Figure 2. Molecular basis of itch signaling.

There are three classes of pruritogen-elicited itch: TRPV1-dependent, TRPA1-dependent, and non-TRPV1-TRPA1-dependent. Histamine, compound 48/80, and HTMT activate HRs, which activate TRPV1 through both PLCβ3 and PLA2/12-LOX signaling pathways. TRPV1 could also mediate LPA-induced itch, either through direct activation or indirect sensitization of TRPV1 through G protein-coupled LPAR as described for LPA-induced pain responses. TRPA1 is required for itch signlaing induced by CQ, SLIGRL, BAM8–22, ET-1, SP, and bile acids, which bind to their respective receptors MrgprA3, MrgprC11, ETAR, NK1R, and TGR5. G_βγ subunit, PLCβ3, and ERK1/2 participate in signaling downstream from these GPCRs and contribute to the activation of TRPA1. TLR3 is involved in both TRPV1- and TRPA1-dependent itch sensations, whereas TRL7 is specificaly involved in TRPA1-dependent itch. The itch sensation induced by serotonin is unique since neither TRPA1 nor TRPV1 is involved, although PLCβ3 plays important roles in both 5-HTR- and TRPA1-dependent itch. In the spinal cord, presynaptically released GRP and Nppb relay itch signals to the second-order spinal neurons by binding to corresponding heteromeric GRPR/MOR1D and NPRA receptors, respectively, which in turn transmit itch signals to the brain, leading to scratching.