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Published November 12, 2002 | Published
Journal Article Open

Orphan G protein-coupled receptors MrgA1 and MrgC11 are distinctively activated by RF-amide-related peptides through the G{alpha}q/11 pathway


MrgA1 and MrgC11 belong to a recently identified family of orphan G-protein coupled receptors, called mrgs (mas-related genes). They are only expressed in a specific subset of sensory neurons that are known to detect painful stimuli. However, the precise physiological function of Mrg receptors and their underlying mechanisms of signal transduction are not known. We therefore have screened a series of neuropeptides against human embryonic kidney (HEK) 293 cells that stably express either MrgA1 or MrgC11 to identify ligands and/or agonists. MrgA1- or MrgC11-specific agonists stimulated dose-dependent increases in intracellular free Ca2+ in a pertussis toxin-insensitive manner, but failed to alter basal or forskolin-stimulated levels of intracellular cAMP. Furthermore, studies using embryonic fibroblasts derived from various G{alpha} protein knockout mice demonstrated that both the MrgA1 and MrgC11 receptors are coupled to the G{alpha}q/11 signaling pathway. Screening of neuropeptides identified surrogate agonists, most of these peptides included a common C-terminal -RF(Y)G or -RF(Y) amide motif. Structure-function studies suggest that endogenous ligands of Mrg receptors are likely to be RF(Y)G and/or RF(Y) amide-related peptides and that postprocessing of these peptides may serve to determine Mrg receptor-ligand specificity. The differences in ligand specificity also suggest functional diversity amongst the Mrg receptors.

Additional Information

© 2002 by the National Academy of Sciences Contributed by Melvin I. Simon and approved September 18, 2002 Published online before print October 23, 2002, 10.1073/pnas.192565799 We thank our laboratory members for helpful discussion and cooperation, and Henry Lester and his laboratory members for help with calcium imaging. S.H., J.K., and M.I.S. are supported by National Institute for General Medical Science Grant GM-34236. X.D. is a postdoctoral fellow of the American Cancer Society, and M.J.Z. is supported by the Cancer Research Fund of the Damon Runyon–Walter Winchell Foundation Fellowship (DRG-1581).

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