Publications by authors named "Walter G Thomas"

Bitter taste receptors (T2R) are a subfamily of G protein-coupled receptors that enable humans to detect aversive and toxic substances. The ability to discern bitter compounds varies between individuals and is attributed mainly to naturally occurring T2R polymorphisms. T2Rs are also expressed in numerous non-gustatory tissues, including the heart, indicating potential contributions to cardiovascular physiology.

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Phenotypic and transcriptomic evidence of early cardiac aging, and associated mechanisms, were investigated in young to middle-aged male mice (C57Bl/6; ages 8, 16, 32, 48 wks). Left ventricular gene expression (profiled via Illumina MouseWG-6 BeadChips), contractile and coronary function, and stress-resistance were assessed in Langendorff perfused hearts under normoxic conditions and following ischemic insult (20 min global ischemia-45 min reperfusion; I-R). Baseline or normoxic contractile function was unaltered by age, while cardiac and coronary 'reserves' (during β-adrenoceptor stimulation; 1 μM isoproterenol) declined by 48 wks.

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Venoms are excellent model systems for studying evolutionary processes associated with predator-prey interactions. Here, we present the discovery of a peptide toxin, MIITX-Mg1a, which is a major component of the venom of the Australian giant red bull ant and has evolved to mimic, both structurally and functionally, vertebrate epidermal growth factor (EGF) peptide hormones. We show that Mg1a is a potent agonist of the mammalian EGF receptor ErbB1, and that intraplantar injection in mice causes long-lasting hypersensitivity of the injected paw.

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Transforming growth factor (TGF)-β signalling commences with the engagement of TGF-β ligand to cell surface TGF-β receptors (TGFBR) stimulating Smad2 carboxyl-terminal phosphorylation (phospho-Smad2C) and downstream biological responses. In several cell models, G protein-coupled receptors (GPCRs) transactivate the TGF-β receptors type-1 (TGFBR1) leading to phospho-Smad2C, however, we have recently published that in keratinocytes thrombin did not transactivate the TGFBR1. The bulk of TGFBRs reside in the cytosol and in response to protein kinase B (Akt phosphorylation) can translocate to the cell surface increasing the cell's responsiveness to TGF-β.

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People with diabetes mellitus are susceptible to both cardiovascular disease and severe influenza A virus infection. We hypothesized that diabetes also increases risks of influenza-associated cardiac complications. A murine type 1 (streptozotocin-induced) diabetes model was employed to investigate influenza-induced cardiac distress.

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Background: Ischemia-reperfusion injury (IRI) is one of the major risk factors implicated in morbidity and mortality associated with cardiovascular disease. During cardiac ischemia, the buildup of acidic metabolites results in decreased intracellular and extracellular pH, which can reach as low as 6.0 to 6.

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Epidermal growth factor (EGF) receptors (ErbB1-ErbB4) promote cardiac development and growth, although the specific EGF ligands and receptor isoforms involved in growth/repair versus pathology remain undefined. We challenged ventricular cardiomyocytes with EGF-like ligands and observed that selective activation of ErbB4 (the receptor for neuregulin 1 [NRG1]), but not ErbB1 (the receptor for EGF, EGFR), stimulated hypertrophy. This lack of direct ErbB1-mediated hypertrophy occurred despite robust activation of extracellular-regulated kinase 1/2 (ERK) and protein kinase B.

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Transactivation of the epidermal growth factor receptor (EGFR) by the angiotensin II (AngII) type 1 (AT) receptor is involved in AT receptor-dependent growth effects and cardiovascular pathologies, however the mechanisms underpinning this transactivation are yet to be fully elucidated. Recently, a potential intermediate of this process was identified following the discovery that a kinase called TRIO was involved in AngII/AT receptor-mediated transactivation of EGFR. To investigate the mechanisms by which TRIO acts as an intermediate in AngII/AT receptor-mediated EGFR transactivation we used bioluminescence resonance energy transfer (BRET) assays to investigate proximity between the AT receptor, EGFR, TRIO and other proteins of interest.

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None of the current superresolution microscopy techniques can reliably image the changes in endogenous protein nanoclustering dynamics associated with specific conformations in live cells. Single-domain nanobodies have been invaluable tools to isolate defined conformational states of proteins, and we reasoned that expressing these nanobodies coupled to single-molecule imaging-amenable tags could allow superresolution analysis of endogenous proteins in discrete conformational states. Here, we used anti-GFP nanobodies tagged with photoconvertible mEos expressed as intrabodies, as a proof-of-concept to perform single-particle tracking on a range of GFP proteins expressed in live cells, neurons, and small organisms.

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The human genome contains ∼29 bitter taste receptors (T2Rs), which are responsible for detecting thousands of bitter ligands, including toxic and aversive compounds. This sentinel function varies between individuals and is underpinned by naturally occurring T2R polymorphisms, which have also been associated with disease. Recent studies have reported the expression of T2Rs and their downstream signaling components within non-gustatory tissues, including the heart.

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Background: Influenza A virus (IAV) causes a wide range of extrarespiratory complications. However, the role of host factors in these complications of influenza virus infection remains to be defined.

Methods: Here, we sought to use transcriptional profiling, virology, histology, and echocardiograms to investigate the role of a high-fat diet in IAV-associated cardiac damage.

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G protein-coupled receptors (GPCRs) convert extracellular stimuli to intracellular responses that regulate numerous physiological processes. Crystallographic and biophysical advances in GPCR structural analysis have aided investigations of structure-function relationships that clarify our understanding of these dynamic receptors, but the molecular mechanisms associated with activation and signaling for individual GPCRs may be more complex than was previously appreciated. Here, we investigated the proposed water-mediated, hydrogen-bonded activation switch between the conserved NPxxY motif on transmembrane helix 7 (TMH7) and a conserved tyrosine in TMH5, which contributes to α-adrenoceptor (α-AR) and β-AR activation.

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The type 1 angiotensin II (AngII) receptor (ATR) transactivates the epidermal growth factor receptor (EGFR), which leads to pathological remodeling of heart, blood vessels and kidney. End-point assays are used as surrogates of EGFR activation, however these downstream readouts are not applicable to live cells, in real-time. Herein, we report the use of a bioluminescence resonance energy transfer (BRET)-based assay to assess recruitment of the EGFR adaptor protein, growth factor receptor-bound protein 2 (Grb2), to the EGFR.

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The mammalian heart undergoes maturation during postnatal life to meet the increased functional requirements of an adult. However, the key drivers of this process remain poorly defined. We are currently unable to recapitulate postnatal maturation in human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs), limiting their potential as a model system to discover regenerative therapeutics.

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Caveolae and associated cavin and caveolins may govern myocardial function, together with responses to mechanical and ischaemic stresses. Abnormalities in these proteins are also implicated in different cardiovascular disorders. However, specific roles of the cavin-1 protein in cardiac and coronary responses to mechanical/metabolic perturbation remain unclear.

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The epidermal growth factor receptor (EGFR) family comprises the ErbB1 (EGFR) and ErbB4 receptors as well as the 'co-receptors' ErbB2 (which does not bind EGF ligands) and ErbB3 (which lack tyrosine kinase activity). This family of receptors is essential for cardiac development, myocardial, renal and vascular function, and cardiac responses to physiological and pathological perturbations. The EGFR appears critical in protecting cardiac cells from injury, while considerable attention has focussed on neuregulin/ErbB4 signalling in potentially ameliorating cardiomyopathy/heart failure.

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Endothelial cells form a critical component of the coronary vasculature, yet the factors regulating their development remain poorly defined. Here we reveal a novel role for the transmembrane protein CRIM1 in mediating cardiac endothelial cell development. In the absence of Crim1 in vivo, the coronary vasculature is malformed, the number of endothelial cells reduced, and the canonical BMP pathway dysregulated.

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Article Synopsis
  • - The epicardium is important for heart development, providing signals and cells that support the formation of the heart during embryonic growth; however, the specific function of the Crim1 protein in this process was previously unclear.
  • - Research using knockout mouse models shows that losing Crim1 leads to significant heart defects, including issues with the epicardium and reduced heart muscle development, and affects critical processes like cell migration and differentiation.
  • - Crim1 is essential for the proper growth and behavior of heart-related cells and may influence growth factor activity, emphasizing its crucial role in both local (cell) and distant (signal) influences on heart development.
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The renin angiotensin system (RAS) produced hormone peptides regulate many vital body functions. Dysfunctional signaling by receptors for RAS peptides leads to pathologic states. Nearly half of humanity today would likely benefit from modern drugs targeting these receptors.

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The carboxyl-terminus of the type 1 angiotensin II receptor (AT1A) regulates receptor activation/deactivation and the amphipathic Helix 8 within the carboxyl-terminus is a high affinity interaction motif for plasma membrane lipids. We have used dual polarisation interferometry (DPI) to examine the role of phosphatidylinositdes in the specific recognition of Helix 8 in the AT1A receptor. A synthetic peptide corresponding to Leu(305) to Lys(325) (Helix 8 AT1A) discriminated between PIPs and different charges on lipid membranes.

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The human population displays high variation in taste perception. Differences in individual taste sensitivity may also impact on nutrient intake and overall appetite. A well-characterized example is the variable perception of bitter compounds such as 6-n-propylthiouracil (PROP) and phenylthiocarbamide (PTC), which can be accounted for at the molecular level by polymorphic variants in the specific type 2 taste receptor (TAS2R38).

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G protein-coupled receptors are the principal mediators of the sweet, umami, bitter, and fat taste qualities in mammals. Intriguingly, the taste receptors are also expressed outside of the oral cavity, including in the gut, airways, brain, and heart, where they have additional functions and contribute to disease. However, there is little known about the mechanisms governing the transcriptional regulation of taste receptor genes.

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G protein-coupled receptors (GPCRs) are seven-transmembrane-spanning proteins that mediate cellular and physiological responses. They are critical for cardiovascular function and are targeted for the treatment of hypertension and heart failure. Nevertheless, current therapies only target a small fraction of the cardiac GPCR repertoire, indicating that there are many opportunities to investigate unappreciated aspects of heart biology.

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