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lüll Fenamates as TRP channel blockers: mefenamic acid selectively blocks TRPM3 Klose C; Straub I; Riehle M; Ranta F; Krautwurst D; Ullrich S; Meyerhof W; Harteneck CBr J Pharmacol 2011[Apr]; 162 (8): 1757-69BACKGROUND AND PURPOSE: Fenamates 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 APPROACH: Firstly, 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 RESULTS: We 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 IMPLICATIONS: This 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 beta-cell function. Our results strongly suggest mefenamic acid is the most selective fenamate to interfere with TRPM3 function.|Animals[MESH]|Anti-Inflammatory Agents, Non-Steroidal/*pharmacology[MESH]|Calcium/metabolism[MESH]|Fenamates/*pharmacology[MESH]|HEK293 Cells[MESH]|Humans[MESH]|Insulin-Secreting Cells/metabolism[MESH]|Insulin/metabolism[MESH]|Mefenamic Acid/*pharmacology[MESH]|Mice[MESH]|TRPC Cation Channels/*antagonists & inhibitors[MESH]|TRPM Cation Channels/antagonists & inhibitors[MESH]|TRPV Cation Channels/antagonists & inhibitors[MESH] |