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Research ArticleArticle

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 and David J. Beech
Molecular Pharmacology June 2011, 79 (6) 1023-1030; DOI: https://doi.org/10.1124/mol.110.069922
Yasser Majeed
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Yahya Bahnasi
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Victoria A. L. Seymour
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Lesley A. Wilson
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Carol J. Milligan
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Anil K. Agarwal
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Piruthivi Sukumar
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Jacqueline Naylor
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David J. Beech
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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 calcium-measurement 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.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported by Wellcome Trust [Grant 083857]; the British Heart Foundation [Grant 26679]; a University of Leeds studentship (to Y.M.); an Egyptian Ministry of Higher Education scholarship (to Y.B.); and a Biotechnology and Biological Sciences Research Council -AstraZeneca PhD Studentship (to L.A.W.).

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.110.069922.

  • ABBREVIATIONS:

    TRP
    transient receptor potential
    TRPC
    transient receptor potential canonical
    TRPM
    transient receptor potential melastatin
    PPAR
    peroxisome-proliferator-activated receptor
    15d-PGJ2
    15-deoxy-Δ12,14-prostaglandin J2
    SBS
    standard bath solution
    BAPTA
    1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid
    GW1929
    N-(2-benzoylphenyl)-O-[2-(methyl-2-pyridinylamino)ethyl]-l-tyrosine
    GW9662
    2-chloro-5-nitrobenzanilide
    PregS
    pregnenolone sulfate
    I-V
    current-voltage.

  • Received November 11, 2010.
  • Accepted March 15, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 79 (6)
Molecular Pharmacology
Vol. 79, Issue 6
1 Jun 2011
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Research ArticleArticle

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 and David J. Beech
Molecular Pharmacology June 1, 2011, 79 (6) 1023-1030; DOI: https://doi.org/10.1124/mol.110.069922

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Research ArticleArticle

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 and David J. Beech
Molecular Pharmacology June 1, 2011, 79 (6) 1023-1030; DOI: https://doi.org/10.1124/mol.110.069922
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