Molecular cloning of an orphan G-protein-coupled receptor that constitutively activates adenylate cyclase

Eggerickx, Dominique; Denef, Jean François; Labbé, Olivier; Hayashi, Yoshitaka; Refetoff, Samuel; Vassart, Gilbert; Parmentier, Marc; Libert, Frédérick

doi:10.1042/bj3090837

Cited by 118 publications

(125 citation statements)

References 36 publications

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“…Thus, overexpression of GPRs should increase the concentration of the R* state and thereby lead to constitutive signaling (34,35). Recent studies from in vitro transient transfection studies with orphan receptors (48) and in vivo transgenic studies with the adrenergic receptors (34,35) support this model. Since edg-1 is an inducible receptor, regulation of signaling pathways by modulation of receptor numbers may be of physiological significance.…”

Section: Fig 1 Pertussis Toxin Substrates Associate With Gst-i 3 Inmentioning

confidence: 97%

The Inducible G Protein-coupled Receptor edg-1 Signals via the Gi/Mitogen-activated Protein Kinase Pathway

Lee

Evans

Hla

1996

Journal of Biological Chemistry

163

123

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The edg-1 gene encodes an inducible G protein-coupled receptor (GPR) homologue that is induced during the in vitro differentiation of human endothelial cells. The aim of this study was to investigate the G proteincoupling and -signaling properties of the edg-1 polypeptide. The third cytosolic loop (i 3 ) of edg-1 associates with G i␣ and G o␣ polypeptides in a guanosine 5-O-(thiotriphosphate)-sensitive manner. Immunoprecipitation of the edg-1 polypeptide in transfected cells results in the co-precipitation of G i␣1 and G i␣3 polypeptides. These data strongly suggest that edg-1 is capable of coupling to the G i pathway. Overexpression of the edg-1 GPR in human embryonic kidney 293 cells results in the sustained activation of the MAP kinase activity that is blocked by pertussis toxin treatment. Moreover, NIH3T3 cells permanently transfected with edg-1 exhibit enhanced MAP kinase and phospholipase A 2 activities. These data suggest that the G i /mitogen-activated protein kinase pathway is a major signaling pathway regulated by the orphan receptor edg-1.

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Section: Fig 1 Pertussis Toxin Substrates Associate With Gst-i 3 Inmentioning

confidence: 97%

The Inducible G Protein-coupled Receptor edg-1 Signals via the Gi/Mitogen-activated Protein Kinase Pathway

Lee

Evans

Hla

1996

Journal of Biological Chemistry

163

123

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“…At some point, a threshold is reached and the active conformation can be detected due to constitutive activation of signaling pathways, which are normally activated after agonist stimulation. The coupling ability of several receptors, including "orphan" receptors, has been characterized by this overexpression in the absence of an agonist (Eggerickx et al, 1995;Schulz and Schöneberg, 2003;Preuss et al, 2007). We transfected cDNA-encoding full-length human GPR126 into COS-7 cells and measured cAMP accumulation using a second messenger assay.…”

Section: Gpr126 Elevates Camp and Couples To Heterotrimeric G-proteinsmentioning

confidence: 99%

Gpr126 Functions in Schwann Cells to Control Differentiation and Myelination via G-Protein Activation

Mogha¹,

Benesh²,

et al. 2013

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The myelin sheath surrounding axons ensures that nerve impulses travel quickly and efficiently, allowing for the proper function of the vertebrate nervous system. We previously showed that the adhesion G-protein-coupled receptor (aGPCR) Gpr126 is essential for peripheral nervous system myelination, although the molecular mechanisms by which Gpr126 functions were incompletely understood. aGPCRs are a significantly understudied protein class, and it was unknown whether Gpr126 couples to G-proteins. Here, we analyze Dhh Cre ; Gpr126 fl/fl conditional mutants, and show that Gpr126 functions in Schwann cells (SCs) for radial sorting of axons and myelination. Furthermore, we demonstrate that elevation of cAMP levels or protein kinase A activation suppresses myelin defects in Gpr126 mouse mutants and that cAMP levels are reduced in conditional Gpr126 mutant peripheral nerve. Finally, we show that GPR126 directly increases cAMP by coupling to heterotrimeric G-proteins. Together, these data support a model in which Gpr126 functions in SCs for proper development and myelination and provide evidence that these functions are mediated via G-protein-signaling pathways.

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“…Thus, the coupling abilities of several receptors, including "orphan" receptors, have been characterized by overexpression in the absence of an agonist (31)(32)(33). For example, the wild-type adenylate cyclase constitutive activator (ACCA), an orphan GPCR, stimulates the G s protein/adenylyl cyclase system to some extent when expressed in COS-7 cells (31). Following this strategy, the human and mouse GPR133 were transiently expressed in HEK293 cells and tested in AP1-, nuclear factor of activated T-cells (NFAT)-, serum responsive element (SRE)-, and CRE-SEAP reporter gene assays.…”

Section: Gpr133 Displays Increased Basal Activity In the G S Protein/mentioning

confidence: 99%

Cell Adhesion Receptor GPR133 Couples to Gs Protein

Bohnekamp

Schöneberg

2011

Journal of Biological Chemistry

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Adhesion G protein-coupled receptors (GPCR), with their very large and complex N termini, are thought to participate in cell-cell and cell-matrix interactions and appear to be highly relevant in several developmental processes. Their intracellular signaling is still poorly understood. Here we demonstrate that GPR133, a member of the adhesion GPCR subfamily, activates the G s protein/adenylyl cyclase pathway. The presence of the N terminus and the cleavage at the GPCR proteolysis site are not required for G protein signaling. G s protein coupling was verified by G␣ s knockdown with siRNA, overexpression of G␣ s , coexpression of the chimeric Gq s4 protein that routes GPR133 activity to the phospholipase C/inositol phosphate pathway, and missense mutation within the transmembrane domain that abolished receptor activity without changing cell surface expression. It is likely that not only GPR133 but also other adhesion GPCR signal via classical receptor/G protein-interaction.Adhesion receptors comprise the second largest subfamily of putatively G protein-coupled receptors (GPCR) 2 with more than 30 members in vertebrates (1, 2). Adhesion GPCR are characterized by long extracellular N termini, which are composed of multiple functional domains, a seven-transmembrane spanning (7TM) domain, and a cytoplasmic tail. Adhesion GPCR are believed to play a role in immune functions (3, 4), angiogenesis (5), cell polarity (6, 7), and development (8, 9). Mutations in some members of the protein family were identified as the cause of inherited developmental defects in humans such as Usher syndrome (VLGR1) (10) and bilateral frontoparietal polymicrogyria (GPR56) (11). Although there is consensus on the fact that this receptor class mediates essential cellcell and cell-matrix interactions (1, 12), the molecular mechanism of intracellular signal transduction of adhesion GPCR remains obscure.There are only a few studies on intracellular signaling mechanisms of adhesion GPCR. Latrophilin 1, the prototype of adhesion GPCR, induces intracellular Ca 2ϩ signaling upon interaction with the exogenous ligand ␣-latrotoxin (13, 14). GPR56 appears to activate the G 12/13 protein/Rho pathway after stimulation with an antibody against the ectodomain (15). BAI1 recognizes phosphatidylserine and can directly recruit a Racguanine nucleotide exchange factor (Rac-GEF) complex to mediate the uptake of apoptotic cells (16). The cytoplasmic domain of BAI2 interacts with GA-binding protein ␥, and GAbinding protein-␣/␥ or GA-binding protein-␣/␤ work as transcriptional repressors of VEGF (17). However, clear evidence of intracellular signaling for most adhesion GPCR via G proteins is still missing (12).Genetic variations in the GPR133 gene, also a member of the adhesion GPCR family, were associated with adult height (18) and the RR interval duration in electrocardiograms (19). GPR133 is expressed in CNS (20) and other tissues; its endogenous agonists and the signal transduction are unknown. Here we demonstrate that GPR133 is coupled to the G s protein/adeny...

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Molecular cloning of an orphan G-protein-coupled receptor that constitutively activates adenylate cyclase

Cited by 118 publications

References 36 publications

The Inducible G Protein-coupled Receptor edg-1 Signals via the Gi/Mitogen-activated Protein Kinase Pathway

The Inducible G Protein-coupled Receptor edg-1 Signals via the Gi/Mitogen-activated Protein Kinase Pathway

Gpr126 Functions in Schwann Cells to Control Differentiation and Myelination via G-Protein Activation

Cell Adhesion Receptor GPR133 Couples to Gs Protein

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