Key result
The synthetic peptide R3614-3643 promoted Ca2+ sparks in frog skeletal muscle fibers in a dose-dependent manner, with a maximal increase in frequency of approximately 5-fold.
The calmodulin binding domain of RyR1 modulates channel activity through direct binding of calmodulin and interactions with other regions of RyR.
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Peptide modulation of RyR1 sparks in frog fibers warrants further mechanistic study; leaves open translation to mammalian muscle or disease models.
The calmodulin C lobe binding region (residues 3614-3643) on the sarcoplasmic reticulum Ca2+ release channel (RyR1) is thought to be a region of contact between subunits within RyR1 homotetramer Ca2+ release channels. To determine whether the 3614-3643 region is a regulatory site/interaction domain within RyR in muscle fibers, we have investigated the effect of a synthetic peptide corresponding to this region (R3614-3643) on Ca2+ sparks in frog skeletal muscle fibers. R3614-3643 (0.2-3.0 microM) promoted the occurrence of Ca2+ sparks in a highly cooperative dose-dependent manner, with a half-maximal activation at 0.47 microM and a maximal increase in frequency of approximately 5-fold. A peptide with a single amino acid substitution within R3614-3643 (L3624D) retained the ability to bind Ca(2+)-free calmodulin but did not increase Ca2+ spark frequency, suggesting that R3614-3643 does not modulate Ca2+ sparks by removal of endogenous calmodulin. Our data support a model in which the calmodulin binding domain of RyR1 modulates channel activity by at least two mechanisms: direct binding of calmodulin as well as interactions with other regions of RyR.
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Rodney et al. (2005) studied Frog skeletal muscle fibers. Synthetic peptide R3614-3643 vs. L3624D peptide was evaluated on Ca2+ spark frequency. The synthetic peptide R3614-3643 promoted Ca2+ sparks in frog skeletal muscle fibers in a dose-dependent manner, with a maximal increase in frequency of approximately 5-fold.
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