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The transient receptor potential channel antagonist SKF96365 is a potent blocker of low‐voltage‐activated T‐type calcium channels
Author(s) -
Singh A,
Hildebrand ME,
Garcia E,
Snutch TP
Publication year - 2010
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2010.00786.x
Subject(s) - trpc , transient receptor potential channel , t type calcium channel , voltage dependent calcium channel , chemistry , trpc5 , channel blocker , patch clamp , voltage gated ion channel , trpc1 , l type calcium channel , biophysics , calcium , pharmacology , receptor , ion channel , biology , biochemistry , organic chemistry
Background and purpose: SKF96365 (SKF), originally identified as a blocker of receptor‐mediated calcium entry, is widely used diagnostically, as a blocker of transient receptor potential canonical type (TRPC) channels. While SKF has been used as a tool to define the functional roles of TRPC channels in various cell and tissue types, there are notable overlapping physiological and pathophysiological associations between TRPC channels and low‐voltage‐activated (LVA) T‐type calcium channels. The activity of SKF against T‐type Ca channels has not been previously explored, and here we systematically investigated the effects of SKF on recombinant and native voltage‐gated Ca channel‐mediated currents. Experimental approach: Effects of SKF on recombinant Ca channels were studied under whole‐cell patch clamp conditions after expression in HEK293 cells. The effect of SKF on cerebellar Purkinje cells (PCs) expressing native T‐type Ca channels was also assessed. Key results: SKF blocked recombinant Ca channels, representative of each of the three main molecular genetic classes (Ca V 1, Ca V 2 and Ca V 3) at concentrations typically utilized to assay TRPC function (10 µM). Particularly, human Ca V 3.1 T‐type Ca channels were more potently inhibited by SKF (IC 50 ∼560 nM) in our experiments than previously reported for similarly expressed TRPC channels. SKF also inhibited native Ca V 3.1 T‐type currents in a rat cerebellar PC slice preparation. Conclusions and implications: SKF was a potent blocker of LVA T‐type Ca channels. We suggest caution in the interpretation of results using SKF alone as a diagnostic agent for TRPC activity in native tissues.