Bronwyn A Evans

Bronwyn A Evans

PhD

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96
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3,403
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Publications

Publications (96)
Article
Full-text available
The β3 -adrenoceptor agonist mirabegron is approved for use for overactive bladder and has been purported to be useful in the treatment of obesity-related metabolic diseases in humans, including those involving disturbances of glucose homeostasis. We investigated the effect of mirabegron on glucose homeostasis with in vitro and in vivo models, focu...
Article
Full-text available
β3-Adrenoceptors exhibit a restricted expression pattern, particularly in humans. However, they have been found to be upregulated in various cancers and under several conditions associated with hypoperfusion such as congestive heart failure and diabetes for instance in the heart and other tissues. These conditions are frequently associated with hyp...
Article
The type 2 diabetes epidemic makes it important to find insulin-independent ways to improve glucose homeostasis. This study examines the mechanisms activated by a dual β2-/β3-adrenoceptor agonist, BRL37344, to increase glucose uptake in skeletal muscle and its effects on glucose homeostasis in vivo. We measured the effect of BRL37344 on glucose upt...
Article
Adrenoceptors play an important role in adipose tissue biology and physiology, that includes regulating the synthesis and storage of triglycerides (lipogenesis), the breakdown of stored triglycerides (lipolysis), thermogenesis (heat production), glucose metabolism, and the secretion of adipocyte derived hormones that can control whole body energy h...
Article
A vital role of adrenoceptors in metabolism and energy balance has been well‐documented in heart, skeletal muscle, and adipose tissue. It has been only recently demonstrated, however, that activation of mechanistic/mammalian target of rapamycin (mTOR) makes a significant contribution to various metabolic and physiological responses to adrenoceptor...
Article
G protein–coupled receptors (GPCRs) are the largest class of cell surface signaling proteins, participate in nearly all physiological processes, and are the targets of 30% of marketed drugs. Typically, nanomolar to micromolar concentrations of ligand are used to activate GPCRs in experimental systems. We detected GPCR responses to a wide range of l...
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Full-text available
The recruitment of brite (or beige) adipocytes has been advocated as a means to combat obesity, due to their ability to phenotypically resemble brown adipocytes (BA). Lineage studies indicate that brite adipocytes are formed by differentiation of precursor cells or by direct conversion of existing white adipocytes, depending on the adipose depot ex...
Article
Insulin-like peptide 5 (INSL5) is a newly discovered gut hormone expressed in colonic enteroendocrine L-cells but little is known about its biological function. Here, we show using RT-qPCR andin situhybridisation thatInsl5mRNA is highly expressed in the mouse colonic mucosa, colocalised with proglucagon immunoreactivity. In comparison, mRNA for RXF...
Article
Introduction: The beta3-adrenoceptor was initially a target for obesity and diabetes treatment, but several beta3-adrenoceptor agonists failed in clinical trials due to their lack of efficacy at the human beta3-adrenoceptor. Recently, the beta3-adrenoceptor agonist mirabegron has been approved for use in humans for overactive bladder, but there is...
Article
Background: Cyclic AMP (cAMP) is a key second messenger involved in β2-adrenoceptor (β2-AR) mediated glucose uptake in skeletal muscle, but in vivo causes adverse effects including altered vasoreactivity and hypertrophy. It has been suggested that BRL37344 (BRL), a dual β2/β3-AR agonist originally developed for the treatment of obesity, increases s...
Article
Background: There has been convincing evidence that cardiac α1A-adrenoceptors (α1A-ARs) increase in expression and have an enhanced compensatory role during advanced heart failure (O'Connell et al, 2014). Mechanistic target of rapamycin (mTOR) signalling is involved in many critical cellular processes, and implicated in early development, normal fu...
Article
Insulin-like peptide 5 (INSL5) is a newly discovered gut hormone with little known about its biological function. Here, we show using RT-qPCR and in situ hybridisation that Insl5 mRNA is highly expressed in the mouse colonic mucosa, colocalised with proglucagon immunoreactivity. In comparison, mRNA for RXFP4 (the cognate receptor for INSL5) is expr...
Article
Full-text available
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 d...
Article
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...
Article
Background and purpose: 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...
Article
Uptake of glucose into skeletal muscle and adipose tissue plays a vital role in metabolism and energy balance. Insulin released from β-islet cells of the pancreas promotes glucose uptake in these target tissues by stimulating translocation of GLUT4 transporters to the cell surface. This process is complex, involving signalling proteins including th...
Article
The relaxin family peptide receptor 4 (RXFP4) is a G protein-coupled receptor (GPCR) expressed in the colorectum with emerging roles in metabolism and appetite regulation. It is activated by its cognate ligand insulin-like peptide 5 (INSL5) that is expressed in enteroendocrine L cells in the gut. Whether other evolutionarily related peptides such a...
Article
Background and purpose: Insulin-like peptide 5 (INSL5) is a two-chain, three-disulphide bonded peptide of the insulin/relaxin superfamily, uniquely expressed in enteroendocrine L-cells of the colon. It is the cognate ligand of relaxin family peptide receptor 4 (RXFP4) that is mainly expressed in the colorectum and enteric nervous system. This stud...
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Full-text available
There are two types of adipose tissue with distinct functions - white adipose tissue (WAT) stores chemical energy as triglycerides, whereas brown adipose tissue (BAT) consumes energy and releases heat (thermogenesis) in response to sympathetic nerve activity. In humans, treatments that promote greater BAT deposition and/or activity would be highly...
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The Concise Guide to PHARMACOLOGY 2013/14 provides concise overviews of the key properties of over 2000 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties from the IUPHAR database. T...
Article
In the July 12 issue of Science magazine, researchers from the Albert Einstein College of Medicine, the Mount Sinai School of Medicine, the Durham VA Medical Centre and Duke University published an elegant study demonstrating that the sympathetic nervous system, acting through beta(2) and beta(3)-adrenoceptors in the prostate, plays an important ro...
Article
Full-text available
ρ-Da1a is a three-finger fold toxin from green mamba venom that is highly selective for the α1A-adrenoceptor. This toxin has atypical pharmacological properties, including incomplete inhibition of 3H-prazosin or 125I-HEAT binding and insurmountable antagonist action. We aimed to clarify its mode of action at the α1A-adrenoceptor. The affinity (pKi...
Data
Recombinant expression of ρ-Da1a. (DOCX)
Article
Full-text available
The capacity of G protein-coupled receptors (GPCRs) to activate multiple G protein isoforms and additional effectors such as β-arrestins has become a well-established paradigm and provides the basis for developing drugs that preferentially activate beneficial signalling pathways. There are many published examples of ligand-directed signalling, and...
Article
Full-text available
Caveolins act as scaffold proteins in multiprotein complexes and have been implicated in signaling by G protein-coupled receptors. Studies using knock-out mice suggest that β3-adrenoceptor (β3-AR) signaling is dependent on caveolin-1; however, it is not known whether caveolin-1 is associated with the β3-AR or solely with downstream signaling protei...
Article
β-Adrenoceptor stimulation induces glucose uptake in several insulin-sensitive tissues by poorly understood mechanisms. We used a model system in CHO-K1 cells expressing the human β(2)-adrenoceptor and glucose transporter 4 (GLUT4) to investigate the signalling mechanisms involved. In CHO-K1 cells, there was no response to β-adrenoceptor agonists....
Article
Full-text available
Although G protein-coupled receptors are often categorized in terms of their primary coupling to a given type of Gα protein subunit, it is now well established that many show promiscuous coupling and activate multiple signaling pathways. Furthermore, some agonists selectively activate signaling pathways by promoting interaction between distinct rec...
Article
β-Adrenoceptors (ARs) classically mediate responses to the endogenous ligands adrenaline and noradrenaline by coupling to Gsα and stimulating cAMP production; however, drugs designed as β-AR agonists or antagonists can activate alternative cell signalling pathways, with the potential to influence clinical efficacy. Furthermore, drugs acting at β-AR...
Article
The role of muscarinic acetylcholine receptors (mAChRs) in regulating glucose uptake in L6 skeletal muscle cells was investigated. [(3)H]-2-Deoxyglucose uptake was increased in differentiated L6 cells by insulin, acetylcholine, oxotremorine-M and carbachol. mAChR-mediated glucose uptake was inhibited by the AMPK inhibitor Compound C. Whole cell rad...
Article
The relaxin family peptide receptors RXFP1 and RXFP2 are highly similar receptors that share approximately 80% amino acid sequence homology. Constitutively active receptors couple to increased cAMP accumulation, which is important for relaxin-mediated decidualization and myometrial inhibition. Despite the high homology, the receptors couple to diff...
Article
Levels of β3-adrenoceptor (AR) mRNA were compared using reverse transcription-polymerase chain reaction (RT–PCR) in white adipose tissue (WAT), brown adipose tissue (BAT), ileum and colon from genetically obese (ob/ob) and lean (+/+) C57BL/6J mice. Functional responses to the β3-AR agonist CL 316243 were also characterized in ileal longitudinal smo...
Article
Full-text available
The relaxin family peptide receptors (RXFP) 1 and 2 are targets for the relaxin family peptides relaxin and insulin-like peptide 3 (INSL3), respectively. Although both receptors and peptides share a high degree of sequence identity, the cAMP signaling pathways activated by the two systems are quite distinct. Relaxin activation of RXFP1 initially re...
Article
Full-text available
This study identifies signaling pathways activated by the beta(2)-/beta(3)-adrenoceptor (AR) agonist zinterol, the selective beta(3)-AR agonist L755507, and the selective beta(3)-AR antagonist L748337 in CHO-K1 cells expressing human beta(3)-adrenoceptors. Zinterol and L755507 caused a robust concentration-dependent increase in cAMP accumulation (p...
Article
Full-text available
Localization of G-protein-coupled receptors within membrane microdomains is associated with differential signalling pathway activation. We have shown that two mouse beta(3)-AR (beta(3)-adrenoceptor) isoforms encoded by alternatively spliced mRNAs differ in their signalling properties; the beta(3a)-AR couples only with G(s), whereas the beta(3b)-AR...
Article
Full-text available
This study examines signaling pathways activated by the mouse beta(3)-adrenoceptor (AR) expressed in Chinese hamster ovary cells at high (CHObeta(3)H) or low (CHObeta(3)L) levels. Functional responses included extracellular acidification rate (ECAR), cAMP accumulation, and p38 mitogen-activated protein kinase (MAPK) or extracellular signal-regulate...
Article
Localization of G-protein-coupled receptors within membrane microdomains is associated with differential signalling pathway activation. We have shown that two mouse β3-AR (β3-adrenoceptor) isoforms encoded by alternatively spliced mRNAs differ in their signalling properties; the β3a-AR couples only with Gs, whereas the β3b-AR couples with both Gs a...
Article
β-adrenoceptor (AR) agonists increase 2-deoxy-[3H]-D-glucose uptake (GU) via β2-AR in rat L6 cells. The β-AR agonists, zinterol (β2-AR) and (−)-isoprenaline, increased cAMP accumulation in a concentration-dependent manner (pEC50=9.1±0.02 and 7.8±0.02). Cholera toxin (% max increase 141.8±2.5) and the cAMP analogues, 8-bromo-cAMP (8Br-cAMP) and dibu...
Article
Full-text available
Alternative splicing of mouse beta3-adrenoceptor transcripts produces an additional receptor isoform (beta3b-adrenoceptor) with a C terminus comprising 17 amino acids distinct from the 13 in the known receptor (beta3a-adrenoceptor). We have shown that the beta3b-adrenoceptor couples to both Gs and Gi, whereas the beta3a-adrenoceptor couples only to...
Article
Full-text available
This study examines the action of the beta(3)-adrenoceptor antagonist SR59230A [3-(2-ethylphenoxy)-1-[(1,S)-1,2,3,4-tetrahydronapth-1-ylamino]-2S-2-propanoloxalate] at cloned mouse beta(3)-adrenoceptors expressed in Chinese hamster ovary cells (CHO-K1-beta(3)) or endogenously expressed in 3T3-F442A adipocytes or ileum. SR59230A displayed partial ag...
Article
1. The adrenoceptors (AR) are an important subfamily of rhodopsin-like G-protein-coupled receptors that couple to an increasingly large number of signalling mechanisms. Two important factors that determine the pathways that are used are the C-terminal region of the receptor and the agonist used to activate the receptor. 2. Studies of splice variant...
Article
This study examines the stereoselectivity profile of recombinant mouse, rat and human beta(3)-adrenoceptors expressed in Chinese Hamster Ovary (CHO-K1) cells using radioligand binding, in comparison with endogenously expressed beta(3)-adrenoceptors mediating relaxation responses in mouse ileum. The enantiomeric ratios for several beta-adrenoceptor...
Article
The receptor that mediates the increase in glucose transport (GT) in response to β-adrenoceptor (β-AR) agonists was characterized in the rat skeletal muscle cell line L6, using the 2-deoxy-[3H]-D-glucose assay. The β3-AR agonist BRL37344 (pEC50=6.89±0.21), the β-AR agonist isoprenaline (pEC50=8.99±0.24) and the β2-AR agonist zinterol (pEC50=9.74±0....
Article
This study characterizes the mouse β3a-adrenoceptor (AR) and the splice variant of the β3-AR (β3b-AR) expressed in Chinese hamster ovary cells (CHO-K1). Stable clones with high (∼1200), medium (∼500) or low receptor expression (∼100 fmol mg protein−1) were determined by saturation binding with [125I]-(−)-cyanopindolol. Competition binding studies s...
Article
This study examines β1-, β2- and β3-adrenoceptor (AR)-mediated responses, mRNA levels and radioligand binding in ileum from β3-AR knock-out (−/−) (KO) and wild type (+/+) (FVB) mice. In KO and FVB mice, SR59230A (100 nM) (β3-AR antagonist) antagonized responses to (−)-isoprenaline in both KO and FVB mice. (−)-Isoprenaline mediated relaxation of ile...
Article
This study examines the relationship between β3a- and β3b-adrenoceptor (AR) mRNA levels, β3-AR binding and changes in ileum responses in mice treated with the β3-AR agonist (R,R)-5-[2[[2-(3-chlorophenyl)-2-hydroxyethyl]-amino]-propyl]1,3-benzodioxole-2,2-dicarboxylate (CL316243), or the β3-AR antagonist 3-(2-ethylphenoxy)-1-[(1S)-1,2,3,4-tetrahydro...
Article
The β3-adrenoceptor (AR) differs from the β1-AR and β2-ARs in having introns within and downstream of the coding block. This study demonstrates two splice variants of the mouse β3-AR which differ within the coding region. Reverse transcription/polymerase chain reaction with intron-spanning primers was used to demonstrate the splice variant of the m...
Article
Functional and molecular approaches were used to characterize the β-AR subtypes mediating relaxation of rat ileal smooth muscle. In functional studies, (−)-isoprenaline relaxation was unchanged by CGP20712A (β1-AR antagonist) or ICI118551 (β2-AR antagonist) but shifted by propranolol (pKB=6.69). (±)-Cyanopindolol, CGP12177 and ICID7114 did not caus...
Article
This study examined mechanisms of beta-adrenergic (AR) desensitization in a myocardial infarction (MI) model of heart failure in the rat. Inotropic responses to isoproterenol (non-selective beta-AR agonist) and RO 363 (selective beta1-AR agonist), in left atria and left papillary muscle, were reduced by up to 65%, while chronotropic responses in ri...
Article
The objectives of this study were to determine whether leptin synthesis is regulated by the sympathetic nervous system and if so whether beta-adrenergic receptors mediate this effect. We show that sympathetic blockade by reserpine increases leptin mRNA levels in brown but not white adipose tissue, while acute cold-exposure decreases leptin expressi...
Data
On or before Jun 10, 2016 this sequence version replaced gi:2842769, gi:2842770, gi:2842771, gi:2842772, gi:2842773, gi:2842774.
Article
Relaxation of carbachol pre-contracted human colonic muscle to (–)-isoprenaline was examined in circular, longitudinal and taenia coli preparations to determine the β-adrenoceptor subtypes involved. β1-, β2- and β3-Adrenoceptor mRNAs were also measured in colonic muscle and mucosa. (–)-Isoprenaline caused relaxation of longitudinal smooth muscle pr...
Article
1. This study examines the expression of beta 3-adrenoceptor messenger RNA (beta 3-AR mRNA) in rat tissues to allow comparison with atypical beta-adrenoceptors determined by functional and radioligand binding techniques. 2. A reverse transcription/polymerase chain reaction protocol has been developed for determining the relative amounts of beta 3-A...
Article
The reverse transcription/polymerase chain reaction was used to demonstrate beta 3-adrenoceptor mRNA in rat brain regions. Levels were highest in hippocampus, cerebral cortex and striatum and lower in hypothalamus, brainstem and cerebellum.
Article
The exact location of the cells which express erythropoietin (Epo) in the kidney is still controversial, with conflicting reports suggesting that both peritubular interstitial cells or proximal tubular epithelial cells are possible sites of Epo expression. In the present study we have examined the location of Epo-expressing cells in fetal and adult...
Article
The reverse transcription/polymerase chain reaction was used to demonstrate β3‐adrenoceptor mRNA in rat brain regions. Levels were highest in hippocampus, cerebral cortex and striatum and lower in hypothalamus, brainstem and cerebellum.
Article
Relaxin is a peptide hormone which has a variety of physiological effects on tissues of the reproductive tract as well as other organs such as the heart and brain. Whereas all non-primates so far examined have only a single relaxin gene, humans have two genes (H1 and H2, or gene 1 and gene 2). H2 relaxin is synthesized in the corpus luteum during p...
Article
Erythropoietin (Epo) production was studied in adult sheep. Nine ewes, body weight (BW) 39 +/- 1.3 kg, were hemorrhaged a volume of blood equivalent to 1.6% BW, and sampled at 0, 2, 4, 6, 24 h. Oxygen content (O2 CT) decreased by 2.7 +/- 0.6 ml/dl at 2 h. Plasma immunoreactive (IR) Epo was only significantly increased at 24 h, from 18.5 +/- 3.5 to...
Article
Relaxin is a polypeptide hormone that has a variety of physiological effects both on remodelling of collagen and on uterine contractility. These are most apparent during pregnancy. The sequences of relaxin cDNAs derived from ovaries of late-pregnant random-bred Swiss mice have been established. Multiple subclones obtained from three independent pol...
Article
Relaxin is a polypeptide hormone that exerts a variety of physiological effects during pregnancy. To investigate the possibility that known genetic mutations affecting aspects of reproductive physiology result in alterations in the structure or production of relaxin, we have determined the chromosomal location of the mouse gene. The finding of a Ba...
Article
Full-text available
Mouse gamma-renin is a member of the group of serine proteases known as glandular kallikreins. These highly homologous proteins process a diverse range of growth factors and hormones to their biologically active form, usually by cleavage at a basic residue. gamma-Renin, however, cleaves at a Leu-Leu bond in a similar fashion to renin. We have ident...
Article
Glandular kallikreins are a family of proteases encoded by a variable number of genes in different mammalian species. In all species examined, however, one particular kallikrein is functionally conserved in its capacity to release the vasoactive peptide, Lys-bradykinin, from low molecular weight kininogen. This kallikrein is found in the kidney, pa...
Article
The process of cleaving one protein with another is a very basic one in biology. In many organisms mature proteins are released from their precursor forms by the action of proteases. Proteolysis is used extensively in other important processes such as the coagulation cascades and in the biosynthesis of biologically active peptides. Peptide biosynth...