title: 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 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.
authors.affiliation: Molecular Pharmacology Research Center, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts (D.H., J.R.D., M.B., A.S.K.); Department of Chemistry, Tufts University, Medford, Massachusetts (V.S.R., K.K.).
authors.forename: Daniel
authors.identifier: http://orcid.org/0000-0003-0549-0646
authors.initials: D
authors.lastname: Heller
authors.affiliation: Molecular Pharmacology Research Center, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts (D.H., J.R.D., M.B., A.S.K.); Department of Chemistry, Tufts University, Medford, Massachusetts (V.S.R., K.K.).
authors.forename: Jamie R
authors.initials: JR
authors.lastname: Doyle
authors.affiliation: Molecular Pharmacology Research Center, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts (D.H., J.R.D., M.B., A.S.K.); Department of Chemistry, Tufts University, Medford, Massachusetts (V.S.R., K.K.).
authors.forename: Venkata S
authors.initials: VS
authors.lastname: Raman
authors.affiliation: Molecular Pharmacology Research Center, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts (D.H., J.R.D., M.B., A.S.K.); Department of Chemistry, Tufts University, Medford, Massachusetts (V.S.R., K.K.).
authors.forename: Martin
authors.initials: M
authors.lastname: Beinborn
authors.affiliation: Molecular Pharmacology Research Center, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts (D.H., J.R.D., M.B., A.S.K.); Department of Chemistry, Tufts University, Medford, Massachusetts (V.S.R., K.K.).
authors.forename: Krishna
authors.initials: K
authors.lastname: Kumar
authors.affiliation: Molecular Pharmacology Research Center, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts (D.H., J.R.D., M.B., A.S.K.); Department of Chemistry, Tufts University, Medford, Massachusetts (V.S.R., K.K.) akopin@tuftsmedicalcenter.org.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Kopin
mesh_terms: D014644:Genetic Variation / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D020125:Mutation, Missense / Q000235:genetics*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism
chemical_list: D008024:Ligands; D043562:Receptors, G-Protein-Coupled; C510803:mas-related gene-X1 receptor, human