Verapamil block of T-type calcium channels.

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Bergson P, Lipkind G, Lee SP, Duban ME, Hanck DA

Verapamil block of T-type calcium channels.

Mol Pharmacol. 2011 Mar;79(3):411-9. doi: 10.1124/mol.110.069492. Epub 2010 Dec 13.

PubMed ID

21149638 [ View in PubMed

]

Abstract

Verapamil is a prototypical phenylalkylamine (PAA), and it was the first calcium channel blocker to be used clinically. It tonically blocks L-type channels in the inner pore with micromolar affinity, and its affinity increases at depolarized membrane potentials. In T-type calcium channels, verapamil blocks with micromolar affinity and has modestly increased affinity at depolarized potentials. We found that a related PAA, 4-desmethoxyverapamil (D888), is comparable with verapamil both in affinity and in state-dependence. Permanently charged verapamil was more effective intracellularly than neutral verapamil. Charged PAAs were able to access their binding site from both inside and outside the cell. Furthermore, membrane-impermeant [2-(trimethylammonium)ethyl]methanethiosulfonate was able to access the inner pore from outside of the cell. We examined a homology model of the T-type calcium channel to look for possible routes of drug entry. Mutation of L1825W produced a channel that was blocked significantly more slowly by charged verapamil from the outside, with an increase in apparent affinity when the drug was applied from the inside. Data suggest that T-type channels have a back pathway through which charged drugs can access the inner pore of the channel without passing through the plasma membrane.

DrugBank Data that Cites this Article

Drugs

Verapamil

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Verapamil	Voltage-dependent T-type calcium channel subunit alpha-1G	Protein	Humans	Unknown	Inhibitor	Details