Direct inhibition of the cold-activated TRPM8 ion channel by Gαq

Activation of the TRPM8 ion channel in sensory nerve endings produces a sensation of pleasant coolness. Here we show that inflammatory mediators such as bradykinin and histamine inhibit TRPM8 in intact sensory nerves, but do not do so through conventional signalling pathways. The G-protein subunit G alpha(q) instead binds to TRPM8 and when activated by a Gq-coupled receptor directly inhibits ion channel activity. Deletion of G alpha(q) largely abolished inhibition of TRPM8, and inhibition was rescued by a G alpha(q) chimaera whose ability to activate downstream signalling pathways was completely ablated. Activated G alpha(q) protein, but not G beta gamma, potently inhibits TRPM8 in excised patches. We conclude that G alpha(q) pre-forms a complex with TRPM8 and inhibits activation of TRPM8, following activation of G-protein-coupled receptors, by a direct action. This signalling mechanism may underlie the abnormal cold sensation caused by inflammation.