Trafficking and potentiation of Nav1.7 and Nav1.8 channels are mediated by IQGAP1

The voltage-gated Nav1.7 and Nav1.8 channels are essential to transmit acute and chronic pain. Increased trafficking of Nav1.7 and Na1.8 channels to the membrane of sensory neurons is a critical mechanism of pain sensitization. However the mechanisms responsible for the trafficking of Nav1.7 and Nav1.8 channels remain unclear. We found that acute nociception and heat and mechanical hyperalgesia induced by the activation of nociceptive TRPV1 and TRPA1 channels were markedly reduced in IQGAP1-deficient mice. The basal excitability of sensory neurons was also significantly reduced in the absence of IQGAP1. Correspondingly the deletion of IQGAP1 reduced the basal membrane expression of Nav1.7 and moreover prevented enhanced trafficking and sensitization of Nav1.7 and Nav1.8 channels in sensory neurons induced by inflammatory mediators (IM). Heat hyperalgesia, mechanical and cold allodynia in nerve injury induced neuropathic pain mediated by Nav1.7 and Nav1.8 channels, respectively, were also prevented in IQGAP1-deficient mice. IQGAP1 thus governs the trafficking and potentiation of both Nav1.7 and Nav1.8 channels and could be exploited for therapeutic interventions for the treatment of acute and chronic pain. KEY POINTS: The enhanced activities of voltage-gated Na⁺ channels Nav1.7 and Nav1.8 in sensory neurons underpin acute and chronic pain. Enhanced activities of Nav1.7 and Nav1.8 channels are due to an increased number of these channels inserted into the plasma membrane of sensory neurons. This study reveals that the scaffold protein IQ motif containing GTPase activating protein 1 (IQGAP1) mediates forward membrane trafficking of Nav1.7/Nav1.8 channels and resultant functional enhancement of these channels. Enhanced pain caused by inflammatory mediators and nerve injury is reduced in the absence of IQGAP1. Our findings elucidate the trafficking mechanisms of Nav1.7 and Nav1.8 channels and suggest IQGPA1 as an alternative treatment option for acute and chronic pain.