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Molecular Pharmacology

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Research ArticleArticle

Clemizole Hydrochloride Is a Novel and Potent Inhibitor of Transient Receptor Potential Channel TRPC5

Julia M. Richter, Michael Schaefer and Kerstin Hill
Molecular Pharmacology November 2014, 86 (5) 514-521; DOI: https://doi.org/10.1124/mol.114.093229
Julia M. Richter
Rudolf-Boehm-Institute of Pharmacology and Toxicology, University of Leipzig, Leipzig, Germany
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Michael Schaefer
Rudolf-Boehm-Institute of Pharmacology and Toxicology, University of Leipzig, Leipzig, Germany
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Kerstin Hill
Rudolf-Boehm-Institute of Pharmacology and Toxicology, University of Leipzig, Leipzig, Germany
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Abstract

Canonical transient receptor potential channel 5 (TRPC5) is a nonselective, Ca2+-permeable cation channel that belongs to the large family of transient receptor potential channels. It is predominantly found in the central nervous system with a high expression density in the hippocampus, the amygdala, and the frontal cortex. Several studies confirm that TRPC5 channels are implicated in the regulation of neurite length and growth cone morphology. We identified clemizole as a novel inhibitor of TRPC5 channels. Clemizole efficiently blocks TRPC5 currents and Ca2+ entry in the low micromolar range (IC50 = 1.0–1.3 µM), as determined by fluorometric intracellular free Ca2+ concentration ([Ca2+]i) measurements and patch-clamp recordings. Clemizole blocks TRPC5 currents irrespectively of the mode of activation, for example, stimulation of G protein–coupled receptors, hypo-osmotic buffer conditions, or by the direct activator riluzole. Electrophysiological whole-cell recordings revealed that the block was mostly reversible. Moreover, clemizole was still effective in blocking TRPC5 single channels in excised inside-out membrane patches, hinting to a direct block of TRPC5 by clemizole. Based on fluorometric [Ca2+]i measurements, clemizole exhibits a sixfold selectivity for TRPC5 over TRPC4β (IC50 = 6.4 µM), the closest structural relative of TRPC5, and an almost 10-fold selectivity over TRPC3 (IC50 = 9.1 µM) and TRPC6 (IC50 = 11.3 µM). TRPM3 and M8 as well as TRPV1, V2, V3, and V4 channels were only weakly affected by markedly higher clemizole concentrations. Clemizole was not only effective in blocking heterologously expressed TRPC5 homomers but also TRPC1:TRPC5 heteromers as well as native TRPC5-like currents in the U-87 glioblastoma cell line.

Footnotes

    • Received April 13, 2014.
    • Accepted August 19, 2014.
  • This work was supported by the Deutsche Forschungsgemeinschaft [HI 829/2-1].

  • dx.doi.org/10.1124/mol.114.093229.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 86 (5)
Molecular Pharmacology
Vol. 86, Issue 5
1 Nov 2014
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Research ArticleArticle

Clemizole Inhibits TRPC5 Channel Activity

Julia M. Richter, Michael Schaefer and Kerstin Hill
Molecular Pharmacology November 1, 2014, 86 (5) 514-521; DOI: https://doi.org/10.1124/mol.114.093229

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Research ArticleArticle

Clemizole Inhibits TRPC5 Channel Activity

Julia M. Richter, Michael Schaefer and Kerstin Hill
Molecular Pharmacology November 1, 2014, 86 (5) 514-521; DOI: https://doi.org/10.1124/mol.114.093229
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