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Biophys J. 2015 Nov 3;109(9):1840-51. doi: 10.1016/j.bpj.2015.09.027.

Functional and Modeling Studies of the Transmembrane Region of the TRPM8 Channel.

Author information

1
Inserm, U1003, Laboratoire de Physiologie Cellulaire, Equipe labellisée par la Ligue contre le Cancer, Villeneuve d'Ascq, France; Laboratory of Excellence, Ion Channels Science and Therapeutics, Université de Lille 1, Villeneuve d'Ascq, France; Laboratoire Biophotonique Cellulaire Fonctionnelle. Institut de Recherche Interdisciplinaire, Villeneuve d'Ascq, France.
2
Centre for Cancer Research and Cell Biology, Queen's University of Belfast, Belfast, United Kingdom.
3
Inserm, U1003, Laboratoire de Physiologie Cellulaire, Equipe labellisée par la Ligue contre le Cancer, Villeneuve d'Ascq, France; Laboratory of Excellence, Ion Channels Science and Therapeutics, Université de Lille 1, Villeneuve d'Ascq, France.
4
UCL School of Pharmacy, London, United Kingdom.
5
Department of Biophysics, Educational and Scientific Centre, "Institute of Biology" Taras Shevchenko, Kiev National University, Kiev, Ukraine. Electronic address: a.zholos@althenia.org.
6
UCL School of Pharmacy, London, United Kingdom. Electronic address: shozeb.haider@ucl.ac.uk.

Abstract

Members of the transient receptor potential (TRP) ion channel family act as polymodal cellular sensors, which aid in regulating Ca(2+) homeostasis. Within the TRP family, TRPM8 is the cold receptor that forms a nonselective homotetrameric cation channel. In the absence of TRPM8 crystal structure, little is known about the relationship between structure and function. Inferences of TRPM8 structure have come from mutagenesis experiments coupled to electrophysiology, mainly regarding the fourth transmembrane helix (S4), which constitutes a moderate voltage-sensing domain, and about cold sensor and phosphatidylinositol 4,5-bisphosphate binding sites, which are both located in the C-terminus of TRPM8. In this study, we use a combination of molecular modeling and experimental techniques to examine the structure of the TRPM8 transmembrane and pore helix region including the conducting conformation of the selectivity filter. The model is consistent with a large amount of functional data and was further tested by mutagenesis. We present structural insight into the role of residues involved in intra- and intersubunit interactions and their link with the channel activity, sensitivity to icilin, menthol and cold, and impact on channel oligomerization.

PMID:
26536261
PMCID:
PMC4643257
DOI:
10.1016/j.bpj.2015.09.027
[Indexed for MEDLINE]
Free PMC Article

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