Contribution of transmembrane channel-like (TMC) proteins 3, 5 and 7 to pain and itch processing.

Abstract

The family of transmembrane channel-like (TMC) genes encodes at least 8 transmembrane proteins that are conserved across species. However, except for TMC1 and TMC2, their functional role is largely unexplored. To determine the extent to which each of these subtypes contributes to pain and itch processing, here we investigated the anatomical and behavioral consequences of deleting 3 members of the TMC family in mice. We report that selective ablation of the Tmc3, Tmc5 or Tmc7 genes leads to different, and in some cases, opposite behavioral effects. Specifically, mice deficient for Tmc3 or Tmc5 exhibited reduced nociception across pain modalities (mechanical, heat and cold), whereas Tmc7 deletion increased nociception. With respect to itch, pruritogen-evoked scratching was increased in Tmc5 and Tmc7, but not Tmc3 knock-out mice. Interestingly, although the expression of Tmc3, Tmc5 and Tmc7 was upregulated in sensory neurons of mice in the spared nerve injury (SNI) model of neuropathic pain, ablating these genes did not prevent the mechanical allodynia that develops following SNI. Responses also did not change in an inflammatory pain setting. Taken together, we conclude that TMC3, TMC5 and TMC7 channels differentially contribute to pain and itch processing. The mechanisms underlying these differences remain to be determined. PERSPECTIVE: Tmc3 and Tmc5 knock-out mice exhibit decreased nociception; Tmc7 knock-out mice exhibit increased nociception; Tmc5 and Tmc7, but not Tmc3, contribute to itch processing.