Journal Club 2017. 06. 23.

Involvement of TRPV1 and TDAG8 in Pruriception Associated with Noxious Acidosis

Shing-Hong Lin1, Martin Steinhoff2,3,4, Akihiko Ikoma4, Yen-Ching Chang5, Yuan-Ren Cheng1,6, Ravi Chandra Kopparaju1,7, Satoshi Ishii8, Wei-Hsin Sun5 and Chih-Cheng Chen1,6,7,9

Acid-Sensing Ion Channel and Pruritus

Itch and pain are closely related but are distinct sensations. Intradermal injection of acid generates pain in both rodents and humans; however, few studies have addressed the intriguing question of whether acid (protons) can evoke itch like other algogens by spatial contrast activation of single nociceptors. Here, we report that (i) citric acid (0.2 mol/L) pH-dependently induced a scratching response in mice when applied intradermally to nape or cheek skin, (ii) acidified buffer elevated intracellular calcium levels in dorsal root ganglion pruri- ceptors, and (iii) injection of intradermal citric acid (pH 3.0) into the nape induced a pruritogen-like but not algogen-like c-Fos immunoreactivity pattern in the cervical spinal cord. Using pharmacological and genetic approaches, we identified potential acid-sensing channels/receptors involved in acidic citrate-evoked itch. Results indicate that TRPV1, but neither ASIC3 nor TRPA1, is involved in the acidic citrate-induced scratching response. Furthermore, one of the proton-sensing G-proteinecoupled receptors, TDAG8, was highly (w71%) expressed in Nppbþ dorsal root ganglion pruriceptors. Itch induced by acidic citrate, but not a-methyl-5- hydroxytryptamine, chloroquine, compound 48/80, or bile acid, was markedly decreased in TDAG8e/e mice. In a heterologous expression system, TDAG8 potentiated the acid-induced calcium response by regulating TRPV1. Thus, protons could evoke pruriception by acting on TDAG8 to regulate TRPV1 activation with its mechanism of future therapeutic relevance.

Journal of Investigative Dermatology (2017) 137, 170e178; doi:10.1016/j.jid.2016.07.037