Dual action of neurokinin-1 antagonists on Mas-related GPCRs

A single amino acid in MRGPRX2 necessary for binding and activation by pruritogens

“…To test this hypothesis, we used molecular modeling and site-specific mutagenesis to evaluate the interaction of Mrgprs with these ligands in the context of itch. The data indeed reveal that a specific amino acid in MRGPRX2 and the corresponding ones in the homologous mouse receptors MrgprA1 2,3 and MrgprB2 1 are critical for binding and activation by pruritogens. Furthermore, predictive alterations in BAM 8–22 rescued activity on mutated MRGPRX2.…”

“…1,2 Ligands of the human receptor MRGPRX2 that induce itch include substance P (SP), 2,3 which is increased in atopic skin, bovine adrenal medulla (BAM) peptide, and compound 48/80. 1,2 In contrast, LL-37, an antimicrobial peptide and MRGPRX2 ligand implicated in inflammation, is not known to mediate itch and is decreased in atopic skin. 5,6 We hypothesized that distinct receptor amino acids would be associated with Mrgpr activation by pruritogens versus non-pruritogens.…”

Implications of MRGPRX2 in human and experimental cardiometabolic diseases

“…First, the anti-inflammatory effects of NK-1R antagonists in animal models of cardiac disease are not predictive of their efficacy in humans. Second, MRGPRX2, a receptor implicated in itch 4, 8 but, to our knowledge, not in any cardiac disease, is mediating substance P-induced mast cell degranulation and might be contributing to pathogenesis of various cardiometabolic disorders. Third, given the pivotal role of MRGPRX2 in itch 4, 5, 8 , allergy 3 , and inflammation 3, 4 , this receptor might be one of the links between cardiovascular events and allergies.…”

“…We have identified that antagonists of NK-1R have an off-target inhibitory effect on mouse Mrgprb2, but not human MRGPRX2 (REF. 4). This finding is critical, because almost all studies in the field of cardiometabolic disease, including the ones cited by Guo-Ping et al , have used NK-1R antagonists and not Nk1r−/− ( Tacr1−/− ) mice to demonstrate that substance P activation of cardiac and coronary mast cells is NK-1R-dependent.…”

“…Third, given the pivotal role of MRGPRX2 in itch 4, 5, 8 , allergy 3 , and inflammation 3, 4 , this receptor might be one of the links between cardiovascular events and allergies. Finally as Shi et al concluded, we believe that novel mast cell stabilizers might have implications for treating various cardiometabolic diseases, and MRGPRX2 antagonists 4 are interesting novel candidates.…”