MrgprX1 mediates neuronal excitability and itch through tetrodotoxin-resistant sodium channels

Tseng, Pang-Yen PhD^a; Zheng, Qin PhD^a; Li, Zhe^a; Dong, Xinzhong PhD^a,b,

Abstract

In this study, we sought to elucidate the molecular mechanism underlying human Mas-related G protein–coupled receptor X1 (MrgprX1)-mediated itch sensation. We found that activation of MrgprX1 by BAM8-22 triggered robust action potential discharges in dorsal root ganglion neurons. This neuronal excitability is not mediated by transient receptor potential (TRP) cation channels, M-type potassium channels, or chloride channels. Instead, activation of MrgprX1 lowers the activation threshold of tetrodotoxin-resistant sodium channels and induces inward sodium currents. These MrgprX1-elicited action potential discharges can be blocked by Pertussis toxin and a Gβγ inhibitor—Gallein. Behavioral results showed that Nav1.9 knockout but not TRPA1 knockout significantly reduced BAM8-22 evoked scratching behavior. Collectively, these data suggest that activation of MrgprX1 triggers itch sensation by increasing the activity of tetrodotoxin-resistant voltage-gated sodium channels.

Keywords: MrgprX1, BAM8-22, Itch, Dorsal root ganglion neurons, TTX-resistant sodium channels, TRPA1, TRPV1