The MRGPRX family of receptors (MRGPRX1-4) is a recently described family of Mas-related G protein-coupled receptors (MRGPRs). Among these, MRGPRX2 and MRGPRX4 stand out as the key physiological and pathological mediators of itch, neurogenic inflammation, atopic dermatitis, ulcerative colitis, preference for menthol cigarettes, pain and several mast-cell-mediated responses. MRGPRX2 pair to both Gi and Gq in mast cells. 

A recent study illustrates agonist-stabilized structures of MRGPRX2 coupled to Gi1 and Gq in ternary complex with the endogenous peptide cortistatin-14 and with a synthetic agonist probe, respectively. It further describes the development of potent antagonist probes for MRGPRX2. 

The study also illustrates a specific MRGPRX4 agonist and the structure of this agonist in a complex with MRGPRX4 and Gq. 

A good understanding of these relatively potent agonists and antagonists will provide chemical probes to investigate the biology of these receptors and structures. This will further accelerate the search for specific medications targeting MRGPRs and ultimately the therapeutics for pain, itch and mast-cell-mediated hypersensitivity.

Source: Cao C, Kang HJ, Singh I, et al. Structure, function and pharmacology of human itch GPCRs. Nature. 2021;600(7887):170-5.