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

Role of SNAREs in Atopic Dermatitis–Related Cytokine Secretion and Skin-Nerve Communication

JianghuiMeng¹²JiafuWang¹JoergBuddenkotte³⁴TimoBuhl⁵MartinSteinhoff²³⁴⁶

The role of soluble N-ethylmaleimide-sensitive factor attachment protein receptors in atopic dermatitis (AD) is unknown. This study identifies the function of soluble N-ethylmaleimide sensitive factor attachment protein receptor in AD-related cytokine secretion and epidermis-nerve communication. Herein, we report that various cytokines were simultaneously upregulated and coreleased in innate immunity–activated primary human keratinocytes. AD-related cytokines thymic stromal lymphopoietin, endothelin-1, and inflammatory tumor necrosis factor-α activated distinct but overlapping sensory neurons. Tumor necrosis factor-α potentiated thymic stromal lymphopoietin–induced Ca²⁺-influx, whereas endothelin-1 caused itch-selective B-type natriuretic peptide release. In primary human keratinocytes, B-type natriuretic peptide upregulated genes promoting dermatological and neuroinflammatory diseases and conditions. VAMP3, SNAP-29, and syntaxin 4 proved important in driving cytokine release from primary human keratinocytes. Depletion of VAMP3 inhibited nearly all the cytokine release including thymic stromal lymphopoietin and endothelin-1. Accordingly, VAMP3 co-occurred with endothelin-1 in the skins of patients with AD. Our study pinpoints the pivotal role of soluble N-ethylmaleimide sensitive factor attachment protein receptors in mediating cytokine secretion related to AD. VAMP3 is identified as a suitable target for developing broad-spectrum anticytokine therapeutics for controlling itch and atopic skin inflammation.