An expressed sequence tag (EST) data mining strategy succeeding in the discovery of new G-protein coupled receptors11Edited by J. Thornton

Wittenberger, Timo; Schaller, Hubert; Hellebrand, Susanne

doi:10.1006/jmbi.2001.4520

Cited by 178 publications

(161 citation statements)

References 38 publications

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“…PKA is known to phosphorylate and activate the p65 subunit of nuclear factor kB (NF-kB) [46] and cAMP response element-binding protein (CREB since renamed SUCNR1 (Figure 3). This indicates that succinate has a signaling role beyond HIF-1a stabilization [27,28]. SUCNR1 is highly expressed in mouse kidney, liver, spleen, small intestine [27], and on DCs [8].…”

Section: Succinate and Hif-1a In Inflammationmentioning

confidence: 99%

Succinate: a metabolic signal in inflammation

Mills

O’Neill

2014

Trends in Cell Biology

537

445

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Succinate is an intermediate of the tricarboxylic acid (TCA) cycle, and plays a crucial role in adenosine triphosphate (ATP) generation in mitochondria. Recently, new roles for succinate outside metabolism have emerged. Succinate stabilizes the transcription factor hypoxia-inducible factor-1a (HIF-1a) in specific tumors and in activated macrophages, and stimulates dendritic cells via its receptor succinate receptor 1. Furthermore, succinate has been shown to post-translationally modify proteins. This expanding repertoire of functions for succinate suggests a broader role in cellular activation. We review the new roles of succinate and draw parallels to other metabolites such as NAD + and citrate whose roles have expanded beyond metabolism and into signaling. Metabolic alterations influence the immune responseThe immune system acts as an internal shield defending against invading pathogens and is made up of an innate system, including macrophages, neutrophils, and dendritic cells (DCs), and an adaptive system composed of T and B lymphocytes. Cells of the innate immune system recognize pathogen-associated molecular patterns (PAMPs) via pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), present on their cell surface and in the cytosol [1]. Once activated, innate immune cells can initiate adaptive immunity to fight infection further and to generate immunological memory. In resting conditions these cells are relatively inactive; however, upon recognition of foreign material they have the ability to respond rapidly, producing a wide array of mediators such as cytokines, chemokines, and antimicrobial peptides to clear the infection.Such rapid induction of immunity represents a significant metabolic demand. In recent years it has become evident that immune cells have the ability to shift their metabolism under varying conditions and that this is essential for proper immune function [2]. Stimulation of DCs and macrophages can result in a decrease in oxidative phosphorylation, which is normally employed under resting conditions, with a concomitant increase in glycolysis and the pentose-phosphate pathway [3,4]. This switch to glycolysis rapidly generates ATP to maintain mitochondrial membrane potential and energy homeostasis, ultimately ensuring cell viability [5]. It also provides biosynthetic precursors required for proliferating cells and for cells with a prodigious biosynthetic capacity, such as macrophages when they are activated to produce cytokines. This altered metabolism is similar to the Warburg effect (aerobic glycolysis) observed in tumor cells [6] (Figure 1, Box 1). Indeed, the metabolic sensor HIF-1a can determine the growth and fate of both tumor cells and immune cells. For example, HIF-1a activation favors differentiation of T lymphocytes into proinflammatory Th17 cells and attenuates regulatory T cell development [7]. Importantly, as well as global changes in metabolism that occur in activated immune cells, individual metabolites, including succinate, citrate, and NAD + , have been d...

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Section: Succinate and Hif-1a In Inflammationmentioning

confidence: 99%

Succinate: a metabolic signal in inflammation

Mills

O’Neill

2014

Trends in Cell Biology

537

445

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“…SUCNR1 gene was later re-discovered as GPR91 in 2001 on human chromosome 3q24-3q25 using an expressed sequence tag data mining strategy (Wittenberger et al, 2001). Of important note is the possibility of two open-reading frames (ORF) for SUCNR1, one giving a protein of 330 amino acids (AA) and the other one 334 AA.…”

Section: Succinate Receptor 1 Structure and Ligandsmentioning

confidence: 99%

“…Of important note is the possibility of two open-reading frames (ORF) for SUCNR1, one giving a protein of 330 amino acids (AA) and the other one 334 AA. Wittenberger et al noted that the 330-AA protein was more likely to be expressed given the Kozak sequence surrounding the second ATG (Wittenberger et al, 2001). In the present article we will use the AA numbering according to a 330-AA protein, although the current databases sometimes report SUCNR1 as being 334-AA long.…”

Section: Succinate Receptor 1 Structure and Ligandsmentioning

confidence: 99%

“…In the present article we will use the AA numbering according to a 330-AA protein, although the current databases sometimes report SUCNR1 as being 334-AA long. There is a high degree of homology between man and mouse (68%) with the exception of the C-terminal tail, which is 12 AA shorter in rodents (Ariza et al, 2012;Wittenberger et al, 2001). In humans, other genes have been found on the same locus and consist in a cluster of P2Y 1 ,P2Y 12 ,P2Y 13 ,H963 (GPR171) and GPR87 (Abbracchio et al, 2006).…”

Section: Succinate Receptor 1 Structure and Ligandsmentioning

confidence: 99%

“…In humans, other genes have been found on the same locus and consist in a cluster of P2Y 1 ,P2Y 12 ,P2Y 13 ,H963 (GPR171) and GPR87 (Abbracchio et al, 2006). In their seminal paper, Wittenberger et al speculated that all these receptors originated from a common ancestor, presumably a nucleotide receptor (Wittenberger et al, 2001). Several comprehensive reviews have been published on the receptor or succinate role in metabolic/oxidative stress conditions (Ariza et al, 2012;PetiPeterdi et al, 2013).…”

Section: Succinate Receptor 1 Structure and Ligandsmentioning

confidence: 99%

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Insight into SUCNR1 (GPR91) structure and function

Gilissen

Jouret

Pirotte

et al. 2016

Pharmacology & Therapeutics

111

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SUCNR1 (or GPR91) belongs to the family of G protein-coupled receptors (GPCR), which represents the largest group of membrane proteins in human genome. The majority of marketed drugs targets GPCRs, directly or indirectly. SUCNR1 has been classified as an orphan receptor until a landmark study paired it with succinate, a citric acid cycle intermediate.According to the current paradigm, succinate triggers SUCNR1 signaling pathways to indicate local stress that may affect cellular metabolism. SUCNR1 implication has been well documented in renin-induced hypertension, ischemia/reperfusion injury, inflammation and immune response, platelet aggregation and retinal angiogenesis. In addition, the SUCNR1-induced increase of blood pressure may contribute to diabetic nephropathy or cardiac hypertrophy.The understanding of SUCNR1 activation, signaling pathways and functions remains largely elusive, which calls for deeper investigations. SUCNR1 shows a high potential as an innovative drug target and is probably an important regulator of basic physiology. In order to achieve the full characterization of this receptor, more specific pharmacological tools such as small-molecules modulators will represent an important asset. In this review, we describe the structural features of SUCNR1, its current ligands and putative binding pocket. We give an exhaustive overview of the known and hypothetical signaling partners of the receptor in different in vitro and in vivo systems. The link between SUCNR1 intracellular pathways and its pathophysiological roles are also extensively discussed.

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P2Y receptors: New subtypes, new functions

Boeynaems

Wilkin

Marteau

et al. 2003

Drug Development Research

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The orphan receptor GPR86 was recently identified as a new ADP receptor coupled to G i and named P2Y 13 . This brings to eight the number of genuine P2Y receptors. On the basis of sequence homology, they can be subdivided into two subgroups: P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , and P2Y 11 ; and P2Y 12 , P2Y 13 , and the UDP-glucose receptor that should be renamed P2Y 14 . Some pharmacological properties of the P2Y 13 receptor are significantly different from those of the P2Y 12 receptor:ATP and 2MeSATP behaved as weak partial agonists. Potency of 2MeSADP was greater than or equal to that of ADP, depending on the expressing cell line and signaling pathway studied.AR-C67085MX behaved as an antagonist, but only with a mM potency as compared to nM at the P2Y 12 receptor.The active metabolite of clopidogrel had no effect. Expression of P2Y 13 mRNA was highest in brain, spleen, and various types of leukocytes, in particular dendritic cells. Recent results underscore the role of other P2Y receptors, especially P2Y 11 , in dendritic cell biology. Indeed, ATP and other nucleotides have multiple effects on human dendritic cells: potentiation of maturation, potentiation, or inhibition of IL-12p40 secretion (depending on the level of stimulation), inhibition of IL-12p70 production, potentiation of IL-10 secretion, and modulation of the repertoire of expressed chemokines and chemokine receptors. These actions are mediated by a rise in cAMP and the rank order of potency of various nucleotides is consistent with the involvement of the P2Y 11 receptor. On the other hand, several nucleotides inhibit the proliferation of human CD4 + T-cells and their secretion of cytokines: these actions also involve a rise in cAMP, apparently mediated by a receptor other than P2Y 11 . These actions are reminiscent of those of PGE 2 and might represent a protective mechanism operating DDR Abbreviations: ATPgS, adenosine 5'-O-(3-thiotriphosphate); BzATP, 2'-and 3'-O-(4-benzoyl-benzoyl) ATP; 2Me-

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An expressed sequence tag (EST) data mining strategy succeeding in the discovery of new G-protein coupled receptors11Edited by J. Thornton

Cited by 178 publications

References 38 publications

Succinate: a metabolic signal in inflammation

Succinate: a metabolic signal in inflammation

Insight into SUCNR1 (GPR91) structure and function

P2Y receptors: New subtypes, new functions

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