Referenced in: none

Automatically associated channels: TRP , TRPM , TRPM8

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

Authors: Gabriel Bidaux, Miriam Sgobba, Loic Lemonnier, Anne-Sophie Borowiec, Lucile Noyer, Srdan Jovanovic, Alexander V Zholos, Shozeb Haider

Journal, date & volume: Biophys. J., 2015 Nov 3 , 109, 1840-51

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/26536261

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.