RT Journal Article
SR Electronic
T1 Rapid and Contrasting Effects of Rosiglitazone on TRPM3 and TRPC5 Channels
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.110.069922
DO 10.1124/mol.110.069922
A1 YASSER MAJEED
A1 YAHYA BAHNASI
A1 VICTORIA A L SEYMOUR
A1 LESLEY A WILSON
A1 CAROL J MILLIGAN
A1 ANIL K AGARWAL
A1 PIRUTHIVI SUKUMAR
A1 JACQUELINE NAYLOR
A1 DAVID J BEECH
YR 2011
UL http://molpharm.aspetjournals.org/content/early/2011/03/15/mol.110.069922.abstract
AB The aim of this study was to generate new insight into chemical regulation of Transient Receptor Potential (TRP) channels with relevance to glucose homeostasis and the metabolic syndrome. Human TRPM2, TRPM3 and TRPC5 were conditionally over-expressed in HEK 293 cells and studied using calcium-measurement and patch-clamp techniques. Rosiglitazone and other peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonists were investigated. TRPM2 was unaffected by rosiglitazone at concentrations up to 10 μM but was inhibited completely at higher concentrations (IC50 ~22.5 μM). TRPM3 was more potently inhibited, with effects occurring in a biphasic concentration-dependent manner such that there was about 20 % inhibition at low concentrations (0.1-1 μM) and full inhibition at higher concentrations (IC50 5-10 μM). PPAR-γ antagonism by GW9662 did not prevent inhibition of TRPM3 by rosiglitazone. TRPC5 was strongly stimulated by rosiglitazone at concentrations of 10 μM and greater (EC50 ~30 μM). Effects on TRPM3 and TRPC5 occurred rapidly and reversibly. Troglitazone and pioglitazone inhibited TRPM3 (IC50s were 12 μM) but lacked effect on TRPC5, suggesting no relevance of PPAR-γ or the thiazolidinedione moiety to rosiglitazone stimulation of TRPC5. A rosiglitazone-related but non-thiazolidinedione PPAR-γ agonist, GW1929, was a weak stimulator of TRPM3 and TRPC5. The natural PPAR-γ agonist, 15-deoxy prostaglandin J2, had no effect on TRPM3 or TRPC5. The data suggest that rosiglitazone contains chemical moieties that rapidly, strongly and differentially modulate TRP channels independently of PPAR-γ, potentially contributing to biological consequences of the agent and providing the basis for novel TRP channel pharmacology.