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Mibefradil represents a new class of benzimidazole TRPM7 channel agonists

  • Ion channels, receptors and transporters
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Transient receptor potential cation channel, subfamily M, member 7 (TRPM7) is a bi-functional protein comprising an ion channel moiety covalently linked to a protein kinase domain. Currently, the prevailing view is that a decrease in the cytosolic Mg2+ concentration leads to activation of divalent cation-selective TRPM7 currents. TRPM7 plays a role in immune responses, hypotension, tissue fibrosis, and tumor progression and, therefore, represents a new promising therapeutic target. Because of the dearth of pharmacological tools, our mechanistic understanding of the role of TRPM7 in physiology and pathophysiology still lags behind. Therefore, we have recently carried out a high throughput screen for small-molecule activators of TRPM7. We have characterized the phenanthrene naltriben as a first stimulatory agonist of the TRPM7 channel. Surprisingly, the effect of naltriben on TRPM7 was found to be unaffected by the physiological levels of cytosolic Mg2+. Here, we demonstrate that mibefradil and NNC 50–0396, two benzimidazole relatives of the TRPM7 inhibitor NS8593, are positive modulators of TRPM7. Using Ca2+ imaging and the patch-clamp technique, we show that mibefradil activates TRPM7-mediated Ca2+ entry and whole-cell currents. The response to mibefradil was fast, reversible, and reproducible. In contrast to naltriben, mibefradil efficiently activates TRPM7 currents only at physiological intracellular Mg2+ concentrations, and its stimulatory effect was fully abrogated by high internal Mg2+ levels. Consequently, a TRPM7 variant harboring a gain-of-function mutation was insensitive to further mibefradil activation. Finally, we observed that the effect of mibefradil was selective for TRPM7 when various TRP channels were tested. Taken together, mibefradil acts as a Mg2+-regulated agonist of the TRPM7 channel and, hence, uncovers a new class of TRPM7 agonists.

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Abbreviations

TRPM7:

Melastatin-related TRP cation channel 7

AITC:

Allyl isothiocyanate

PS:

Pregnenolone sulfate

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Acknowledgements

S.S. was supported by the Förderprogramm für Forschung und Lehre Fellowship (FöFoLe) of the LMU, Munich. V.C., S.Z., and T.G. were supported by the Deutsche Forschungsgemeinschaft, TRR 152. S.Z. was supported by Marie-Curie Fellowship (REA) FP7-PEOPLE-2012-CIG. We thank Joanna Zaißerer and Anna Erbacher for their excellent technical assistance.

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  1. Walther-Straub-Institute of Pharmacology and Toxicology, University of Munich, Goethestrasse 33, 80336, Munich, Germany

    Sebastian Schäfer, Silvia Ferioli, Thomas Hofmann, Susanna Zierler, Thomas Gudermann & Vladimir Chubanov

  2. Comprehensive Pneumology Center Munich (CPC-M), German Center for Lung Research, Munich, Germany

    Thomas Gudermann

  3. DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance, Munich, Germany

    Thomas Gudermann

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  1. Sebastian Schäfer
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  2. Silvia Ferioli
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  3. Thomas Hofmann
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  4. Susanna Zierler
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  5. Thomas Gudermann
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  6. Vladimir Chubanov
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Correspondence to Vladimir Chubanov.

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Schäfer, S., Ferioli, S., Hofmann, T. et al. Mibefradil represents a new class of benzimidazole TRPM7 channel agonists. Pflugers Arch - Eur J Physiol 468, 623–634 (2016). https://doi.org/10.1007/s00424-015-1772-7

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  • DOI: https://doi.org/10.1007/s00424-015-1772-7

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