Characterization of the Mas-related gene family: structural and functional conservation of human and rhesus MrgX receptors.
Recently, a large family of G-protein-coupled receptors called Mas-related genes (Mrgs), which is selectively expressed in small-diameter sensory neurons of dorsal root ganglia, was described. A subgroup of human Mrg receptors (MrgX1-X4) is not found in rodents and this has hampered efforts to define the physiological roles of these receptors. MrgX receptors were cloned from rhesus monkey and functionally characterized alongside their human orthologs. Most of the human and rhesus MrgX receptors displayed high constitutive activity in a cellular proliferation assay. Proliferative responses mediated by human or rhesus MrgX1, or rhesus MrgX2 were partially blocked by pertussis toxin (PTX). Proliferative responses mediated by rhesus MrgX3 and both human and rhesus MrgX4 were PTX insensitive. These results indicate that human and rhesus MrgX1 and MrgX2 receptors activate both Gq- and Gi-regulated pathways, while MrgX3 and MrgX4 receptors primarily stimulate Gq-regulated pathways. Peptides known to activate human MrgX1 and MrgX2 receptors activated the corresponding rhesus receptors in cellular proliferation assays, Ca(2+)-mobilization assays, and GTP-gammaS-binding assays. Cortistatin-14 was selective for human and rhesus MrgX2 receptors over human and rhesus MrgX1 receptors. BAM22 and related peptides strongly activated human MrgX1 receptors, but weakly activated rhesus MrgX1, human MrgX2, and rhesus MrgX2 receptors. These data suggest that the rhesus monkey may be a suitable animal model for exploring the physiological roles of the MrgX receptors.
Burstein
Ethan S
ES
Acadia Pharmaceuticals Inc., 3911 Sorrento Valley Boulevard, San Diego, CA 92121, U.S.A. eburstein@acadia-pharm.com
Ott
Thomas R
TR
Feddock
Michele
M
Ma
Jian-Nong
JN
Fuhs
Steve
S
Wong
Steven
S
Schiffer
Hans H
HH
Brann
Mark R
MR
Nash
Norman R
NR
D000595:Amino Acid Sequence; D000818:Animals; D017124:Conserved Sequence; D006801:Humans; D008253:Macaca mulatta / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D005810:Multigene Family; D041681:NIH 3T3 Cells; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000737:chemistry* / Q000235:genetics* / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000235:genetics* / Q000502:physiology; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics* / Q000502:physiology
C491669:MORF4L2 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D014157:Transcription Factors