Browsing School of Dentistry by Author "Chung, Man-Kyo"
The Contribution of TRPV1 S801 Phosphorylation to Nociception and Inflammatory Pain in VivoJoseph, John; Chung, Man-Kyo (2020)Transient receptor potential vanilloid subtype 1 (TRPV1) is a nonselective cation permeable channel activated by painful stimuli, such as capsaicin and noxious heat, and enriched in many primary afferent neurons of the pain pathway. During inflammation, chemical mediators activate protein kinases (such as PKC) that phosphorylate TRPV1 and thereby enhance its function, which results in nociceptor sensitization. And this can result in a lower threshold for pain. However, the causal relationships between TRPV1 phosphorylation and pathological pain remain unexplored. To directly investigate the roles of one specific TRPV1 phosphorylation event in vivo, we genetically altered a major PKC phosphorylation site, mouse TRPV1 S801, to alanine. The TRPV1 expression pattern in sensory neurons of S801A knock-in (KI) mice was comparable to that in wildtype (WT) controls. In sensory neurons from KI mice, following the activation of PKC, the usual increase of capsaicin-induced currents was substantially impaired. Thermal hyperalgesia induced by PMA or burn injury in KI was identical to WT. Thermal hyperalgesia was only marginally attenuated in KI mice duirng inflammation. In contrast, PMA-evoked nocifensive responses and hyperalgesia to capsaicin were significantly attenuated in the hindpaws of KI mice. Ongoing pain from inflamed masseter muscle was also reduced in KI mice, and the pain was further inhibited by the TRPV1 antagonist AMG9810. These results suggest that PKC-mediated phosphorylation of TRPV1 S801 contributes to inflammation-mediated sensitization of TRPV1 to ligand, but not heat, in vivo. Further, this suggests that interference with TRPV1 S801 phosphorylation might represent a potential way to reduce inflammatory pain in the clinic, yet spare basal sensitivity and produce fewer side effects than with a more general TRPV1 inhibition.