Abstract
Both in vivo and in vitro studies suggest that the Glu(724)-Pro(760) (peptide C) region of the dihydropyridine receptor alpha1 II-III loop is important for excitation-contraction coupling, although its actual function has not yet been elucidated. According to our recent studies, peptide C inhibits Ca(2+) release induced by T-tubule depolarization or peptide A. Here we report that peptide C has Ca(2+)-dependent dual functions on the skeletal muscle ryanodine receptor. Thus, at above-threshold [Ca(2+)]s (> or =0.1 microm) peptide C blocked peptide A-induced activation of the ryanodine receptor (ryanodine binding and Ca(2+) release); peptide C also blocked T-tubule depolarization-induced Ca(2+) release. However, at sub-threshold [Ca(2+)]s (<0.1 microm), peptide C enhanced ryanodine binding and induced Ca(2+) release. If peptide A was present, together with peptide C, both peptides produced additive activation effects. Neither peptide A nor peptide C produced any appreciable effect on the cardiac muscle ryanodine receptor at both high (1.0 microm) and low (0.01 microm) Ca(2+) concentrations. These results suggest the possibility that the in vivo counterpart of peptide C retains both activating and blocking functions of the skeletal muscle-type excitation-contraction coupling.
Highlights
From ‡Boston Biomedical Research Institute, Watertown, Massachusetts 02472, §Harvard University, Cambridge, Massachusetts 02138, and ¶Department of Neurology, Harvard Medical School, Boston, Massachusetts 02115. Both in vivo and in vitro studies suggest that the Glu724–Pro760 region of the dihydropyridine receptor ␣1 II-III loop is important for excitation-contraction coupling, its actual function has not yet been elucidated
What kind of function or functions does this region retain? Can we find any of the functions required for E-C coupling, such as activation, re-priming, and physical linking of the II-III loop with the RyR? As described previously (6, 13–15), peptide C that corresponds to essentially the same region as the Leu720–Leu764 region suppresses activation of the RyR by peptide A and T-tubule depolarization, suggesting that this region may be required for at least the blocking or re-priming process of E-C coupling
In our previous studies (6, 11, 13, 14), we reported that peptide A enhances ryanodine binding and induces a rapid Ca2ϩ release, whereas peptide C antagonizes the activation of ryanodine binding and Ca2ϩ release by peptide A
Summary
Both in vivo and in vitro studies suggest that the Glu724–Pro760 (peptide C) region of the dihydropyridine receptor ␣1 II-III loop is important for excitation-contraction coupling, its actual function has not yet been elucidated. Neither peptide A nor peptide C produced any appreciable effect on the cardiac muscle ryanodine receptor at both high (1.0 M) and low (0.01 M) Ca2؉ concentrations These results suggest the possibility that the in vivo counterpart of peptide C retains both activating and blocking functions of the skeletal muscle-type excitation-contraction coupling. According to the more recent report of Ahern et al (18) deletion of the Thr671–Leu690 peptide A region from the ␣1 subunit produced virtually no effect on Ca2ϩ conductance, charge movement, and Ca2ϩ transients These reports raised the possibility that the only Leu720–Leu764 region, containing the Phe725–Pro742 region (the so-called determinant of skeletal-type E-C coupling), may be sufficient for the in vivo E-C coupling without the requirement of the peptide A region. According to the recent report by Stange et al (12), the peptide
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