Determinants of voltage-dependent inactivation affect Mibefradil block of calcium channels.

Article Details

Citation

Jimenez C, Bourinet E, Leuranguer V, Richard S, Snutch TP, Nargeot J

Determinants of voltage-dependent inactivation affect Mibefradil block of calcium channels.

Neuropharmacology. 2000;39(1):1-10.

PubMed ID
10665814 [ View in PubMed
]
Abstract

The voltage gated calcium channel family is a major target for a range of therapeutic drugs. Mibefradil (Ro 40-5967) belongs to a new chemical class of these molecules which differs from other Ca2+ antagonists by its ability to potently block T-type Ca2+ channels. However, this molecule has also been shown to inhibit other Ca2+ channel subtypes. To further analyze the mechanism governing the Ca2+ channel-Mibefradil interaction, we examined the effect of Mibefradil on various recombinant Ca2+ channels expressed in mammalian cells from their cloned cDNAs, using Ca2+ as the permeant ion at physiological concentration. Expression of alpha1A, alpha1C, and alpha1E in tsA 201 cells resulted in Ca2+ currents with functional characteristics closely related to those of their native counterparts. Mibefradil blocked alpha1A and alpha1E with a Kd comparable to that reported for T-type channels, but had a lower affinity (approximately 30-fold) for alpha1C. For each channel, inhibition by Mibefradil was consistent with high-affinity binding to the inactivated state. Modulation of the voltage-dependent inactivation properties by the nature of the coexpressed beta subunit or the alpha1 splice variant altered block at the Mibefradil receptor site. Therefore, we conclude that the tissue and sub-cellular localization of calcium channel subunits as well as their specific associations are essential parameters to understand the in vivo effects of Mibefradil.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
MibefradilVoltage-dependent L-type calcium channel subunit alpha-1CProteinHumans
Yes
Inhibitor
Details
MibefradilVoltage-dependent L-type calcium channel subunit alpha-1DProteinHumans
Yes
Inhibitor
Details
MibefradilVoltage-dependent L-type calcium channel subunit alpha-1FProteinHumans
Yes
Inhibitor
Details
MibefradilVoltage-dependent L-type calcium channel subunit alpha-1SProteinHumans
Yes
Inhibitor
Details
MibefradilVoltage-dependent L-type calcium channel subunit beta-1ProteinHumans
Yes
Inhibitor
Details
MibefradilVoltage-dependent L-type calcium channel subunit beta-2ProteinHumans
Yes
Inhibitor
Details
MibefradilVoltage-dependent L-type calcium channel subunit beta-3ProteinHumans
Yes
Inhibitor
Details
MibefradilVoltage-dependent L-type calcium channel subunit beta-4ProteinHumans
Yes
Inhibitor
Details