Direct inhibition of the cold-activated TRPM8 ion channel by Gα(q)

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 via conventional signalling pathways. The G-protein subunit Ga(q) instead binds to TRPM8 and when activated by a Gq-coupled receptor directly inhibits ion channel activity. Deletion of Ga(q) largely abolished inhibition of TRPM8, and inhibition was rescued by a Ga(q) chimera whose ability to activate downstream signalling pathways was completely ablated. Activated Ga(q) protein, but not Gβγ, potently inhibits TRPM8 in excised patches. We conclude that Ga(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.