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

Bladen, Chris; Zamponi, Gerald W.

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

dc.contributor.author	Bladen, Chris
dc.contributor.author	Zamponi, Gerald W.
dc.date.accessioned	2018-05-28T17:50:13Z
dc.date.available	2018-05-28T17:50:13Z
dc.date.issued	2012-09
dc.description.abstract	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.	en_US
dc.identifier.citation	Bladen, C., & Zamponi, G. W. (2012). Common mechanisms of drug interactions with sodium and T-type calcium channels. Molecular Pharmacology, 82(3), 481–7. https://doi.org/10.1124/mol.112.079715	en_US
dc.identifier.doi	http://dx.doi.org/10.1124/mol.112.079715	en_US
dc.identifier.uri	http://hdl.handle.net/1880/106694
dc.identifier.uri	https://doi.org/10.11575/PRISM/43783
dc.language.iso	en	en_US
dc.publisher	The American Society for Pharmacology and Experimental Therapeutics	en_US
dc.publisher.department	Physiology & Pharmacology	en_US
dc.publisher.faculty	Cumming School of Medicine	en_US
dc.publisher.institution	University of Calgary	en_US
dc.rights.uri	https://creativecommons.org/licenses/by/4.0	en_US
dc.title	Common mechanisms of drug interactions with sodium and T-type calcium channels	en_US
dc.type	unknown