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Pflügers Archiv

, Volume 419, Issue 6, pp 651–656 | Cite as

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

  • Patrick Bois
  • Georges Romey
  • Michel Lazdunski
Excitable Tissues and Central Nervous Physiology

Abstract

The α1 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 α1 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 α1 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 μM). The results indicate that SR33557 has a much higher affinity for the α1 subunit inserted into the voltage-sensor structure. They also suggest that the voltage-sensor structure, which probably includes most of the total T-tubule α1 subunit, has intrinsic (but relatively small) Ca2+ channel activity. BayK8644, a L-type Ca2+ channel activator of the 1,4-dihydropyridine family, drastically increased contraction in parallel with an increase of the L-type Ca2+ current. SR33557 at low concentrations completely abolished contraction in BayK8644-treated myotubes while leaving a L-type Ca2+ current component larger than the normal L-type Ca2+ current observed in untreated control myotubes. SR33557 is the first reported molecule which can discriminate between the two functions of the α1 subunit and eliminate contraction while leaving large L-type Ca2+ currents. For that reason it should become a potent tool for future studies of excitation-contraction coupling in skeletal muscle.

Key words

Voltage-clamp Contraction BayK8644 

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Copyright information

© Springer-Verlag 1991

Authors and Affiliations

  • Patrick Bois
    • 1
  • Georges Romey
    • 1
  • Michel Lazdunski
    • 1
  1. 1.Institut de Pharmacologie Moléculaire et CellulaireSophia, AntipolisFrance

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