FGF13 enhances the function of TRPV1 by stabilizing microtubules and regulates acute and chronic itch

• Published in: The FASEB journal 2024-05, Vol.38 (10), p.e23661-n/a
• Main Authors: Dong, Zi‐shan, Zhang, Xue‐rou, Xue, Da‐zhong, Liu, Jia‐hui, Yi, Fan, Zhang, Yi‐yi, Xian, Fu‐yu, Qiao, Ruo‐yang, Liu, Bo‐yi, Zhang, Hai‐lin, Wang, Chuan
• Format: Article
• Language: English
• Subjects: Animals; dorsal root ganglion neurons; FGF13; Fibroblast Growth Factors - genetics; Fibroblast Growth Factors - metabolism; Ganglia, Spinal - metabolism; HEK293 Cells; Humans; itch; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; microtubule; Microtubules - metabolism; Pruritus - genetics; Pruritus - metabolism; TRPA1; TRPA1 Cation Channel - genetics; TRPA1 Cation Channel - metabolism; TRPV Cation Channels - genetics; TRPV Cation Channels - metabolism; TRPV1
• ISSN: 0892-6638; 1530-6860; 1530-6860
• DOI: 10.1096/fj.202400096R

Itching is an aversive somatosensation that triggers the desire to scratch. Transient receptor potential (TRP) channel proteins are key players in acute and chronic itch. However, whether the modulatory effect of fibroblast growth factor 13 (FGF13) on acute and chronic itch is associated with TRP channel proteins is unclear. Here, we demonstrated that conditional knockout of Fgf13 in dorsal root ganglion neurons induced significant impairment in scratching behaviors in response to acute histamine‐dependent and chronic dry skin itch models. Furthermore, FGF13 selectively regulated the function of the TRPV1, but not the TRPA1 channel on Ca2+ imaging and electrophysiological recordings, as demonstrated by a significant reduction in neuronal excitability and current density induced by TRPV1 channel activation, whereas TRPA1 channel activation had no effect. Changes in channel currents were also verified in HEK cell lines. Subsequently, we observed that selective modulation of TRPV1 by FGF13 required its microtubule‐stabilizing effect. Furthermore, in FGF13 knockout mice, only the overexpression of FGF13 with a tubulin‐binding domain could rescue TRP channel function and the impaired itch behavior. Our findings reveal a novel mechanism by which FGF13 is involved in TRPV1‐dependent itch transduction and provide valuable clues for alleviating pathological itch syndrome. A graphical diagram of the mechanism by which FGF13 modulates itch. In Loxp mice, FGF13 binds to microtubules and increases microtubules stability, which maintains the normal function of TRPV1 and promotes the development of acute and chronic pruritus. After FGF13 conditional knockout, the stability of microtubule was reduced and TRPV1 channel function was damaged, and acute and chronic pruritus behavior was alleviated.