EFFECT OF SR33557 ON INTRAMEMBRANE CHARGE MOVEMENT IN NORMAL AND MUSCULAR DYSGENESIS MOUSE SKELETAL-MUSCLE CELLS

It has been reported that the indolizinsulphone SR33557, which binds t o a site on the alpha(1) subunit of the dihydropyridine receptor, bloc ks both L-type calcium channel activity and contraction in skeletal mu scle. Moreover, we know that charge movement plays a key role in the m echanism of excitation-contraction coupling and in controlling the ope ning of L-type calcium channels. We demonstrate here that SR33557 redu ces intramembrane charge movement in skeletal muscle from normal mice with an IC50 Of similar to 10 nM. The drug does not completely inhibit charge movement since similar to 20% of total charge movement persist s even in the presence of 30 mu M SR33557. However, the SR33557-sensit ive charge component is more important than the dihydropyridine-sensit ive one. Surprisingly, SR33557 also reduces intramembrane charge movem ent in dysgenic myotubes which are characterized by a very strong redu ction of the number of dihydropyridine binding sites. In these muscles , 10 mu M SR33557 reduces similar to 40% of total charge movement. The se observations suggest the presence of a new component of charge move ment which is sensitive to SR33557 but insensitive to nifedipine. This component is also present in dysgenic myotubes, and it could be produ ced by the lower molecular weight alpha(1) subunit described by Malouf , N. N., McMahon, D. K., Hainsworth, C. N. and Kay, B. K. (1992) (Neur on, 8, 899-906).