Quantitative expression profiling of G‐protein‐coupled receptors (GPCRs) in metastatic melanoma: the constitutively active orphan GPCR GPR18 as novel drug target

Qin, Yongjun; Verdegaal, Els M.E.; Siderius, Marco; Bebelman, Jan Paul; Smit, Martine J.; Leurs, Rob; Willemze, R.; Tensen, Cornelis P.; Osanto, S.

doi:10.1111/j.1755-148x.2010.00781.x

Cited by 108 publications

(108 citation statements)

References 34 publications

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“…A protein sequence alignment of GPR18 (Supplemental Fig. 1C) suggests the mouse GPR18 clone used in our study is similar to functional GPR18 in other studies (Kohno et al, 2006;Qin et al, 2011;McHugh et al, 2012) and capable of proper protein expression. Other downstream effectors of Ga i/o were examined, but NAGly failed to activate GPR18.…”

Section: Discussionmentioning

confidence: 98%

“…A recent study found endogenous GPR18 is constitutively active and differentially expressed in melanoma metastases (Qin et al, 2011). However, we found no indication GPR18 expressed in SCG neurons was constitutively active (basal FR, 1.3 6 0.04, n 5 25; NE-mediated I Ca inhibition, 47.4% 6 3.6% baseline I Ca , n 5 17; I Ca density, 2 25.4 6 2.2 picoamperes per picofarad, pA/pF, n 5 25).…”

Section: Lack Of Gpr18 Activation By Naglymentioning

confidence: 99%

“…Although a positive effect from GPR18 has been observed from mouse-derived cell lines endogenously expressing GPR18 (McHugh et al, 2010;Burstein et al, 2011;Takenouchi et al, 2012), most GPR18 studies have used human GPR18 (Gantz et al, 1997;Kohno et al, 2006;Qin et al, 2011;McHugh et al, 2012). To assess the variability of GPR18 across species, protein sequences from different species were analyzed by protein alignment.…”

Section: Lack Of Gpr18 Activation By Naglymentioning

confidence: 99%

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N-Arachidonyl Glycine Does Not Activate G Protein–Coupled Receptor 18 Signaling via Canonical Pathways

Puhl

Ikeda

2012

Mol Pharmacol

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Recent studies propose that N-arachidonyl glycine (NAGly), a carboxylic analogue of anandamide, is an endogenous ligand of the Ga i/o protein-coupled receptor 18 (GPR18). However, a high-throughput b-arrestin-based screen failed to detect activation of GPR18 by NAGly (Yin et al., 2009; JBC, 18:12328). To address this inconsistency, this study investigated GPR18 coupling in a native neuronal system with endogenous signaling pathways and effectors. GPR18 was heterologously expressed in rat sympathetic neurons, and the modulation of N-type (Ca v 2.2) calcium channels was examined. Proper expression and trafficking of receptor were confirmed by the "rim-like" fluorescence of fluorescently tagged receptor and the positive staining of external hemagglutinin-tagged GPR18-expressing cells. Application of NAGly on GPR18-expressing neurons did not inhibit calcium currents but instead potentiated currents in a voltage-dependent manner, similar to what has previously been reported (Guo et al., 2008; J Neurophysiol, 100:1147). Other proposed agonists of GPR18, including anandamide and abnormal cannabidiol, also failed to induce inhibition of calcium currents. Mutants of GPR18, designed to constitutively activate receptors, did not tonically inhibit calcium currents, indicating a lack of GPR18 activation or coupling to endogenous G proteins. Other downstream effectors of Ga i/ocoupled receptors, G protein-coupled inwardly rectifying potassium channels and adenylate cyclase, were not modulated by GPR18 signaling. Furthermore, GPR18 did not couple to other G proteins tested: Ga s , Ga z , and Ga 15 . These results suggest NAGly is not an agonist for GPR18 or that GPR18 signaling involves noncanonical pathways not examined in these studies.

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Section: Discussionmentioning

confidence: 98%

Section: Lack Of Gpr18 Activation By Naglymentioning

confidence: 99%

Section: Lack Of Gpr18 Activation By Naglymentioning

confidence: 99%

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N-Arachidonyl Glycine Does Not Activate G Protein–Coupled Receptor 18 Signaling via Canonical Pathways

Puhl

Ikeda

2012

Mol Pharmacol

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“…Some of these GPCRs have been linked to cancer development and progression on the basis of their overexpression and/or up-regulation by diverse factors [173][174][175] . For instance, an elevated expression of the orphan G-proteincoupled receptor GPR49 was involved in the formation and proliferation of basal cell carcinoma [176] , while GPR18 was found associated with melanoma metastases [177] . In lung, cervix, skin, urinary bladder, testis, head and neck squamous cell carcinomas were detected high levels of GPR87 [178,179] for which UDP-glucose, cysteinyl-leukotrienes and LPA exhibited binding properties [180] .…”

Section: Orphan Gpcrs and Cancermentioning

confidence: 99%

GPCRs and cancer

Lappano

2012

Acta Pharmacol Sin

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G-protein-coupled receptors (GPCRs), which represent the largest gene family in the human genome, play a crucial role in multiple physiological functions as well as in tumor growth and metastasis. For instance, various molecules like hormones, lipids, peptides and neurotransmitters exert their biological effects by binding to these seven-transmembrane receptors coupled to heterotrimeric G-proteins, which are highly specialized transducers able to modulate diverse signaling pathways. Furthermore, numerous responses mediated by GPCRs are not dependent on a single biochemical route, but result from the integration of an intricate network of transduction cascades involved in many physiological activities and tumor development. This review highlights the emerging information on the various responses mediated by a selected choice of GPCRs and the molecular mechanisms by which these receptors exert a primary action in cancer progression. These findings provide a broad overview on the biological activity elicited by GPCRs in tumor cells and contribute to the identification of novel pharmacological approaches for cancer patients.

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“…The expression pattern of GPR174 is similar to the expression pattern of P2Y10 and A630033H20 with high expression in lymphoid tissues. However, GPR174 is also strongly expressed in some melanoma cells ( 55 ). GPR174 mainly coupled with both G ␣ s and G ␣ 13 ( 54 ).…”

Section: Gpr174/lpsmentioning

confidence: 99%

Novel lysophosphoplipid receptors: their structure and function

Makide

Uwamizu

Shinjo

et al. 2014

Journal of Lipid Research

141

133

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This article is available online at http://www.jlr.org with plasma concentrations of 10-30 nM and several hundred nanomoles, respectively ( 3, 4 ). Both LPA and S1P have critical roles in multiple cellular events through G protein-coupled receptors (GPCRs). Six GPCRs have been identifi ed for LPA (LPA 1-6 ) and fi ve GPCRs have been identifi ed for S1P (S1P 1-5 ) ( 5 ), and nomenclature of these LysoGPs receptors has recently been proposed by Kihara et al. ( 6 ). These receptors are grouped into two classes, the Edg and P2Y families, respectively. LPA 1-3 and all fi ve of the S1P receptors, S1P [1][2][3][4][5] , are members of the Edg family, while LPA 4-6 are members of the P2Y family. In addition, LPA is an endogenous ligand for PPAR ␥ ( 7 ), and was shown to activate transient receptor potential cation channel subfamily V member 1 (TRPV1) channels leading to an infl ux of Ca 2+ ions through TRPV1 ( 8 ). Studies on gene-targeted mice and human genetic diseases have clearly shown that each receptor has specifi c roles in both physiological and pathological conditions. For example, LPA has a pivotal role in neurogenesis ( 9 ) and has also been implicated in the development of lung fi brosis ( 10 ) via LPA 1 . LPA exhibits unique roles in implantation of fertilized eggs via LPA 3 ( 11 ) and hair follicle formation via LPA 6 ( 12 ). LPA is produced by at least two pathways where multiple phospholipase activities are involved ( 3 ). Lysophospholipase D/autotaxin/NPP2 produces LPA from LysoGPs such as LPC, while phosphatidic acid (PA)-selective PLA 1 ␣ (PA-PLA 1 ␣ ) and PA-PLA 1 ␤ produce LPA from PA by their PLA 1 activities. In contrast, S1P is produced intracellularly by phosphorylation Abstract It is now accepted that lysophospholipids (LysoGPs) have a wide variety of functions as lipid mediators that are exerted through G protein-coupled receptors (GPCRs) specifi c to each lysophospholipid. While the roles of some LysoGPs, such as lysophosphatidic acid and sphingosine 1-phosphate, have been thoroughly examined, little is known about the roles of several other LysoGPs, such as lysophosphatidylserine (LysoPS), lysophosphatidylthreonine, lysophosphatidylethanolamine, lysophosphatidylinositol (LPI), and lysophosphatidylglycerol. Recently, a GPCR was found for LPI (GPR55) and three GPCRs (GPR34/LPS 1 , P2Y10/ LPS 2 , and GPR174/LPS 3 ) were found for LysoPS. In this review, we focus on these newly identifi ed GPCRs and summarize the actions of LysoPS and LPI as lipid mediators.

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Quantitative expression profiling of G‐protein‐coupled receptors (GPCRs) in metastatic melanoma: the constitutively active orphan GPCR GPR18 as novel drug target

Cited by 108 publications

References 34 publications

N-Arachidonyl Glycine Does Not Activate G Protein–Coupled Receptor 18 Signaling via Canonical Pathways

N-Arachidonyl Glycine Does Not Activate G Protein–Coupled Receptor 18 Signaling via Canonical Pathways

GPCRs and cancer

Novel lysophosphoplipid receptors: their structure and function

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