Modest CaV1.342-selective inhibition by compound 8 is β-subunit dependent

Abstract

Two voltage-gated calcium channel subtypes-CaV1.2 and Ca V1.3-underlie the major L-type Ca2+ currents in the mammalian central nervous system. Owing to their high sequence homology, the two channel subtypes share similar pharmacological properties, and at high doses classic calcium channel blockers, such as dihydropyridines, phenylalkylamines and benzothiazepines, do not discriminate between the two channel subtypes. Recent progress in treating Parkinson's disease (PD) was marked by the discovery of synthetic compound 8, which was reported to be a highly selective inhibitor of the CaV1.3 L-type calcium channels (LTCC). However, despite a previously reported IC50 of ∼24μM, in our hands inhibition of the full-length CaV1.3 42 by compound 8 at 50μM reaches a maximum of 45%. Moreover, we find that the selectivity of compound 8 towards Ca V1.3 relative to CaV1.2 B15 channels is greatly influenced by the βsubunit type and its splice isoform variants. © 2014 Macmillan Publishers Limited.