Abstract
The human transient receptor potential melastatin 8 (hTRPM8) ion channel is a primary sensor of environmental cold temperature. hTRPM8 is gated in a polymodal manner by voltage, lipids, modulatory proteins, and chemical ligands, including menthol and icilin. TRPM8 is also involved in human health and disease, playing roles in pathophysiologies including cancer, pain, obesity, and diabetes. A better understanding of the molecular mechanism of channel activation may prove useful in unlocking the TRPM8 therapeutic potential. Here, we analyze the sensing domain (transmembrane helices S1-S4) as a function of temperature and menthol with circular dichroism (CD), and compare it with the S1-S6 transmembrane domain and full-length hTRPM8. Additionally, planar bilayer electrophysiology measurements of the S1-S6 transmembrane domain in presence of PIP2 and menthol indicate similar thermosensitivity when compared to the full-length protein. The temperature and menthol dependent conformational change of the sensing domain was further investigated by solution nuclear magnetic resonance (NMR) spectroscopy. Narrowing down from the full-length protein to the sensing domain, our data suggest that the S1-S4 sensing domain is important for both TRPM8 temperature- and menthol-dependent gating of the ion channel.
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