Common mechanisms of drug interactions with sodium and T-type calcium channels

Christopher Bladen, Gerald W. Zamponi

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)

Abstract

Voltage-gated sodium (Nav) and calcium (Cav) channels play important roles in physiological processes, including neuronal and cardiac pacemaker activity, vascular smooth muscle contraction, and nociception. They are thought to share a common ancestry, and, in particular, T-type calcium (T-type) channels share structural similarities with Nav channels, both with regard to membrane topology and with regard to gating kinetics, including rapid inactivation. We thus reasoned that certain drugs acting on Nav channels may also modulate the activities of T-type channels. Here we show that the specific Nav1.8 blocker 5-(4-chlorophenyl-N-(3,5-dimethoxyphenyl)furan-2-carboxamide (A803467) tonically blocks T-type channels in the low micromolar range. Similarly to Nav1.8, this compound causes a significant hyperpolarizing shift in the voltage dependence of inactivation and seems to promote a slow inactivation-like phenotype. We further hypothesized that the structural similarity between T-type and Nav channels may extend to structurally similar drug-binding sites. Sequence alignment revealed several highly conserved regions between T-type and Nav channels that corresponded to drug-binding sites known to alter voltage-dependent gating kinetics. Mutation of amino acid residues in this regions within human Cav3.2 T-type channels altered A803467 blocking affinity severalfold, suggesting that these sites may be exploited for the design of mixed T-type and Nav channel blockers that could potentially act synergistically to normalize aberrant neuronal activity.
Original languageEnglish
Pages (from-to)481-487
JournalMolecular Pharmacology
Volume82
Issue number3
DOIs
Publication statusPublished - 2012
Externally publishedYes

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