Tissue distribution and functional analyses of the constitutively active orphan G protein coupled receptors, GPR26 and GPR78

Jones, Philip; Nawoschik, Stanley; Sreekumar, K. R.; Uveges, Albert J.; Tseng, Eugene; Zhang, Lynn; Johnson, Jeremy W.; He, Lan; Paulsen, Janet; Bates, Brian; Pausch, Mark H.

doi:10.1016/j.bbagen.2007.01.013

Cited by 51 publications

(51 citation statements)

References 37 publications

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“…They are classically composed of seven membrane-spanning domains and constitute one of the largest and most diverse gene families in the mammalian genome (Ostrom & Insel 2004). Some novel GPCRs do not have obvious endogenous ligands and are termed orphan receptors, a number of which appear to be constitutively active (Jones et al 2007. The cognate ligands for some of these orphan GPCRs have been identified, often based on the cellular and tissue distributions of the orphan GPCRs and occasionally using 'reverse pharmacology', where orphan GPCRs have been used to isolate novel endogenous substances.…”

Section: Introductionmentioning

confidence: 99%

The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis

O’Carroll

Lolait

Harris

et al. 2013

Journal of Endocrinology

293

216

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The apelin receptor (APJ; gene symbol APLNR) is a member of the G protein-coupled receptor gene family. Neural gene expression patterns of APJ, and its cognate ligand apelin, in the brain implicate the apelinergic system in the regulation of a number of physiological processes. APJ and apelin are highly expressed in the hypothalamo-neurohypophysial system, which regulates fluid homeostasis, in the hypothalamic-pituitary-adrenal axis, which controls the neuroendocrine response to stress, and in the forebrain and lower brainstem regions, which are involved in cardiovascular function. Recently, apelin, synthesised and secreted by adipocytes, has been described as a beneficial adipokine related to obesity, and there is growing awareness of a potential role for apelin and APJ in glucose and energy metabolism. In this review we provide a comprehensive overview of the structure, expression pattern and regulation of apelin and its receptor, as well as the main second messengers and signalling proteins activated by apelin. We also highlight the physiological and pathological roles that support this system as a novel therapeutic target for pharmacological intervention in treating conditions related to altered water balance, stress-induced disorders such as anxiety and depression, and cardiovascular and metabolic disorders.

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Section: Introductionmentioning

confidence: 99%

The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis

O’Carroll

Lolait

Harris

et al. 2013

Journal of Endocrinology

293

216

View full text Add to dashboard Cite

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“…GPR78 is an orphan G-protein coupled receptor (GPCR) that is highly expressed in human placenta and brain tissues (6). However, the expression pattern and function of GPR78 in human cancer cells is still unknown.…”

Section: Resultsmentioning

confidence: 99%

“…Expression analysis revealed it was highly expressed in human brain tissue. Later studies demonstrated that GPR78 overexpression in HEK293 cells was constitutively active, and induced the cAMP production (6). However, the cellular function of GPR78 remains unknown.…”

Section: Introductionmentioning

confidence: 99%

GPR78 promotes lung cancer cell migration and metastasis by activation of Gαq-Rho GTPase pathway

Dong¹,

Zhou²,

Gao³

2016

BMB Reports

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GPR78 is an orphan G-protein coupled receptor (GPCR) that is predominantly expressed in human brain tissues. Currently, the function of GPR78 is unknown. This study revealed that GPR78 was expressed in lung cancer cells and functioned as a novel regulator of lung cancer cell migration and metastasis. We found that knockdown of GPR78 in lung cancer cells suppressed cell migration. Moreover, GPR78 modulated the formation of actin stress fibers in A549 cells, in a RhoA- and Rac1-dependent manner. At the molecular level, GPR78 regulated cell motility through the activation of Gαq-RhoA/Rac1 pathway. We further demonstrated that in vivo, the knockdown of GPR78 inhibited lung cancer cell metastasis. These findings suggest that GPR78 is a novel regulator for lung cancer metastasis and may serve as a potential drug target against metastatic human lung cancer.

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“…Because increased cAMP production might occur in some brain regions in GPR20-deficient mice, the abnormal cAMP levels in these areas may be related to the hyperactivity disorder (4). Intriguingly, it has been demonstrated that several orphan GPCRs, including GPR3 (30, 31), GPR6, GPR12 (32), GPR26, GPR78 (33), and GPR101 (34), have the ability to augment cAMP formation by constitutive activation of G s in a ligandindependent fashion. Specifically, GPR26, GPR78, and GPR101 are expressed in some regions of the brain, including the caudate nuclei, putamen, and the thalamus (33,34), suggesting that they may counteract GPR20 in these areas.…”

Section: Discussionmentioning

confidence: 99%

“…Intriguingly, it has been demonstrated that several orphan GPCRs, including GPR3 (30, 31), GPR6, GPR12 (32), GPR26, GPR78 (33), and GPR101 (34), have the ability to augment cAMP formation by constitutive activation of G s in a ligandindependent fashion. Specifically, GPR26, GPR78, and GPR101 are expressed in some regions of the brain, including the caudate nuclei, putamen, and the thalamus (33,34), suggesting that they may counteract GPR20 in these areas. Because the intracellular cAMP level is essential for cellular homeostasis, including cell proliferation and differentiation, the amount of intracellular cAMP may be regulated by the balance in expression of these G i -and G s -coupled receptors.…”

Section: Discussionmentioning

confidence: 99%

Characterization of an Orphan G Protein-coupled Receptor, GPR20, That Constitutively Activates Gi Proteins

Hase

Yokomizo

Shimizu

et al. 2008

Journal of Biological Chemistry

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GPR20 was isolated as an orphan G protein-coupled receptor from genomic DNA by PCR amplification. Although GPR20 was closely related to nucleotide or lipid receptors, the functional role of this receptor, as well as its endogenous ligand, remains unclear. Here we demonstrate that GPR20 is constitutively active in the absence of ligand, leading to continuous activation of its coupled G proteins. When GPR20 was exogenously expressed in HEK293 cells, both the basal level and the prostaglandin E 2 -induced production of cAMP were significantly decreased. A remarkable increase in [35 S]guanosine 5-(␥-thio)triphosphate (GTP␥S) binding to membrane preparations was also observed in GPR20-expressing cells. These effects of GPR20 overexpression were diminished in cells treated with pertussis toxin, suggesting that the expression of GPR20 results in the activation of G i/o proteins. Involvement of GPR20 in the activation of G i/o proteins was also supported by evidence that the disruption of a conserved DRY motif in GPR20 attenuated both [35 S]GTP␥S incorporation and inhibition of the prostaglandin E 2 -induced cAMP production. Knockdown of GPR20 in PC12h cells resulted in an elevation of the basal cAMP level, suggesting that the endogenous GPR20 achieves a constitutively or spontaneously active conformation. Furthermore, enhancement of [ 3 H]thymidine incorporation was also observed in the GPR20-silencing cells, implying that the GPR20 expression seems to attenuate PC12h cell growth. Taken together, these data indicate that GPR20 constitutively activates G i proteins without ligand stimulation. The receptor may be involved in cellular processes, including control of intracellular cAMP levels and mitogenic signaling. Mammalian G protein-coupled receptors (GPCRs)2 are a diverse superfamily of proteins with hundreds of members, and these receptors regulate many processes in vivo via interactions with a variety of ligands, including small organic molecules, lipids, protons, hormones, short and large polypeptides, glycoproteins, and even photons. Despite the vast and longstanding efforts of academic and industrial researchers to pair GPCRs with potential ligands, more than 150 nonsensory GPCRs still remain orphan receptors, for which the cognate ligands have not yet been identified (1). Because GPCRs have proven particularly amenable to modulation by small molecules and are the targets of approximately half of currently marketed prescription drugs, the nonsensory GPCRs are clearly important therapeutic targets (2). Consequently, the orphan GPCRs constitute a vast reservoir of potential drug targets for therapeutic development. Indeed, numerous research groups, including ours, work on characterizing these receptors.GPR20 is one of the orphan GPCRs that has been identified from human genomic DNA by PCR amplification using primers based on the sequences of the opioid/somatostatin-related receptors, GPR7 and GPR8 (3). The expression of human GPR20 has been detected in several brain regions, including the caudate nuclei, putamen, a...

show abstract

Tissue distribution and functional analyses of the constitutively active orphan G protein coupled receptors, GPR26 and GPR78

Cited by 51 publications

References 37 publications

The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis

The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis

GPR78 promotes lung cancer cell migration and metastasis by activation of Gαq-Rho GTPase pathway

Characterization of an Orphan G Protein-coupled Receptor, GPR20, That Constitutively Activates Gi Proteins

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