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

1995 ◽  
Vol 309 (3) ◽  
pp. 837-843 ◽  
Author(s):  
D Eggerickx ◽  
J F Denef ◽  
O Labbe ◽  
Y Hayashi ◽  
S Refetoff ◽  
...  
Keyword(s):  
Adenylate Cyclase ◽  
G Protein ◽  
Rnase Protection Assay ◽  
Biological Significance ◽  
Orphan Receptor ◽  
Constitutive Activity ◽  
G Protein Coupled Receptor ◽  
Rnase Protection ◽  
G Protein Coupled ◽  
Stimulation Of

A human gene encoding an orphan G-protein-coupled receptor named ACCA (adenylate cyclase constitutive activator) was isolated from a genomic library using as a probe a DNA fragment obtained by low-stringency PCR. Human ACCA (hACCA) is a protein of 330 amino acids that exhibits all the structural hallmarks of the main family of G-protein-coupled receptors. Expression of hACCA resulted in a dramatic stimulation of adenylate cyclase, similar in amplitude to that obtained with other Gs-coupled receptors fully activated by their respective ligands. This stimulation was obtained in a large variety of stable cell lines derived from various organs, and originating from different mammalian species. hACCA was found to be the human homologue of a recently reported mouse orphan receptor (GPCR21). The mouse ACCA (mACCA) was therefore recloned by PCR, and expression of mACCA in Cos-7 cells demonstrated that the mouse receptor behaved similarly as a constitutive activator of adenylate cyclase. It is not known presently whether the stimulation of adenylate cyclase is the result of a true constitutive activity of the receptor or, alternatively, is the consequence of a permanent stimulation by a ubiquitous ligand. The tissue distribution of mACCA was determined by RNase protection assay. Abundant transcripts were found in the brain, whereas lower amounts were detected in testis, ovary and eye. Various hypotheses concerning the constitutive activity of ACCA and their potential biological significance are discussed.

Involvement of the constitutive activity of the GHS-R1a (ghrelin G-protein coupled receptor) in the tumorigenesis of somatotroph adenomas

2013 ◽  
Author(s):  
Yves Louis Mear ◽  
Xavier Come Donato ◽  
Marie Pierre Blanchard ◽  
Celine Defilles ◽  
Christophe Lisbonis ◽  
...  
Keyword(s):  
G Protein ◽  
Constitutive Activity ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

scholarly journals Cutting Edge: Identification of the Orphan Receptor G-Protein-Coupled Receptor 2 as CCR10, a Specific Receptor for the Chemokine ESkine

2000 ◽  
Vol 164 (7) ◽  
pp. 3460-3464 ◽  
Author(s):  
David I. Jarmin ◽  
Miriam Rits ◽  
Dalena Bota ◽  
Norma P. Gerard ◽  
Gerard J. Graham ◽  
...  
Keyword(s):  
G Protein ◽  
Cutting Edge ◽  
Orphan Receptor ◽  
Specific Receptor ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

scholarly journals Identification of the first surrogate agonists for the G protein-coupled receptor GPR132

RSC Advances ◽  
2015 ◽  
Vol 5 (60) ◽  
pp. 48551-48557 ◽  
Author(s):  
Mohamed A. Shehata ◽  
Hanna Belcik Christensen ◽  
Vignir Isberg ◽  
Daniel Sejer Pedersen ◽  
Andreas Bender ◽  
...  
Keyword(s):  
G Protein ◽  
Binding Mode ◽  
Orphan Receptor ◽  
G Protein Coupled Receptor ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
G Protein Coupled

We report the first pharmacological tool agonist for in vitro characterization of the orphan receptor GPR132, preliminary structure–activity relationships based on 32 analogs and a suggested binding mode from docking.

Involvement of G protein-coupled receptor kinase 4 and 6 in rapid desensitization of dopamine D1 receptor in rat IEC-6 intestinal epithelial cells

2004 ◽  
Vol 287 (4) ◽  
pp. R772-R779 ◽  
Author(s):  
Sónia Fraga ◽  
Pedro A. Jose ◽  
Patrício Soares-da-Silva
Keyword(s):  
G Protein ◽  
D1 Receptor ◽  
Skf 38393 ◽  
Epithelial Cell Line ◽  
Intestinal Epithelial ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
Dependent Inhibition ◽  
G Protein Coupled ◽  
Stimulation Of

Dopamine-induced inhibition of Na+-K+-ATPase has been suggested to play a role in the regulation of Na+ absorption at the intestinal level, and these effects were mediated by dopamine D1-like receptors. The aim of this work was to evaluate the effect of the activation of the D1-like receptors on the activity of the Na+/H+ exchanger (NHE) in the rat intestinal epithelial cell line IEC-6. The presence of D1 receptors was confirmed by immunoblotting. The dopamine D1-like receptor agonist SKF-38393 produced a concentration-dependent inhibition of NHE activity and stimulation of adenylyl cyclase (AC), this being antagonized by the D1 selective antagonist SKF-83566. Effects of SKF-38393 on NHE and AC activities were maximal at 5 min of exposure to the agonist and rapidly diminished with no effect at 25 min. Exposure of cells for 25 min to dibutyryl-cAMP (0.5 mM) or to the AC activator forskolin (3 μM) effectively inhibited NHE activity. Pretreatment of cells with heparin (1 μM), a nonselective G protein-coupled receptor kinase (GRK) inhibitor, prevented the loss of effects on NHE activity after 25 min exposure to SKF-38393. The presence of GRK4, GRK6A, and GRK6B was confirmed by immunoblotting. Overnight treatment with the anti-GRK4–6 antibody complexed with Lipofectin was also effective in preventing loss of the effects of SKF-38393 on NHE and AC activities. It is concluded that dopamine D1 receptors in IEC-6 rapidly desensitize to D1-like agonist stimulation and GRK4 and 6 appear to be involved in agonist-mediated responsiveness and desensitization.

Development of pig oocytes activated by stimulation of an exogenous G-protein coupled receptor

1998 ◽  
Vol 49 (1) ◽  
pp. 154
Author(s):  
J.H. Kim ◽  
Z. Macháty ◽  
R. Cabot ◽  
Y.M. Han ◽  
R.S. Prather
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled ◽  
Stimulation Of

scholarly journals In vitro profiling of orphan G protein coupled receptor (GPCR) constitutive activity

2021 ◽  
Author(s):  
Lyndsay R. Watkins ◽  
Cesare Orlandi
Keyword(s):  
G Protein ◽  
Luciferase Reporter ◽  
List Type ◽  
Constitutive Activity ◽  
Protein Signaling ◽  
G Protein Coupled Receptor ◽  
Orphan Receptors ◽  
Gpcr Family ◽  
Orphan Gpcrs ◽  
G Protein Coupled

AbstractBackground and PurposeMembers of the G protein coupled receptor (GPCR) family are targeted by a significant fraction of the available FDA-approved drugs. However, the physiological role and pharmacological properties of many GPCRs remain unknown, representing untapped potential in drug design. Of particular interest are ~100 less-studied GPCRs known as orphans because their endogenous ligands are unknown. Intriguingly, disease-causing mutations identified in patients, together with animal studies, have demonstrated that many orphan receptors play crucial physiological roles, and thus, represent attractive drug targets.Experimental ApproachThe majority of deorphanized GPCRs demonstrate coupling to Gi/o, however a limited number of techniques allow the detection of intrinsically small constitutive activity associated with Gi/o protein activation which represents a significant barrier in our ability to study orphan GPCR signaling. Using luciferase reporter assays, we effectively detected constitutive Gs, Gq, and G12/13 protein signaling by unliganded receptors, and introducing various G protein chimeras, we provide a novel, highly-sensitive tool capable of identifying Gi/o coupling in unliganded orphan GPCRs.Key ResultsUsing this approach, we measured the constitutive activity of the entire class C GPCR family that includes 8 orphan receptors, and a subset of 20 prototypical class A GPCR members, including 11 orphans. Excitingly, this approach illuminated the G protein coupling profile of 8 orphan GPCRs (GPR22, GPR137b, GPR88, GPR156, GPR158, GPR179, GPRC5D, and GPRC6A) previously linked to pathophysiological processes.Conclusion and ImplicationsWe provide a new platform that could be utilized in ongoing studies in orphan receptor signaling and deorphanization efforts.What is already knownA large group of understudied orphan GPCRs controls a variety of physiological process.What this study addsA new strategy to identify G protein signaling associated with orphan GPCRs.Identification of Gi/o coupling for 8 orphan GPCRs.What is the clinical significanceMany orphan GPCRs are associated with pathological conditions and represent promising druggable targets.

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