Mas-related G protein-coupled receptor member X1 (MRGPRX1)

Mas-related G protein-coupled receptor member X1 (MRGPRX1) is a Class A GPCR predominantly expressed in human primary sensory neurons, especially nociceptors in the dorsal root ganglion[1][2][4]. It is implicated in mediating both pain and itch through G-protein-coupled signaling pathways[1][3][4]. MRGPRX1 is activated by peptide ligands such as BAM8-22 and the pruritogenic protease mucunain, as well as by synthetic modulators like ML382 and compound 16[1][2][4]. Upon activation, MRGPRX1 plays a dual role: it inhibits high-voltage-activated calcium channels to reduce neurotransmitter release and pain transmission, and it also mediates itch by initiating calcium-dependent signaling in sensory neurons[1][2][3][4]. The receptor is structurally characterized by a shallow orthosteric binding pocket, which grants it selectivity and conformational flexibility in ligand recognition[3][4]. Due to its restricted expression and key roles in sensory pathology, MRGPRX1 is considered a promising therapeutic target for the treatment of chronic pain and pruritus[2][3][4]. Notable safety and translational challenges include species differences and the potential for itch induction with some agonists[2][4].

Other names

MRGX1SNSR4MGRG2Sensory neuron-specific G-protein coupled receptor 3Mas-related GPR, member X1

Agonism (activation) of MRGPRX1 to inhibit high-voltage-activated Ca²⁺ channels, thereby suppressing pain signaling; Positive allosteric modulation (increasing sensitivity of MRGPRX1 to agonists); Triggering Gq/Gi protein-mediated signaling cascades in sensory neurons, modulating neurotransmitter release