the cytoplasmic [Ca2+] was 100 nM, but either inhibited or did not affect channel activity when the cytoplasmic [Ca2+] was 10 or 100 microM. Both activation and inhibition were independent of bilayer potential. Activation by AS, but not by AC or AS(D-R18), was reduced at peptide concentrations >1 mM in a voltage-dependent manner (at +40 mV). In control experiments, channels were not activated by the scrambled AS sequence (ASS) or skeletal II-III loop peptide (NB). Resting Ca2+ release from cardiac sarcoplasmic reticulum was not altered by peptide AC, but Ca2+-induced Ca2+ release was depressed. Resting and Ca2+-induced Ca2+ release were enhanced by both the native and modified AS peptides. NMR revealed (i) that the structure of peptide AS(D-R18) is not influenced by [Ca2+] and (ii) that peptide AC adopts a helical structure, particularly in the region containing positively charged residues. This is the first report of specific functional interactions between dihydropyridine receptor A region peptides and cardiac RyR ion channels in lipid bilayers.
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Dulhunty et al. (2004) studied Cardiac ryanodine receptor channel activity. Peptide fragments of the dihydropyridine receptor (AC, AS, AS(D-R18)) vs. Control conditions (no peptide or scrambled peptide) was evaluated on Cardiac RyR channel open probability and Ca2+ release. Peptide fragments of the dihydropyridine receptor II-III loop activated cardiac ryanodine receptor channels at sub-activating cytoplasmic Ca2+ concentrations (100 nM) but inhibited them at activating concentrations (10-100 µM).
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