Bidaux, G; Sgobba, M; Lemonnier, L; Borowiec, A-S; Noyer, L; Jovanovic, S; Zholos, AV; Bidaux, G; Sgobba, M; Lemonnier, L; Borowiec, A-S; Noyer, L; Jovanovic, S; Zholos, AV; Haider, S; - view fewer (2015) Functional and Modeling Studies of the Transmembrane Region of the TRPM8 Channel. Biophysical Journal , 109 (9) pp. 1840-1851. 10.1016/j.bpj.2015.09.027.

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Abstract

Members of the transient receptor potential (TRP) ion channel family act as polymodal cellular sensors, which aid in regulating Ca2+ 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.

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