Constitutive Activity among Orphan Class-A G Protein Coupled Receptors

Martin, Adam L.; Steurer, Michael; Aronstam, Robert S.

doi:10.1371/journal.pone.0138463

Cited by 115 publications

(124 citation statements)

References 31 publications

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“…This G-protein promiscuity has been observed by independent research groups using different GPR6 or GPR12-transfected cell lines and a variety of functional outcomes (Uhlenbrock et al 2002; Ignatov et al 2003a; Ignatov et al 2003b; Martin et al 2015). However, this G-protein dual coupling ability was not demonstrated for GPR3.…”

Section: Pharmacologymentioning

confidence: 69%

“…A high constitutive activation of adenylyl cyclase has been consistently observed in GPR3, GPR6 and GPR12 (Eggerickx et al 1995; Uhlenbrock et al 2002; Martin et al 2015). In the absence of a ligand, the basal activity of these receptors was found to be similar to the activity of fully activated Gα s -coupled receptors with their corresponding modulators (Eggerickx et al 1995; Uhlenbrock et al 2002).…”

Section: Pharmacologymentioning

confidence: 91%

See 1 more Smart Citation

Towards a better understanding of the cannabinoid-related orphan receptors GPR3, GPR6, and GPR12

Morales

Isawi

Reggio

2018

Drug Metabolism Reviews

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GPR3, GPR6 and GPR12 are three orphan receptors that belong to the Class A family of G protein-coupled receptors (GPCRs). These GPCRs share over 60% of sequence similarity among them. Because of their close phylogenetic relationship GPR3, GPR6 and GPR12 share a high percentage of homology with other lipid receptors such as the lysophospholipid and the cannabinoid receptors. On the basis of sequence similarities at key structural motifs, these orphan receptors have been related to the cannabinoid family. However, further experimental data is required to confirm this association. GPR3, GPR6 and GPR12 are predominantly expressed in mammalian brain. Their high constitutive activation of adenylyl cyclase triggers increases in cAMP levels similar in amplitude to fully activated GPCRs. This feature defines their physiological role under certain pathological conditions. In this review, we aim to summarize the knowledge attained so far on the understanding of these receptors. Expression patterns, pharmacology, physiopathological relevance, and molecules targeting GPR3, GPR6 and GPR12 will be analyzed herein. Interestingly, certain cannabinoid ligands have been reported to modulate these orphan receptors. The current debate about sphingolipids as putative endogenous ligands will also be addressed. A special focus will be on their potential role in the brain, particularly under neurological conditions such as Parkinson or Alzheimer’s disease. Reported physiological roles outside the central nervous system will also be covered. This critical overview may contribute to a further comprehension of the physiopathological role of these orphan GPCRs, hopefully attracting more research towards a future therapeutic exploitation of these promising targets.

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Section: Pharmacologymentioning

confidence: 69%

Section: Pharmacologymentioning

confidence: 91%

Towards a better understanding of the cannabinoid-related orphan receptors GPR3, GPR6, and GPR12

Morales

Isawi

Reggio

2018

Drug Metabolism Reviews

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“…Gpr176 is an SCN-enriched orphan GPCR that sets the pace of the central clock in the SCN [7]. Gpr176 couples to Gz, and even in the absence of known ligand, it possesses an agonist-independent basal activity to repress cAMP signaling [7,8]. Besides Gpr176 and Gz, this review also emphasizes a role for the regulator of G-protein signaling 16 (RGS16) in the temporal regulation of G-protein-cAMP signaling in the SCN [9,10].…”

Section: The Scn Is the Center Of The Body Clockmentioning

confidence: 99%

“…The magnitude of this basal activity differs considerably between GPCRs. Comparative studies examining basal activities of class-A GPCRs [8] revealed that Gpr176 is among those possessing high-level constitutive activities.…”

Section: Gpr176 Cycles In Abundance and Colocalizes With Vipr2mentioning

confidence: 99%

G-protein-coupled receptor signaling through Gpr176, Gz, and RGS16 tunes time in the center of the circadian clock [Review]

et al. 2017

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Abstract. G-protein-coupled receptors (GPCRs) constitute an immensely important class of drug targets with diverse clinical applications. There are still more than 120 orphan GPCRs whose cognate ligands and physiological functions are not known. A set of circadian pacemaker neurons that governs daily rhythms in behavior and physiology resides in the suprachiasmatic nucleus (SCN) in the brain. Malfunction of the circadian clock has been linked to a multitude of diseases, such as sleeping disorders, obesity, diabetes, cardiovascular diseases, and cancer, which makes the clock an attractive target for drug development. Here, we review a recently identified role of Gpr176 in the SCN. Gpr176 is an SCN-enriched orphan GPCR that sets the pace of the circadian clock in the SCN. Even without known ligand, this orphan receptor has an agonist-independent basal activity to reduce cAMP signaling. A unique cAMP-repressing G-protein subclass Gz is required for the activity of Gpr176. We also provide an overview on the circadian regulation of G-protein signaling, with an emphasis on a role for the regulator of G-protein signaling 16 (RGS16). RGS16 is indispensable for the circadian regulation of cAMP in the SCN. Developing drugs that target the SCN remains an unfulfilled opportunity for the circadian pharmacology. This review argues for the potential impact of focusing on GPCRs in the SCN for the purpose of tuning the body clock.

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“…GPR12 is constitutively active and couples to both G s and G i proteins [7–9]. However, GPR12 is an orphan receptor with no confirmed endogenous ligands.…”

Section: Introductionmentioning

confidence: 99%

Cannabidiol, a novel inverse agonist for GPR12

Brown

Laun

Song

2017

Biochemical and Biophysical Research Communications

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GPR12 is a constitutively active, Gs protein-coupled receptor that currently has no confirmed endogenous ligands. GPR12 may be involved in physiological processes such as maintenance of oocyte meiotic arrest and brain development, as well as pathological conditions such as metastatic cancer. In this study, the potential effects of various classes of cannabinoids on GPR12 were tested using a cAMP accumulation assay. Our data demonstrate that cannabidiol (CBD), a major non-psychoactive phytocannabinoid, acted as an inverse agonist to inhibit cAMP accumulation stimulated by the constitutively active GPR12. Thus, GPR12 is a novel molecular target for CBD. The structure-activity relationship studies of CBD indicate that both the free hydroxyl and the pentyl side chain are crucial for the effects of CBD on GPR12. Furthermore, studies using cholera toxin, which blocks Gs protein and pertussis toxin, which blocks Gi protein, revealed that Gs, but not Gi is involved in the inverse agonism of CBD on GPR12. CBD is a promising novel therapeutic agent for cancer, and GPR12 has been shown to alter viscoelasticity of metastatic cancer cells. Since we have demonstrated that CBD is an inverse agonist for GPR12, this provides novel mechanism of action for CBD, and an initial chemical scaffold upon which highly potent and efficacious agents acting on GPR12 may be developed with the ultimate goal of blocking cancer metastasis.

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Constitutive Activity among Orphan Class-A G Protein Coupled Receptors

Cited by 115 publications

References 31 publications

Towards a better understanding of the cannabinoid-related orphan receptors GPR3, GPR6, and GPR12

Towards a better understanding of the cannabinoid-related orphan receptors GPR3, GPR6, and GPR12

G-protein-coupled receptor signaling through Gpr176, Gz, and RGS16 tunes time in the center of the circadian clock [Review]

Cannabidiol, a novel inverse agonist for GPR12

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