Rapid and contrasting effects of rosiglitazone on transient receptor potential TRPM3 and TRPC5 channels

Yasser Majeed, Yahya Bahnasi, Victoria A L Seymour, Lesley A. Wilson, Carol J. Milligan, Anil K. Agarwal, Piruthivi Sukumar, Jacqueline Naylor, David J. Beech

Research output: Contribution to journalArticle

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Abstract

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 TRP melastatin 2 (TRPM2), TRPM3, and TRP canonical 5 (TRPC5) were conditionally overexpressed in human embryonic kidney 293 cells and studied by using calciummeasurement and patch-clamp techniques. Rosiglitazone and other peroxisome proliferator-activated receptor-γ (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 approximately 20% inhibition at low concentrations (0.1-1 μM) and full inhibition at higher concentrations (IC50, 5-10 μM). PPAR-γ antagonism by 2-chloro-5-nitrobenzanilide (GW9662) did not prevent inhibition of TRPM3 by rosiglitazone. TRPC5 was strongly stimulated by rosiglitazone at concentrations of ≥10 μM (EC50, ∼30 μM). Effects on TRPM3 and TRPC5 occurred rapidly and reversibly. Troglitazone and pioglitazone inhibited TRPM3 (IC50, 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 nonthiazolidinedione PPAR-γ agonist, N-(2-benzoylphenyl)-O-[2-(methyl-2- pyridinylamino)ethyl]-L-tyrosine (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.

Original languageEnglish
Pages (from-to)1023-1030
Number of pages8
JournalMolecular Pharmacology
Volume79
Issue number6
DOIs
Publication statusPublished - 1 Jun 2011
Externally publishedYes

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rosiglitazone
Peroxisome Proliferator-Activated Receptors
Transient Receptor Potential Channels
Inhibitory Concentration 50
pioglitazone
troglitazone
Biological Factors
Patch-Clamp Techniques
Tyrosine

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

Majeed, Y., Bahnasi, Y., Seymour, V. A. L., Wilson, L. A., Milligan, C. J., Agarwal, A. K., ... Beech, D. J. (2011). Rapid and contrasting effects of rosiglitazone on transient receptor potential TRPM3 and TRPC5 channels. Molecular Pharmacology, 79(6), 1023-1030. https://doi.org/10.1124/mol.110.069922

Rapid and contrasting effects of rosiglitazone on transient receptor potential TRPM3 and TRPC5 channels. / Majeed, Yasser; Bahnasi, Yahya; Seymour, Victoria A L; Wilson, Lesley A.; Milligan, Carol J.; Agarwal, Anil K.; Sukumar, Piruthivi; Naylor, Jacqueline; Beech, David J.

In: Molecular Pharmacology, Vol. 79, No. 6, 01.06.2011, p. 1023-1030.

Research output: Contribution to journalArticle

Majeed, Y, Bahnasi, Y, Seymour, VAL, Wilson, LA, Milligan, CJ, Agarwal, AK, Sukumar, P, Naylor, J & Beech, DJ 2011, 'Rapid and contrasting effects of rosiglitazone on transient receptor potential TRPM3 and TRPC5 channels', Molecular Pharmacology, vol. 79, no. 6, pp. 1023-1030. https://doi.org/10.1124/mol.110.069922
Majeed, Yasser ; Bahnasi, Yahya ; Seymour, Victoria A L ; Wilson, Lesley A. ; Milligan, Carol J. ; Agarwal, Anil K. ; Sukumar, Piruthivi ; Naylor, Jacqueline ; Beech, David J. / Rapid and contrasting effects of rosiglitazone on transient receptor potential TRPM3 and TRPC5 channels. In: Molecular Pharmacology. 2011 ; Vol. 79, No. 6. pp. 1023-1030.
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