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Research Interests: Endocrinology, Chemistry, Biology, Membrane Proteins, Medicine, and 15 moreGene expression, Multidisciplinary, Humans, Internal Medicine, Female, Ovulation, Connective tissue, Menstrual Cycle, Binding Site, Endometrium, Gene Expression Regulation, Myometrium, Follicular phase, G Protein Coupled Receptors, and Luteal phase
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Research Interests: Chemistry, Medicine, Signal Transduction, Humans, Internal Medicine, and 12 moreEndothelial Cells, G protein-coupled receptors, cyclic AMP, Recombinant Proteins, cyclic GMP, Indomethacin, Relaxin, Vascular Smooth Muscle, G Protein Coupled Receptors, coculture techniques, Pharmacology and pharmaceutical sciences, and Coronary Vessels
Research Interests: Kinetics, Biology, Medicine, Signal Transduction, Humans, and 15 moreEndothelial Cells, G protein-coupled receptors, cyclic AMP, Phosphorylation, Receptor, Molecular Conformation, Protein Binding, Ligands, cyclic GMP, Agonist, Allosteric regulation, Relaxin, Myoblasts, Mitogen- Activated Protein Kinases, and G Protein Coupled Receptors
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IntroductionA potential role for the orphan G protein-coupled receptor, GPR21, in linking immune cell infiltration into tissues and obesity-induced insulin resistance has been proposed, although limited studies in mice are complicated by... more
IntroductionA potential role for the orphan G protein-coupled receptor, GPR21, in linking immune cell infiltration into tissues and obesity-induced insulin resistance has been proposed, although limited studies in mice are complicated by non-selective deletion of Gpr21.Research design and methodsWe hypothesized that a Gpr21-selective knockout mouse model, coupled with type 2 diabetes patient samples, would clarify these issues and enable clear assessment of GPR21 as a potential therapeutic target.ResultsHigh-fat feeding studies in Gpr21−/− mice revealed improved glucose tolerance and modest changes in inflammatory gene expression. Gpr21−/− monocytes and intraperitoneal macrophages had selectively impaired chemotactic responses to monocyte chemoattractant protein (MCP)-1, despite unaltered expression of Ccr2. Further genotypic analysis revealed that chemotactic impairment was due to dysregulated monocyte polarization. Patient samples revealed elevated GPR21 expression in peripheral b...
Research Interests: Endocrinology, Obesity, Inflammation, Endocrinology & Metabolism, Medicine, and 15 moreGene expression, Insulin Resistance, Internal Medicine, Diabetes mellitus, Homeostasis, Monocytes, Science Technology, Receptors, Type, Glucose Homeostasis, Chemokines, CCR, CCL, G Protein Coupled Receptors, and Monocyte
Relaxin family peptide receptors (RXFP, nomenclature as agreed by the NC-IUPHAR Subcommittee on Relaxin family peptide receptors [18, 81]) may be divided into two pairs, RXFP1/2 and RXFP3/4. Endogenous agonists at these receptors are... more
Relaxin family peptide receptors (RXFP, nomenclature as agreed by the NC-IUPHAR Subcommittee on Relaxin family peptide receptors [18, 81]) may be divided into two pairs, RXFP1/2 and RXFP3/4. Endogenous agonists at these receptors are heterodimeric peptide hormones structurally related to insulin: relaxin-1, relaxin, relaxin-3 (also known as INSL7), insulin-like peptide 3 (INSL3) and INSL5. Species homologues of relaxin have distinct pharmacology and relaxin interacts with RXFP1, RXFP2 and RXFP3, whereas mouse and rat relaxin selectively bind to and activate RXFP1 [184]. relaxin-3 is the ligand for RXFP3 but it also binds to RXFP1 and RXFP4 and has differential affinity for RXFP2 between species [183]. INSL5 is the ligand for RXFP4 but is a weak antagonist of RXFP3. relaxin and INSL3 have multiple complex binding interactions with RXFP1 [189] and RXFP2 [91] which direct the N-terminal LDLa modules of the receptors together with a linker domain to act as a tethered ligand to direct re...
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The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective... more
The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.14748. G protein‐coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic rec...
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Background and PurposeStrontium ranelate, a drug approved and until recently used for the treatment of osteoporosis, mediates its effects on bone at least in part via the calcium‐sensing (CaS) receptor. However, it is not known whether... more
Background and PurposeStrontium ranelate, a drug approved and until recently used for the treatment of osteoporosis, mediates its effects on bone at least in part via the calcium‐sensing (CaS) receptor. However, it is not known whether bone‐targeted CaS receptor positive allosteric modulators (PAMs; calcimimetics) represent an alternative (or adjunctive) therapy to strontium (Sr2+o).Experimental ApproachWe assessed three structurally distinct calcimimetics [cinacalcet, AC‐265347 and a benzothiazole tri‐substituted urea (BTU‐compound 13)], alone and in combination with extracellular calcium (Ca2+o) or Sr2+o, in G protein‐dependent signalling assays and trafficking experiments in HEK293 cells and their effects on cell differentiation, tartrate‐resistant acid phosphatase (TRAP) activity and hydroxyapatite resorption assays in human blood‐derived osteoclasts.Key ResultsSr2+o activated CaS receptor‐dependent signalling in HEK293 cells in a similar manner to Ca2+o, and inhibited the matur...
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Research Interests: Biology, Medicine, Signal Transduction, Humans, Endothelial Cells, and 10 moreG protein-coupled receptors, Mitogen Activated Protein Kinase, Recombinant Proteins, Gtp Binding Proteins, Matrix Metalloproteinase, Relaxin, fibroblasts, Umbilical Artery PH, G Protein Coupled Receptors, and Pharmacology and pharmaceutical sciences
Significance Statement Studies have shown that the hormone serelaxin, which has organ-protective actions mediated via relaxin family peptide receptor 1 (RXFP1), its cognate G protein–coupled receptor, requires the angiotensin II type 2... more
Significance Statement Studies have shown that the hormone serelaxin, which has organ-protective actions mediated via relaxin family peptide receptor 1 (RXFP1), its cognate G protein–coupled receptor, requires the angiotensin II type 2 receptor (AT2R) to ameliorate renal fibrogenesis in vitro and in vivo. In this study, the authors describe a functional interaction between RXFP1, AT2R, and the angiotensin II type 1 receptor (AT1R), all of which are expressed on extracellular matrix–producing myofibroblasts, the cellular basis of progressive fibrosis. The crosstalk between these G protein–coupled receptors allows antagonists acting at each receptor to directly or allosterically block the antifibrotic actions of agonists acting at AT2R or RXFP1. These findings have significant therapeutic implications for a mechanistic understanding of the concomitant use of drugs acting at each receptor. Background Recombinant human relaxin-2 (serelaxin), which has organ-protective actions mediated v...
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The nomenclature of the Adrenoceptors has been agreed by the NC-IUPHAR Subcommittee on Adrenoceptors [60, 186]. Adrenoceptors, α1 The three α1-adrenoceptor subtypes α1A, α1B and α1D are activated by the endogenous agonists (-)-adrenaline... more
The nomenclature of the Adrenoceptors has been agreed by the NC-IUPHAR Subcommittee on Adrenoceptors [60, 186]. Adrenoceptors, α1 The three α1-adrenoceptor subtypes α1A, α1B and α1D are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. -(-)phenylephrine, methoxamine and cirazoline are agonists and prazosin and doxazosin antagonists considered selective for α1- relative to α2-adrenoceptors. [3H]prazosin and [125I]HEAT (BE2254) are relatively selective radioligands. S(+)-niguldipine also has high affinity for L-type Ca2+ channels. Fluorescent derivatives of prazosin (Bodipy FLprazosin- QAPB) are used to examine cellular localisation of α1-adrenoceptors. α1-Adrenoceptor agonists are used as nasal decongestants; antagonists to treat symptoms of benign prostatic hyperplasia (alfuzosin, doxazosin, terazosin, tamsulosin and silodosin, with the last two compounds being α1A-adrenoceptor selective and claiming to relax bladder neck tone with less hypotension); and to ...
Research Interests: Pharmacology, Medicine, Phenylephrine, Prazosin, terazosin, and 3 moreYohimbine, Doxazosin, and Silodosin
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G protein-coupled receptors (GPCRs), the largest family of cell surface receptors, are targeted by approximately 35% of approved drugs that treat a wide variety of diseases including those of the cardiovascular, respiratory, metabolic,... more
G protein-coupled receptors (GPCRs), the largest family of cell surface receptors, are targeted by approximately 35% of approved drugs that treat a wide variety of diseases including those of the cardiovascular, respiratory, metabolic, and reproductive systems, and of the central, and peripheral nervous system. Currently the great majority of approved drugs interact with orthosteric binding sites on the receptor as agonists, partial agonists, antagonists or inverse agonists. Of some 800 GPCRs only about 12% have been utilised therapeutically with the remainder being either olfactory or orphan receptors with many having poorly understood signalling mechanisms. Drug development involving GPCRs in the early stages often utilises recombinant systems that tend to assume that cellular environment has little influence on response. However recent work suggests that membrane phospholipids, sphingolipids, glycolipids and sterols, and in particular cholesterol, influence membrane fluidity and ...
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In the phase III clinical trial, RELAX-AHF, serelaxin caused rapid and long-lasting haemodynamic changes. The cellular mechanisms involved are unclear in humans. This study examined the effects of serelaxin in co-cultures of human primary... more
In the phase III clinical trial, RELAX-AHF, serelaxin caused rapid and long-lasting haemodynamic changes. The cellular mechanisms involved are unclear in humans. This study examined the effects of serelaxin in co-cultures of human primary endothelial cells (ECs) and smooth muscle cells (SMCs) on cAMP and cGMP signalling. Stimulation of human umbilical vein endothelial cells (HUVECs) or human coronary artery endothelial cells (HCAECs) with serelaxin, concentration-dependently increased cGMP accumulation in co-cultured SMCs to a greater extent than in monocultures of either cell type. This was not observed in human umbilical artery endothelial cells (HUAECs) that do not express RXFP1. Treatment of ECs with L-NG-nitro arginine (L-NOARG) (30 μM, 30 min) inhibited serelaxin-mediated (30nM) cGMP accumulation in HUVECs, HCAECs and co-cultured SMCs. In HCAECs but not HUVECs, pre-incubation with indomethacin (30 μM, 30 min), also inhibited cGMP accumulation in SMCs. Pre-incubation of SMCs wi...
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arch 4, 2016 jpet.aspetjournals.org D ow nloaded from JPET #76901
Ligand-directed signaling at the β3-adrenoceptor produced by SR59230A relative to receptor agonists
The β3-adrenoceptor agonist L755507 and antagonist L748337 activate different signaling pathways in CHO-K1 cells stably expressing the human β3-adrenoceptor
Relaxin family peptide receptors, RXFP1 and RXFP2, modulate cAMP signalling by distinct mechanisms
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The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an... more
The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15538. G protein‐coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
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Relaxin family peptide receptors (RXFP, nomenclature as agreed by the NC-IUPHAR Subcommittee on Relaxin family peptide receptors [18, 75]) may be divided into two pairs, RXFP1/2 and RXFP3/4. Endogenous agonists at these receptors are... more
Relaxin family peptide receptors (RXFP, nomenclature as agreed by the NC-IUPHAR Subcommittee on Relaxin family peptide receptors [18, 75]) may be divided into two pairs, RXFP1/2 and RXFP3/4. Endogenous agonists at these receptors are heterodimeric peptide hormones structurally related to insulin: relaxin-1, relaxin, relaxin-3 (also known as INSL7), insulin-like peptide 3 (INSL3) and INSL5. Species homologues of relaxin have distinct pharmacology and relaxin interacts with RXFP1, RXFP2 and RXFP3, whereas mouse and rat relaxin selectively bind to and activate RXFP1 [172]. relaxin-3 is the ligand for RXFP3 but it also binds to RXFP1 and RXFP4 and has differential affinity for RXFP2 between species [170]. INSL5 is the ligand for RXFP4 but is a weak antagonist of RXFP3. relaxin and INSL3 have multiple complex binding interactions with RXFP1 [176] and RXFP2 [84] which direct the N-terminal LDLa modules of the receptors together with a linker domain to act as a tethered ligand to direct re...
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The nomenclature of the Adrenoceptors has been agreed by the NC-IUPHAR Subcommittee on Adrenoceptors [58], see also [180]. Adrenoceptors, α1α1-Adrenoceptors are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline.... more
The nomenclature of the Adrenoceptors has been agreed by the NC-IUPHAR Subcommittee on Adrenoceptors [58], see also [180]. Adrenoceptors, α1α1-Adrenoceptors are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. phenylephrine, methoxamine and cirazoline are agonists and prazosin and cirazoline antagonists considered selective for α1- relative to α2-adrenoceptors. [3H]prazosin and [125I]HEAT (BE2254) are relatively selective radioligands. S(+)-niguldipine also has high affinity for L-type Ca2+ channels. Fluorescent derivatives of prazosin (Bodipy PLprazosin- QAPB) are used to examine cellular localisation of α1-adrenoceptors. Selective α1-adrenoceptor agonists are used as nasal decongestants; antagonists to treat hypertension (doxazosin, prazosin) and benign prostatic hyperplasia (alfuzosin, tamsulosin). The α1- and β2-adrenoceptor antagonist carvedilol is used to treat congestive heart failure, although the contribution of α1-adrenoceptor blockade to the ther...
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The effects of two beta-adrenoceptor antagonists, propranolol (0.2 mg/kg) and metoprolol (0.2 mg/kg) on some physiological and metabolic changes produced by maximal exercise in the horse were investigated. Both drugs reduced the elevation... more
The effects of two beta-adrenoceptor antagonists, propranolol (0.2 mg/kg) and metoprolol (0.2 mg/kg) on some physiological and metabolic changes produced by maximal exercise in the horse were investigated. Both drugs reduced the elevation in heart rate seen immediately following exercise and reduced performance as was seen by the increased time taken to perform each gallop. The rise in plasma glucose, glycerol and lactate, and the fall in blood pH seen following exercise were attenuated by both drugs. However, a greater increase in plasma free fatty acids occurred. Exercise produced a nine- to 12-fold increase in plasma noradrenaline levels. Neither drug had any effect on resting levels of noradrenaline but after metoprolol the levels during exercise were increased.
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The capacity of G protein-coupled receptors to modulate mammalian target of rapamycin (mTOR) activity is a newly emerging paradigm with the potential to link cell surface receptors with cell survival. Cardiomyocyte viability is linked to... more
The capacity of G protein-coupled receptors to modulate mammalian target of rapamycin (mTOR) activity is a newly emerging paradigm with the potential to link cell surface receptors with cell survival. Cardiomyocyte viability is linked to signaling pathways involving Akt and mTOR, as well as increased glucose uptake and utilization. Our aim was to determine whether the α1A-adrenoceptor (AR) couples to these protective pathways, and increased glucose uptake. We characterised α1A-AR signalling in CHO-K1 cells co-expressing the human α1A-AR and GLUT4 (CHOα1AGLUT4myc) and in neonatal rat ventricular cardiomyocytes (NRVM), and measured glucose uptake, intracellular Ca2+ mobilization, and phosphorylation of mTOR, Akt, 5' adenosine monophosphate-activated kinase (AMPK) and S6 ribosomal protein. In both systems, noradrenaline and the α1A-AR selective agonist A61603 stimulated glucose uptake by parallel pathways involving mTOR and AMPK, whereas another α1-AR agonist oxymetazoline increase...
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Recruitment and activation of brite (or beige) adipocytes has been advocated as a potential avenue for manipulating whole-body energy expenditure. Despite numerous studies illustrating the differences in gene and protein markers between... more
Recruitment and activation of brite (or beige) adipocytes has been advocated as a potential avenue for manipulating whole-body energy expenditure. Despite numerous studies illustrating the differences in gene and protein markers between brown, brite and white adipocytes, there is very little information on the adrenergic regulation and function of these brite adipocytes. We have compared the functional (cyclic AMP accumulation, oxygen consumption rates, mitochondrial function, glucose uptake, extracellular acidification rates, calcium influx) profiles of mouse adipocytes cultured from three contrasting depots, namely interscapular brown adipose tissue, and inguinal or epididymal white adipose tissues, following chronic treatment with the peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone. Prototypical brown adipocytes readily express β3-adrenoceptors, and β3-adrenoceptor stimulation increases cyclic AMP accumulation, oxygen consumption rates, mitochondrial fu...
Research Interests: Endocrinology, Chemistry, Biology, Mitochondria, Medicine, and 15 moreSignal Transduction, Adipose tissue, Cellular Signalling, Internal Medicine, Glucose, Mice, cyclic AMP, Animals, Male, Primary Cell Culture, Rosiglitazone, Uncoupling Protein, Oxygen Consumption, Biochemistry and cell biology, and Gene Expression Regulation
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Pertussis-like toxins are secreted by several bacterial pathogens during infection. They belong to the AB5 virulence factors, which bind to glycans on host cell membranes for internalization. Host cell recognition and internalization are... more
Pertussis-like toxins are secreted by several bacterial pathogens during infection. They belong to the AB5 virulence factors, which bind to glycans on host cell membranes for internalization. Host cell recognition and internalization are mediated by toxin B subunits sharing a unique pentameric ring-like assembly. While the role of pertussis toxin in whooping cough is well established, pertussis-like toxins produced by other bacteria are less studied and their mechanisms of action are unclear. Here, we report that some extra-intestinal Escherichia coli pathogens (i.e. those that reside in the gut but can spread to other bodily locations) encode a pertussis-like toxin that inhibits mammalian cell growth in vitro. We found that this protein, EcPlt is related to toxins produced by both nontyphoidal and typhoidal Salmonella serovars. Pertussis-like toxins are secreted as disulfide-bonded heterohexamers in which the catalytic ADP-ribosyltransfersase subunit is activated when exposed to th...
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Activation of the relaxin receptor RXFP1 has been associated with improved survival in acute heart failure. ML290 is a small molecule RXFP1 agonist with simple structure, long half-life and high stability. Here we demonstrate that ML290... more
Activation of the relaxin receptor RXFP1 has been associated with improved survival in acute heart failure. ML290 is a small molecule RXFP1 agonist with simple structure, long half-life and high stability. Here we demonstrate that ML290 is a biased agonist in human cells expressing RXFP1 with long-term beneficial actions on markers of fibrosis in human cardiac fibroblasts (HCFs). ML290 did not directly compete with orthosteric relaxin binding and did not affect binding kinetics, but did increase binding to RXFP1. In HEK-RXFP1 cells, ML290 stimulated cAMP accumulation and p38MAPK phosphorylation but not cGMP accumulation or ERK1/2 phosphorylation although prior addition of ML290 increased p-ERK1/2 responses to relaxin. In human primary vascular endothelial and smooth muscle cells that endogenously express RXFP1, ML290 increased both cAMP and cGMP accumulation but not p-ERK1/2. In HCFs, ML290 increased cGMP accumulation but did not affect p-ERK1/2 and given chronically activated MMP-2...
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Agonists acting at G protein-coupled receptors promote biased signalling via Gα or Gβγ subunits, G protein-coupled receptor kinases and β-arrestins. Since demonstration of biased agonism has implications for drug discovery, it is... more
Agonists acting at G protein-coupled receptors promote biased signalling via Gα or Gβγ subunits, G protein-coupled receptor kinases and β-arrestins. Since demonstration of biased agonism has implications for drug discovery, it is essential to consider confounding factors contributing to bias. We have examined bias at human α1A -adrenoceptors stably expressed at low levels in CHO-K1 cells, identifying off-target effects at endogenous receptors that contribute to ERK1/2 phosphorylation in response to the agonist oxymetazoline. Intracellular Ca(2+) mobilization was monitored in a Flexstation® using Fluo 4-AM. cAMP accumulation and ERK1/2 phosphorylation were measured using AlphaScreen® proximity assays. mRNA expression was measured by RT-qPCR. Ligand bias was determined using the operational model of agonism. Noradrenaline, phenylephrine, methoxamine and A61603 increased Ca(2+) mobilisation, cAMP accumulation and ERK1/2 phosphorylation. However, oxymetazoline showed low efficacy for Ca...