Indolizinsulphones. A class of blockers with dual but discriminative effects on L-type Ca2+ channel activity and excitation-contraction coupling in skeletal muscle.

The alpha 1 subunit of the L-type Ca2+ channel plays a dual role in skeletal muscle. It is essential both for L-type Ca2+ channel activity and for the functioning of the voltage-sensor structure that is situated in the triads as a key element for excitation-contraction coupling. This paper shows, with mouse muscle cells in primary culture, that indolizinsulphone SR33557 which has its binding site on the alpha 1 subunit blocks both L-type Ca2+ channel activity and contraction as the more classical 1,4-dihydropyridine blockers. However, unlike other Ca2+ channel blockers, it can pharmacologically discriminate between the two different roles of the alpha 1 subunit. SR33557 inhibition of both contractile and L-type Ca2+ channel activities is very voltage dependent and increases at depolarized potentials. Complete blockade of contraction was observed at low SR33557 concentrations (K0.5 = 20 nM) and was associated with only minor L-type Ca2+ channel blockade (30%). The remaining and major part of the L-type Ca2+ channel activity (70%) was blocked at much higher SR33557 concentrations (K0.5 = 0.6 microM). The results indicate that SR33557 has a much higher affinity for the alpha 1 subunit inserted into the voltage-sensor structure. They also suggest that the voltage-sensor structure, which probably includes most of the total T-tubule alpha 1 subunit, has intrinsic (but relatively small) Ca2+ channel activity.(ABSTRACT TRUNCATED AT 250 WORDS)