Is GPR17 a P2Y/Leukotriene Receptor? Examination of Uracil Nucleotides, Nucleotide Sugars, and Cysteinyl Leukotrienes as Agonists of GPR17

Qi, Ai Dong; Harden, T. Kendall; Nicholas, Robert A.

doi:10.1124/jpet.113.207647

Cited by 51 publications

(57 citation statements)

References 45 publications

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“…However, these compounds have subsequently been questioned as pharmacological modulators of GPR17 (14,15). In this study, we confirm that Gpr17 is highly expressed in the hypothalamus of mice.…”

Section: Discussionsupporting

confidence: 74%

“…Consistent with these findings, intracerebroventricular injection of UDP glucose and LTD4 in mice stimulated food intake, whereas administration of Cangrelor suppressed it (11). However, other studies have failed to demonstrate activation of GPR17 with UDP glucose and LTD4 (14,15). In this study, we generated and fed Gpr17-deficient (Gpr17 −/− ) mice a normal and a high-fat diet (HFD).…”

supporting

confidence: 63%

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GPR17 gene disruption does not alter food intake or glucose homeostasis in mice

Mastaitis

Min

Elvert

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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G protein-coupled receptor 17 (GPR17) was recently reported to be a Foxo1 target in agouti-related peptide (AGRP) neurons. Intracerebroventricular injection of GPR17 agonists induced food intake, whereas administration of an antagonist to the receptor reduced feeding. These data lead to the conclusion that pharmacological modulation of GPR17 has therapeutic potential to treat obesity. Here we report that mice deficient in Gpr17 (Gpr17−/−) have similar food intake and body weight compared with their wild-type littermates. Gpr17−/− mice have normal hypothalamic Agrp mRNA expression, AGRP plasma levels, and metabolic rate. GPR17 deficiency in mice did not affect glucose homeostasis or prevent fat-induced insulin resistance. These data do not support a role for GPR17 in the control of food intake, body weight, or glycemic control.

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Section: Discussionsupporting

confidence: 74%

supporting

confidence: 63%

GPR17 gene disruption does not alter food intake or glucose homeostasis in mice

Mastaitis

Min

Elvert

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…GPR17, a GPCR homologous to CysLT 1 R and CysLT 2 R,30 was originally "deorphanized" as a dual-specific receptor for cys-LTs and uracil nucleotides 31. However, we and others could not reproduce GPR17 activation by either ligand type in various assay systems 30,32,33. Instead, GPR17 functions as a negative regulator of LTD 4 -mediated CysLT 1 R activation, and markedly reduces binding of LTD 4 when the two receptors are co-expressed in cell lines 30.…”

Section: Introductionmentioning

confidence: 94%

Cysteinyl Leukotrienes and Their Receptors; Emerging Concepts

Kanaoka

Boyce

2014

Allergy Asthma Immunol Res

115

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Cysteinyl leukotrienes (cys-LTs) are potent mediators of inflammation derived from arachidonic acid through the 5-lipoxygenase/leukotriene C4 synthase pathway. The derivation of their chemical structures and identification of their pharmacologic properties predated the cloning of their classical receptors and the development of drugs that modify their synthesis and actions. Recent studies have revealed unanticipated insights into the regulation of cys-LT synthesis, the function of the cys-LTs in innate and adaptive immunity and human disease, and the identification of a new receptor for the cys-LTs. This review highlights these studies and summarizes their potential pathobiologic and therapeutic implications.

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“…Different signaling cascades downstream of activated G protein-coupled receptors have been identified as modulators of * This work was supported by a grant from the German Federal Ministry for Education and Research (BMBF) within the BioPharma Initiative "Neuroallianz" (Grant 1615609B; to E. K. 49-228-733250; E-mail: jgomeza@uni-bonn.de. 5 The abbreviations used are: OPC, oligodendrocyte precursor cell; MS, multiple sclerosis; MBP, myelin basic protein; CREB, cAMP-response elementbinding protein; EPAC, exchange protein directly activated by cAMP; MDL29,951, 2-carboxy-4,6-dichloro-1H-indole-3-propionic acid; Sp-6-BnzcAMPS, N 6 -benzoyladenosine-3,5-cyclic monophosphate; CPT, chlorophenylthio-; DMR, dynamic mass redistribution; PTX, pertussis toxin. …”

mentioning

confidence: 99%

“…During postnatal development, oligodendrocytes progress through a sequence of differentiation steps from oligodendrocyte precursor cells (OPCs) 5 to myelinating mature oligodendrocytes (1). Failure during this process leads to impaired myelination and, consequently, to slow conduction of signals along nerves, which results in debilitating symptoms such as paralysis and cognitive impairments.…”

mentioning

confidence: 99%

The Orphan G Protein-coupled Receptor GPR17 Negatively Regulates Oligodendrocyte Differentiation via Gαi/o and Its Downstream Effector Molecules

Simon

Hennen

Merten

et al. 2016

Journal of Biological Chemistry

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Recent studies have recognized G protein-coupled receptors as important regulators of oligodendrocyte development. GPR17, in particular, is an orphan G protein-coupled receptor that has been identified as oligodendroglial maturation inhibitor because its stimulation arrests primary mouse oligodendrocytes at a less differentiated stage. However, the intracellular signaling effectors transducing its activation remain poorly understood. Here, we use Oli-neu cells, an immortalized cell line derived from primary murine oligodendrocytes, and primary rat oligodendrocyte cultures as model systems to identify molecular targets that link cell surface GPR17 to oligodendrocyte maturation blockade. We demonstrate that stimulation of GPR17 by the small molecule agonist MDL29,951 (2-carboxy-4,6-dichloro-1H-indole-3-propionic acid) decreases myelin basic protein expression levels mainly by triggering the G␣ i/o signaling pathway, which in turn leads to reduced activity of the downstream cascade adenylyl cyclase-cAMP-PKA-cAMP response element-binding protein (CREB). In addition, we show that GPR17 activation also diminishes myelin basic protein abundance by lessening stimulation of the exchange protein directly activated by cAMP (EPAC), thus uncovering a previously unrecognized role for EPAC to regulate oligodendrocyte differentiation. Together, our data establish PKA and EPAC as key downstream effectors of GPR17 that inhibit oligodendrocyte maturation. We envisage that treatments augmenting PKA and/or EPAC activity represent a beneficial approach for therapeutic enhancement of remyelination in those demyelinating diseases where GPR17 is highly expressed, such as multiple sclerosis.Myelination is a central nervous system (CNS) process where oligodendrocytes establish myelin sheaths that stabilize, protect, and electrically insulate neuronal axons. During postnatal development, oligodendrocytes progress through a sequence of differentiation steps from oligodendrocyte precursor cells (OPCs) 5 to myelinating mature oligodendrocytes (1). Failure during this process leads to impaired myelination and, consequently, to slow conduction of signals along nerves, which results in debilitating symptoms such as paralysis and cognitive impairments. Likewise, in many severe neurological disorders, among others multiple sclerosis (MS), loss of oligodendrocytes and destruction of CNS myelin precedes the serious neurological deficits. Although OPCs are abundant in chronic MS lesion sites, no remyelination occurs, which suggests that oligodendrocyte differentiation does not take place due to either the absence of pro-myelinating signals or presence of myelination inhibitors in the MS lesion (2, 3).During the previous years, an increasing number of oligodendroglial differentiation inhibitors have been identified (for review see Ref. 4). Genetic evidence from transgenic mice supports the notion that the orphan G protein-coupled receptor GPR17 (5) negatively regulates oligodendrocyte maturation and myelination (6). Notably, GPR17 is highly abundant...

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Is GPR17 a P2Y/Leukotriene Receptor? Examination of Uracil Nucleotides, Nucleotide Sugars, and Cysteinyl Leukotrienes as Agonists of GPR17

Cited by 51 publications

References 45 publications

GPR17 gene disruption does not alter food intake or glucose homeostasis in mice

GPR17 gene disruption does not alter food intake or glucose homeostasis in mice

Cysteinyl Leukotrienes and Their Receptors; Emerging Concepts

The Orphan G Protein-coupled Receptor GPR17 Negatively Regulates Oligodendrocyte Differentiation via Gαi/o and Its Downstream Effector Molecules

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