The α1S N-terminus is not essential for bi-directional coupling with RyR1

The dihydropyridine receptor (DHPR) α1S II-III loop has been shown to be critical for excitation-contraction (EC) coupling in skeletal muscle, but the importance of other cytoplasmic regions, especially the N-terminus (residues 1-51), remains unclear. In this study, we found that deletion of α1S residues 2-37 (weakly conserved with N-termini of other L-type Ca2+ channels) had little effect on the ability of α1S to serve as a Ca2+ channel or voltage sensor for EC coupling. Strikingly, deletion of 10 additional residues, which are conserved in L-type channels, resulted in ablation of DHPR function. Specifically, confocal microscopy and measurement of charge movement showed that removal of residues 2-47 resulted in a failure of sarcolemmal insertion. Our results indicate that the weakly conserved, distal α1S N-terminus is not critical for EC coupling or function as a Ca2+ channel. However, integrity of the proximal α1S N-terminus is necessary for sarcolemmal expression of the DHPR.