• Chihab Klose, Isabelle Straub, Marc Riehle, Felicia Ranta, Dietmar Krautwurst, Susanne Ullrich, Wolfgang Meyerhof, and Christian Harteneck.
• Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Interfaculty Center of Pharmacogenomics and Pharmaceutical Research (ICePhA), Eberhard-Karls-University, Tübingen, Germany.
• Br. J. Pharmacol. 2011 Apr 1; 162 (8): 1757-69.

Background And PurposeFenamates are N-phenyl-substituted anthranilic acid derivatives clinically used as non-steroid anti-inflammatory drugs in pain treatment. Reports describing fenamates as tools to interfere with cellular volume regulation attracted our attention based on our interest in the role of the volume-modulated transient receptor potential (TRP) channels TRPM3 and TRPV4.Experimental ApproachFirstly, we measured the blocking potencies and selectivities of fenamates on TRPM3 and TRPV4 as well as TRPC6 and TRPM2 by Ca(2+) imaging in the heterologous HEK293 cell system. Secondly, we further investigated the effects of mefenamic acid on cytosolic Ca(2+) and on the membrane voltage in single HEK293 cells that exogenously express TRPM3. Thirdly, in insulin-secreting INS-1E cells, which endogenously express TRPM3, we validated the effect of mefenamic acid on cytosolic Ca(2+) and insulin secretion.Key ResultsWe identified and characterized mefenamic acid as a selective and potent TRPM3 blocker, whereas other fenamate structures non-selectively blocked TRPM3, TRPV4, TRPC6 and TRPM2.Conclusions And ImplicationsThis study reveals that mefenamic acid selectively inhibits TRPM3-mediated calcium entry. This selectivity was further confirmed using insulin-secreting cells. K(ATP) channel-dependent increases in cytosolic Ca(2+) and insulin secretion were not blocked by mefenamic acid, but the selective stimulation of TRPM3-dependent Ca(2+) entry and insulin secretion induced by pregnenolone sulphate were inhibited. However, the physiological regulator of TRPM3 in insulin-secreting cells remains to be elucidated, as well as the conditions under which the inhibition of TRPM3 can impair pancreatic β-cell function. Our results strongly suggest mefenamic acid is the most selective fenamate to interfere with TRPM3 function.© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

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