Novel Probes Establish Mas-Related G Protein-Coupled Receptor X1 Variants as Receptors with Loss or Gain of Function

Abstract

The Mas-related G protein-coupled receptor X1 (MrgprX1) is a human seven transmembrane-domain protein with a putative role in nociception and pruritus. This receptor is expressed in dorsal root ganglion neurons and is activated by a variety of endogenous peptides, including bovine adrenal medulla peptide (BAM) and g2-melanocyte-stimulating hormone (g2-MSH). In the present work, we study how naturally occurring missense mutations alter the activity of MrgprX1. To characterize selected receptor variants, we initially used the endogenous peptide ligand BAM8-22. In addition, we generated and characterized a panel of novel recombinant and synthetic peptide ligands. Our studies identified a mutation in the second intracellular loop of MrgprX1, R131S, that causes a decrease in both ligandmediated and constitutive signaling. Another mutation in this region, H133R, results in a gain of function phenotype reflected by an increase in ligand-mediated signaling. Using epitope-tagged variants, we determined that the alterations in basal and ligand-mediated signaling were not explained by changes in receptor expression levels. Our results demonstrate that naturally occurring mutations can alter the pharmacology of MrgprX1. This study provides a theoretical basis for exploring whether MrgprX1 variability underlies differences in somatosensation within human populations.

Neurotransmitter and neuropeptide regulation of mast cell function: a systematic review

“…SP might signal via MRGPRX2 to activate human cultured MCs, resulting in a type of MC degranulation characterized by the rapid release of small spherical granules [69]. On the other hand, naturally occurring missense MRGPRX2 variants display a loss of function phenotype for MC degranulation in response to SP, indicating that individuals expressing certain naturally occurring MrgprX2 missense variants might have a degree of protection against neurogenic inflammation [70,71]. In vitro SP activation of human MCs led to the release of multiple proinflammatory cytokines and chemokines via MRGPRX2, independent of NK-1R, and MRGPRX2 mediated neurogenic inflammation and pain in an incision mouse model [72].…”