Structural and functional evolution of the P2Y12-like receptor group

Schöneberg, Torsten; Hermsdorf, Thomas; Engemaier, Eva; Engel, Kathrin M.; Liebscher, Ines; Thor, Doreen; Zierau, Klaas; Römpler, Holger; Schulz, Angela

doi:10.1007/s11302-007-9064-0

Cited by 40 publications

(28 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A value of p Ͻ 0.05 was considered significant. 4 Activation-Based on their amino acid sequence, CysLT 1 R and CysLT 2 R belong to the nucleotide P2Y G proteincoupled receptor family (25). Within the P2Y 1 subgroup, GPR91 and GPR99 do not bind to nucleotides but do bind to the glucose metabolism intermediates, succinate and oxoglutarate (␣-ketoglutarate), respectively (23).…”

Section: Methodsmentioning

confidence: 99%

Identification of GPR99 Protein as a Potential Third Cysteinyl Leukotriene Receptor with a Preference for Leukotriene E4 Ligand

Kanaoka

Maekawa

Austen

2013

Journal of Biological Chemistry

162

154

View full text Add to dashboard Cite

Background: A most stable cysteinyl leukotriene, LTE 4 , mediates vascular permeability in mice lacking the two known receptors. Results: GPR99 deficiency abolishes LTE 4 -induced vascular permeability in mice also lacking the two known receptors. Conclusion: GPR99 is a potential third cysteinyl leukotriene receptor. Significance: GPR99 may be a therapeutic target for inflammatory diseases.The cysteinyl leukotrienes (cys-LTs), leukotriene C 4 (LTC 4 ), a conjugation product of glutathione and eicosatetraenoic acid, and its metabolites, LTD 4 and LTE 4 , are lipid mediators of smooth muscle constriction and inflammation in asthma. LTD 4 is the most potent ligand for the type 1 cys-LT receptor (CysLT 1 R), and LTC 4 and LTD 4 have similar lesser potency for CysLT 2 R, whereas LTE 4 has little potency for either receptor. Cysltr1/Cysltr2 ؊/؊ mice, lacking the two defined receptors, exhibited a comparable dose-dependent vascular leak to intradermal injection of LTC 4 or LTD 4 and an augmented response to LTE 4 as compared with WT mice. As LTE 4 retains a cysteine residue and might provide recognition via a dicarboxylic acid structure, we screened cDNAs within the P2Y nucleotide receptor family containing CysLTRs and dicarboxylic acid receptors with trans-activator reporter gene assays. GPR99, previously described as an oxoglutarate receptor (Oxgr1), showed both a functional and a binding response to LTE 4 in these transfectants. We generated Gpr99 ؊/؊ and Gpr99/Cysltr1/Cysltr2 ؊/؊ mice for comparison with WT and Cysltr1/Cysltr2 ؊/؊ mice. Strikingly, GPR99 deficiency in the Cysltr1/Cysltr2 ؊/؊ mice virtually eliminated the vascular leak in response to the cys-LT ligands, indicating GPR99 as a potential CysLT 3 R active in the Cysltr1/Cysltr2 ؊/؊ mice. Importantly, the Gpr99 ؊/؊ mice showed a dose-dependent loss of LTE 4 -mediated vascular permeability, but not to LTC 4 or LTD 4 , revealing a preference of GPR99 for LTE 4 even when CysLT 1 R is present. As LTE 4 is the predominant cys-LT species in inflamed tissues, GPR99 may provide a new therapeutic target.Leukotriene C 4 (LTC 4 ), 2 LTD 4 , and LTE 4 , collectively called cysteinyl leukotrienes (cys-LTs), are proinflammatory mediators derived from arachidonic acid through the 5-lipoxygenase/ LTC 4 synthase pathway (1, 2). Intracellularly synthesized LTC 4 is exported via multidrug resistance-associated proteins and is rapidly metabolized in the extracellular space by cleavage removal of glutamic acid and then glycine to LTD 4 and LTE 4 , respectively. The type 1 cys-LT receptor (CysLT 1 R) is the high affinity receptor for LTD 4 , whereas the type 2 receptor (CysLT 2 R) can bind both LTC 4 and LTD 4 with one-log less affinity than that of CysLT 1 R for LTD 4 in transfected cells (3, 4). The cys-LTs are mediators of bronchial asthma on the basis of their potent bronchoconstrictive activity via the CysLT 1 R in pharmacologic studies and the clinical effectiveness of CysLT 1 R antagonists (5, 6).LTE 4 , the most abundant cys-LT at sites of inflammation due to its stab...

show abstract

Section: Methodsmentioning

confidence: 99%

Identification of GPR99 Protein as a Potential Third Cysteinyl Leukotriene Receptor with a Preference for Leukotriene E4 Ligand

Kanaoka

Maekawa

Austen

2013

Journal of Biological Chemistry

162

154

View full text Add to dashboard Cite

show abstract

“…Indeed, conserved synteny indicates that chromosomal duplication generated a set of paralogous genes on chromosomes 4 and 5 including the dopamine and adrenergic receptor paralogs, DRD5 and DRD1 and ADRA2C and ADRA1, respectively [67]. M a n u s c r i p t -6 -A number of GPCR subfamilies that were subject to independent rapid yet species-specific expansion, including olfactory [68][69][70], chemokine [71], aminergic [72], trace amineassociated (TAAR) [73,74], vomeronasal [75] and nucleotide receptor-like receptors [76], occur in clusters within the vertebral genomes and are often arranged in a tandem fashion. This implies a duplication mechanism that is confined to a genomic region.…”

Section: Gpcr Repertoiresmentioning

confidence: 99%

Evolution of GPCR: Change and continuity

Strotmann

Schröck

Böselt

et al. 2011

Molecular and Cellular Endocrinology

Self Cite

View full text Add to dashboard Cite

Once introduced into the very early eukaryotic blueprint, seven-transmembrane receptors soon became the central and versatile components of the evolutionary highly successful G protein-coupled transmembrane signaling mechanism. In contrast to all other components of this signal transduction pathway, G protein-coupled receptors (GPCR) evolved in various structural families, eventually comprising hundreds of members in vertebrate genomes. Their functional diversity is in contrast to the conserved transmembrane core and the invariant set of intracellular signaling mechanisms, and it may be the interplay of these properties that is the key to the evolutionary success of GPCR. The GPCR repertoires retrieved from extant vertebrate genomes are the recent endpoints of this long evolutionary process. But the shaping of the fine structure and the repertoire of GPCR is still ongoing, and signatures of recent selection acting on GPCR genes can be made visible by modern population genetic methods. The very dynamic evolution of GPCR can be analyzed from different perspectives: at the levels of sequence comparisons between species from different families, orders and classes, and at the level of populations within a species. Here, we summarize the main conclusions from studies at these different levels with a specific focus on the more recent evolutionary dynamics of GPCR.

show abstract

“…In addition to their role in platelets, ADP receptors mediate a range of inflammatory effects in nonplatelet tissues 31 and have been shown to enhance the proliferative responses to certain growth factors, such as platelet-derived growth factor. 32 Genetic variability of P2Y12, such as the H2 haplotype, has also been associated with advanced atherosclerosis and may be a determinant of atherogenic SMC responses.…”

Section: Rauch Et Al Thrombin Induces Active P2y12 In Human Smc 2439mentioning

confidence: 99%

Regulation of Functionally Active P2Y12 ADP Receptors by Thrombin in Human Smooth Muscle Cells and the Presence of P2Y12 in Carotid Artery Lesions

Rauch

Rosenkranz

Ermler

et al. 2010

ATVB

View full text Add to dashboard Cite

Objective-The platelet P2Y12 ADP receptor is a well-known target of thienopyridine-type antiplatelet drugs. This study is the first to describe increased transcriptional expression of a functionally active P2Y12 in response to thrombin in human vascular smooth muscle cells (SMC). Methods and Results-On exposure to thrombin, P2Y12 mRNA was transiently increased, whereas total protein and cell surface expression of P2Y12 were markedly increased within 6 hours and remained elevated over 24 hours. This effect was mediated by activation of nuclear factor B. Preincubation with thrombin significantly enhanced the efficacy of the P2Y receptor agonist 2-methylthio-ADP to induce interleukin 6 expression and SMC mitogenesis. Effects induced by 2-methylthio-ADP were prevented by RNA interference-mediated knockdown of P2Y12 and a selective P2Y12-antagonist R-138727, the active metabolite of prasugrel. In addition, positive P2Y12 immunostaining was shown in SMC of human carotid artery plaques and was found to colocalize with tissue factor, the rate-limiting factor of thrombin formation in vivo. Conclusion-These data suggest that the P2Y12 receptor not only is central to ADP-induced platelet activation but also may mediate platelet-independent responses, specifically under conditions of enhanced thrombin formation, such as local vessel injury and atherosclerotic plaque rupture. Key Words: atherosclerosis Ⅲ thrombin Ⅲ P2Y12 receptor Ⅲ inflammation Ⅲ vascular smooth muscle P 2Y12 ADP receptor antagonists, such as the thienopyridines, are widely used as antiplatelet drugs. 1,2 Besides their role as inhibitors of platelet aggregation, there is increasing evidence that these compounds also exert antiinflammatory actions. Reduced plasma levels of inflammatory markers, such as CD40 ligand, C-reactive protein, P-selectin, and platelet-leukocyte aggregates, have been shown with P2Y12 antagonists in atherothrombotic patients, 3 and platelet P2Y12 has also been shown recently to influence vessel wall responses to injury and thrombosis. 4 Thus far, these effects have been attributed solely to the antiplatelet action and have led to the concept that antiplatelet agents exert their antiinflammatory actions via platelet-related mechanisms. 5 The ADP receptor P2Y12 was originally identified in platelets and in the brain. 6 It is a member of the P2 receptor family, which consists of the ion-channel P2X and the G-protein-coupled P2Y receptors. 7 P2 receptors are activated by the adenine nucleotides ATP and ADP, which can be released from platelets, endothelial cells, sympathetic nerve terminals, and immune cells. 8 P2 receptors have been shown to be involved in a variety of inflammatory processes, such as allergen-driven lung inflammation. 9 In addition, the P2Y12 receptor has been associated with enhanced cell growth in certain brain tumors. 10 Recently, P2Y12 was found to be expressed in vascular smooth muscle cells (SMC), 11 and a role in vessel contraction was suggested. 12 However, no functional changes were seen after thienopyridine tr...

show abstract

Structural and functional evolution of the P2Y12-like receptor group

Cited by 40 publications

References 74 publications

Identification of GPR99 Protein as a Potential Third Cysteinyl Leukotriene Receptor with a Preference for Leukotriene E4 Ligand

Identification of GPR99 Protein as a Potential Third Cysteinyl Leukotriene Receptor with a Preference for Leukotriene E4 Ligand

Evolution of GPCR: Change and continuity

Regulation of Functionally Active P2Y12 ADP Receptors by Thrombin in Human Smooth Muscle Cells and the Presence of P2Y12 in Carotid Artery Lesions

Contact Info

Product

Resources

About