Abstract
We found that the fetal variants, ASI(-) of the ryanodine receptor 1 (RyR1) which lacks residue 3481-3485 and sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 1b which differs at the C-terminal, were significantly increased in skeletal muscles from Myotonic dystrophy type 1 (DM1) patients and the transgenic mouse model of DM1. Channel open probability was significantly decreased in ASI(-) than in adult isoform of RyR1, ASI(+). To determine how this aberrant splicing affects the activity of RyR1 channels, we tested whether the splicing region is involved in an inter-domain interaction using synthetic peptides. Both peptides corresponding to the Thr3471 -Gly3500 around the ASI region in the presence (ASI(+)) and the absence (ASI(-)) of exon ASI increased RyR1. The results suggest that ASI(-) peptide interrupts an inhibitory interdomain interaction in the native RyR1 more strongly than the ASI(+) peptide. We therefore suggest that ASI(-) region may interact more tightly with other domains and produce stronger inhibition of ASI(-) RyR1, resulting in reduced activity of the ASI(-) RyR1. Moreover, peptide ASI+/- includes highly positively charged residues similar to A region of dihydropyridine receptor II-III loop which has been reported to activate RyR1. We further tested if these highly positively charged residues in peptide ASI(+/-) are essential for the activation and if peptide A and peptides ASI(+/-) activates RyR1 competitively. [J Physiol Sci. 2007;57 Suppl:S234]
