IQGAP1 promotes chronic pain by regulating the trafficking and sensitization of TRPA1 channels

Abstract

TRPA1 channels have been implicated in mechanical and cold hypersensitivity in chronic pain. But how TRPA1 mediates this process is unclear. Here we show that IQ-motif containing GTPase activating protein 1 (IQGAP1) is responsible using a combination of biochemical, molecular, Ca2+ imaging and behavioural approaches. TRPA1 and IQGAP1 bind to each other and are highly colocalised in sensory DRG neurons in mice. The expression of IQGAP1 but not TRPA1 is increased in chronic inflammatory and neuropathic pain. However, TRPA1 undergoes increased trafficking to the membrane of DRG neurons catalysed by the small GTPase Cdc42 associated with IQGAP1, leading to functional sensitization of the channel. Activation of PKA is also sufficient to evoke TRPA1 trafficking and sensitization. All these responses are, however, completely prevented in the absence of IQGAP1. Concordantly, deletion of IQGAP1 markedly reduces mechanical and cold hypersensitivity in chronic inflammatory and neuropathic pain in mice. IQGAP1 thus promotes chronic pain by coupling the trafficking and signalling machineries to TRPA1 channels.