@article {Heller276, author = {Daniel Heller and Jamie R. Doyle and Venkata S. Raman and Martin Beinborn and Krishna Kumar and Alan S. Kopin}, title = {Novel Probes Establish Mas-Related G Protein-Coupled Receptor X1 Variants as Receptors with Loss or Gain of Function}, volume = {356}, number = {2}, pages = {276--283}, year = {2016}, doi = {10.1124/jpet.115.227058}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, 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 γ2-melanocyte-stimulating hormone (γ2-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 ligand-mediated 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.}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/356/2/276}, eprint = {https://jpet.aspetjournals.org/content/356/2/276.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }