Direct inhibition of the cold-activated TRPM8 ion channel by Galphaq. Nat Cell Biol 14: 851–858

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 Gaq instead binds to TRPM8 and when activated by a Gq-coupled receptor directly inhibits ion channel activity. Deletion of Gaq largely abolished inhibition of TRPM8, and inhibition was rescued by a Gaq chimera whose ability to activate downstream signalling pathways was completely ablated. Activated Gaq protein, but not Gβγ, potently inhibits TRPM8 in excised patches. We conclude that Gaq 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. Keywords pain; TRPM8; G proteins; GPCR; inflammatory mediators; sensory transduction The temperature sensitive ion channels TRPV1 and TRPM8 play an essential role in the pain pathway. Inflammatory mediators released during tissue injury or inflammatio