title: Indolizinsulphones. A class of blockers with dual but discriminative effects on L-type Ca2+ channel activity and excitation-contraction coupling in skeletal muscle.
abstract: 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)
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, Valbonne, France.
authors.forename: P
authors.initials: P
authors.lastname: Bois
authors.forename: G
authors.initials: G
authors.lastname: Romey
authors.forename: M
authors.initials: M
authors.lastname: Lazdunski
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001665:Binding Sites; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D007212:Indolizines / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D009132:Muscles / Q000187:drug effects* / Q000502:physiology; D010627:Phenethylamines / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D007212:Indolizines; D010627:Phenethylamines; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; C059901:fantofarone