Common Mechanisms of Drug Interactions with Sodium and T-Type Calcium Channels

Voltage-gated sodium (Na-v) and calcium (Ca-v) 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 Na-v channels, both with regard to membrane topology and with regard to gating kinetics, including rapid inactivation. We thus reasoned that certain drugs acting on Na-v channels may also modulate the activities of T-type channels. Here we show that the specific Na-v 1.8 blocker 5-(4-chlorophenyl-N-(3,5-dimethoxyphenyl) furan-2-carboxamide (A803467) tonically blocks T-type channels in the low micromolar range. Similarly to Na-v 1.8, 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 Na-v channels may extend to structurally similar drug-binding sites. Sequence alignment revealed several highly conserved regions between T-type and Na-v channels that corresponded to drug-binding sites known to alter voltage-dependent gating kinetics. Mutation of amino acid residues in this regions within human Ca(v)3.2 T-type channels altered A803467 blocking affinity severalfold, suggesting that these sites may be exploited for the design of mixed T-type and Na-v channel blockers that could potentially act synergistically to normalize aberrant neuronal activity.