Differential inhibition of the TRPM8 ion channel by Gαq and Gα11

Cold temperature is encoded by the cold-sensitive ion channel TRPM8 in somatosensory neurons. It has been unclear how TRPM8 is modulated so that it can mediate distinct type of cold signaling. We have recently reported that activated Gα_q directly inhibits TRPM8 after activation of Gq-coupled receptors. Here, we further show that activation of the muscarinic receptor M1R, which is known to inhibit M currents through PLCβ-mediated hydrolysis of PtdIns(4,5)P₂, similarly inhibited TRPM8 potently, but inhibition was not prevented by the PLC inhibitor U73122. Interestingly, although Gα_q and Gα₁₁ are indistinguishable in activating PLCβ and hydrolysing PtdIns(4,5)P₂, activated Gα₁₁ inhibited TRPM8 to a lesser extent than activated Gα_q. The differential TRPM8 inhibition is determined by a specific residue E197 on Gα₁₁, because mutating this residue to the corresponding residue on Gα_q restored TRPM8 inhibition to a similar degree as mediated by Gα_q. These results reinforce the idea that activated Gα_q directly inhibits TRPM8 independently from PtdIns(4,5)P₂ hydrolysis-mediated inhibition of TRPM8.