How do small molecule drugs modulate voltage-gated calcium channels?

Three distinct classes of small molecule drugs that modulate L-type calcium channels are currently in clinical use: dihydropyridines (DHP), phenylalkylamines (PAA) and benzothiazepines (BZP). These drugs are used extensively to treat cardiovascular disorders such as hypertension, angina pectoris and some arrhythmias. Using site-directed mutagenesis, expression of recombinant channels in tsA 201 cells, and whole-cell patch-clamp recording techniques, we have identified key amino acid residues for the interaction of each class of drugs with L-type channels.

Using this information, we were able to construct a dihydropyridine binding site in a normally DHP-insensitive P/Q- type calcium channel by making only 9 amino acid substitutions. The resulting mutant channel exhibited dihydropyridine modulation nearly identical to that of L-type channels. This result suggests that DHPs may be a useful starting point in the search for calcium channel type selective drugs.

Recent work in my lab has ... more.

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