Effect of SR33557 on intramembrane charge movement in normal and 'muscular dysgenesis' mouse skeletal muscle cells.

Abstract

It has been reported that the indolizinsulphone SR33557, which binds to a site on the alpha 1 subunit of the dihydropyridine receptor, blocks both L-type calcium channel activity and contraction in skeletal muscle. Moreover, we know that charge movement plays a key role in the mechanism of excitation-contraction coupling and in controlling the opening of L-type calcium channels. We demonstrate here that SR33557 reduces intramembrane charge movement in skeletal muscle from normal mice with an IC50 of approximately 10 nM. The drug does not completely inhibit charge movement since approximately 20% of total charge movement persists even in the presence of 30 microM SR33557. However, the SR33557-sensitive charge component is more important than the dihydropyridine-sensitive one. Surprisingly, SR33557 also reduces intramembrane charge movement in dysgenic myotubes which are characterized by a very strong reduction of the number of dihydropyridine binding sites. In these muscles, 10 microM SR33557 reduces approximately 40% of total charge movement. These observations suggest the presence of a new component of charge movement which is sensitive to SR33557 but insensitive to nifedipine. This component is also present in dysgenic myotubes, and it could be produced by the lower molecular weight alpha 1 subunit described by Malouf, N. N., McMahon, D. K., Hainsworth, C. N. and Kay, B. K. (1992) (Neuron, 8, 899-906).