PT  - JOURNAL ARTICLE
AU  - Bergson, Pamela
AU  - Lipkind, Gregory
AU  - Lee, Steven P.
AU  - Duban, Mark-Eugene
AU  - Hanck, Dorothy A.
TI  - Verapamil Block of T-Type Calcium Channels
AID  - 10.1124/mol.110.069492
DP  - 2011 Mar 01
TA  - Molecular Pharmacology
PG  - 411--419
VI  - 79
IP  - 3
4099  - http://molpharm.aspetjournals.org/content/79/3/411.short
4100  - http://molpharm.aspetjournals.org/content/79/3/411.full
SO  - Mol Pharmacol2011 Mar 01; 79
AB  - 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.