Crucial Positively Charged Residues for Ligand Activation of the GPR35 Receptor

Zhao, Pingwei; Lane, Tom R.; Gao, Helen G. L.; Hurst, Dow P.; Kotsikorou, Evangelia; Le, Long S.; Brǎiloiu, Eugen; Reggio, Patricia H.; Abood, Mary E.

doi:10.1074/jbc.m113.508382

Cited by 20 publications

(17 citation statements)

References 52 publications

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“…For example, indoxyl sulfate, kynurenine and kynurenate signal via the aryl hydrocarbon receptor (AHR) 52 – 54 , which is expressed in most tissues, including those affected in uremia such as the liver, intestine and kidney 55 , 56 . Kynurenate can also activate the orphan G-couple protein receptor, GPR35 57 , which is largely expressed in tissues affected in uremia, such as the gut and CNS 58 , 59 . CMPF, on the other hand, has been implicated in a glucose sensing mechanism involving OAT3, which is expressed in the pancreas (among other non-renal tissues), leading to altered metabolism 32 .…”

Section: Discussionmentioning

confidence: 99%

Key Role for the Organic Anion Transporters, OAT1 and OAT3, in the in vivo Handling of Uremic Toxins and Solutes

Bush

Nigám

2017

Sci Rep

168

176

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In vitro data indicates that the kidney proximal tubule (PT) transporters of uremic toxins and solutes (e.g., indoxyl sulfate, p-cresol sulfate, kynurenine, creatinine, urate) include two “drug” transporters of the organic anion transporter (OAT) family: OAT1 (SLC22A6, originally NKT) and OAT3 (SLC22A8). Here, we have examined new and prior metabolomics data from the Oat1KO and Oat3KO, as well as newly obtained metabolomics data from a “chemical double” knockout (Oat3KO plus probenecid). This gives a picture of the in vivo roles of OAT1 and OAT3 in the regulation of the uremic solutes and supports the centrality of these “drug” transporters in independently and synergistically regulating uremic metabolism. We demonstrate a key in vivo role for OAT1 and/or OAT3 in the handling of over 35 uremic toxins and solutes, including those derived from the gut microbiome (e.g., CMPF, phenylsulfate, indole-3-acetic acid). Although it is not clear whether trimethylamine-N-oxide (TMAO) is directly transported, the Oat3KO had elevated plasma levels of TMAO, which is associated with cardiovascular morbidity in chronic kidney disease (CKD). As described in the Remote Sensing and Signaling (RSS) Hypothesis, many of these molecules are involved in interorgan and interorganismal communication, suggesting that uremia is, at least in part, a disorder of RSS.

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Section: Discussionmentioning

confidence: 99%

Key Role for the Organic Anion Transporters, OAT1 and OAT3, in the in vivo Handling of Uremic Toxins and Solutes

Bush

Nigám

2017

Sci Rep

168

176

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“…Finally, Zhao et al (2014) have reported the results of human GPR35/CXCR8 mutation and computational studies. Homology models of human WT GPR35/CXCR8 in an inactive (R) and active (R*) state were constructed, as well as an R* model of R6.58(240)A GPR35/CXCR8.…”

Section: Gpr35/cxcr8 Structure and Modelingmentioning

confidence: 99%

The therapeutic potential of orphan GPCRs, GPR35 and GPR55

Shore

Reggio

2015

Front. Pharmacol.

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The G protein-coupled receptor (GPCR) superfamily of integral proteins is the largest family of signal transducers, comprised of ∼1000 members. Considering their prevalence and functional importance, it’s not surprising that ∼60% of drugs target GPCRs. Regardless, there exists a subset of the GPCR superfamily that is largely uncharacterized and poorly understood; specifically, more than 140 GPCRs have unknown endogenous ligands—the so-called orphan GPCRs. Orphan GPCRs offer tremendous promise, as they may provide novel therapeutic targets that may be more selective than currently known receptors, resulting in the potential reduction in side effects. In addition, they may provide access to signal transduction pathways currently unknown, allowing for new strategies in drug design. Regardless, orphan GPCRs are an important area of inquiry, as they represent a large gap in our understanding of signal transduction at the cellular level. Here, we focus on the therapeutic potential of two recently deorphanized GPCRs: GPR35/CXCR8 and GPR55. First, GPR35/CXCR8 has been observed in numerous tissues/organ systems, including the gastrointestinal tract, liver, immune system, central nervous system, and cardiovascular system. Not surprisingly, GPR35/CXCR8 has been implicated in numerous pathologies involving these tissues/systems. While several endogenous ligands have been identified, GPR35/CXCR8 has recently been observed to bind the chemokine CXCL17. Second, GPR55 has been observed to be expressed in the central nervous system, adrenal glands, gastrointestinal tract, lung, liver, uterus, bladder, kidney, and bone, as well as, other tissues/organ systems. Likewise, it is not surprising that GPR55 has been implicated in pathologies involving these tissues/systems. GPR55 was initially deorphanized as a cannabinoid receptor and this receptor does bind many cannabinoid compounds. However, the GPR55 endogenous ligand has been found to be a non-cannabinoid, lysophophatidylinositol (LPI) and subsequent high throughput assays have identified other GPR55 ligands that are not cannabinoids and do not bind to either the cannabinoid CB1 and CB2 receptors. Here, we review reports that suggest that GPR35/CXCR8 and GPR55 may be promising therapeutic targets, with diverse physiological roles.

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“…Receptor homology modeling efforts based on the protease-activated receptor 1 structure (the most closely related GPCR to GPR35 for which an atomic level structure is known) indicated that the species-equipotent ligands behaved like human-selective ligands at the human receptor and rat-selective ligands at the rat receptor ( Mackenzie et al, 2014 ), i.e., in order to generate an equipotent response the ligand must bind differently to each ortholog ( Figure 1 ). A number of similar residues were implicated in GPR35 ligand binding in an independent study, in which alanine substitutions were generated at putative ligand-binding residues, and the resulting mutants functionally assessed in a number of distinct assay formats including β-arrestin-2 translocation, extracellular-signal regulated kinase phosphorylation and calcium mobilization ( Zhao et al, 2014 ). In conjunction with receptor homology modeling efforts based on the β 2 -adrenoceptor, arginine residues at positions 4.60, 164, 167, and 6.58 were found to be involved in the binding and/or function of zaprinast and pamoic acid at human GPR35 ( Zhao et al, 2014 ).…”

Section: Receptor Homology Modeling Efforts Indicate That the Bindingmentioning

confidence: 99%

“…A number of similar residues were implicated in GPR35 ligand binding in an independent study, in which alanine substitutions were generated at putative ligand-binding residues, and the resulting mutants functionally assessed in a number of distinct assay formats including β-arrestin-2 translocation, extracellular-signal regulated kinase phosphorylation and calcium mobilization ( Zhao et al, 2014 ). In conjunction with receptor homology modeling efforts based on the β 2 -adrenoceptor, arginine residues at positions 4.60, 164, 167, and 6.58 were found to be involved in the binding and/or function of zaprinast and pamoic acid at human GPR35 ( Zhao et al, 2014 ).…”

Section: Receptor Homology Modeling Efforts Indicate That the Bindingmentioning

confidence: 99%

G protein-coupled receptor 35: an emerging target in inflammatory and cardiovascular disease

et al. 2015

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G protein-coupled receptor 35 (GPR35) is an orphan receptor, discovered in 1998, that has garnered interest as a potential therapeutic target through its association with a range of diseases. However, a lack of pharmacological tools and the absence of convincingly defined endogenous ligands have hampered the understanding of function necessary to exploit it therapeutically. Although several endogenous molecules can activate GPR35 none has yet been confirmed as the key endogenous ligand due to reasons that include lack of biological specificity, non-physiologically relevant potency and species ortholog selectivity. Recent advances have identified several highly potent synthetic agonists and antagonists, as well as agonists with equivalent potency at rodent and human orthologs, which will be useful as tool compounds. Homology modeling and mutagenesis studies have provided insight into the mode of ligand binding and possible reasons for the species selectivity of some ligands. Advances have also been made in determining the role of the receptor in disease. In the past, genome-wide association studies have associated GPR35 with diseases such as inflammatory bowel disease, type 2 diabetes, and coronary artery disease. More recent functional studies have implicated it in processes as diverse as heart failure and hypoxia, inflammation, pain transduction and synaptic transmission. In this review, we summarize the progress made in understanding the molecular pharmacology, downstream signaling and physiological function of GPR35, and discuss its emerging potential applications as a therapeutic target.

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Crucial Positively Charged Residues for Ligand Activation of the GPR35 Receptor

Cited by 20 publications

References 52 publications

Key Role for the Organic Anion Transporters, OAT1 and OAT3, in the in vivo Handling of Uremic Toxins and Solutes

Key Role for the Organic Anion Transporters, OAT1 and OAT3, in the in vivo Handling of Uremic Toxins and Solutes

The therapeutic potential of orphan GPCRs, GPR35 and GPR55

G protein-coupled receptor 35: an emerging target in inflammatory and cardiovascular disease

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