Academic literature on the topic 'Gαs-Coupled Receptor Signalling'
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Journal articles on the topic "Gαs-Coupled Receptor Signalling"
1
Sainz, Eduardo, Margaret M. Cavenagh, Joanne Gutierrez, James F. Battey, John K. Northup, and Susan L. Sullivan. "Functional characterization of human bitter taste receptors." Biochemical Journal 403, no. 3 (April 12, 2007): 537–43. http://dx.doi.org/10.1042/bj20061744.
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The T2Rs belong to a multi-gene family of G-protein-coupled receptors responsible for the detection of ingested bitter-tasting compounds. The T2Rs are conserved among mammals with the human and mouse gene families consisting of about 25 members. In the present study we address the signalling properties of human and mouse T2Rs using an in vitro reconstitution system in which both the ligands and G-proteins being assayed can be manipulated independently and quantitatively assessed. We confirm that the mT2R5, hT2R43 and hT2R47 receptors respond selectively to micromolar concentrations of cycloheximide, aristolochic acid and denatonium respectively. We also demonstrate that hT2R14 is a receptor for aristolochic acid and report the first characterization of the ligand specificities of hT2R7, which is a broadly tuned receptor responding to strychnine, quinacrine, chloroquine and papaverine. Using these defined ligand–receptor interactions, we assayed the ability of the ligand-activated T2Rs to catalyse GTP binding on divergent members of the Gα family including three members of the Gαi subfamily (transducin, Gαi1 and Gαo) as well as Gαs and Gαq. The T2Rs coupled with each of the three Gαi members tested. However, none of the T2Rs coupled to either Gαs or Gαq, suggesting the T2Rs signal primarily through Gαi-mediated signal transduction pathways. Furthermore, we observed different G-protein selectivities among the T2Rs with respect to both Gαi subunits and Gβγ dimers, suggesting that bitter taste is transduced by multiple G-proteins that may differ among the T2Rs.
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MALBON, Craig C. "Insulin signalling: putting the G- in protein-protein interactions." Biochemical Journal 380, no. 1 (May 15, 2004): e11-e12. http://dx.doi.org/10.1042/bj20040619.
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Cell signalling via receptor tyrosine kinases, such as the insulin receptor, and via heterotrimeric G-proteins, such as Gαi, Gαs and Gαq family members, constitute two of most avidly studied paradigms in cell biology. That elements of these two populous signalling pathways must cross-talk to achieve proper signalling in the regulation of cell proliferation, differentiation and metabolism has been anticipated, but the evolution of our thinking and the analysis of such cross-talk have lagged behind the ever-expanding troupe of players and the recognition of multivalency as the rule, rather than the exception, in signalling biology. New insights have been provided by Kreuzer et al. in this issue of the Biochemical Journal, in which insulin is shown to provoke recruitment of Gαi-proteins to insulin-receptor-based complexes that can regulate the gain of insulin-receptor-catalysed autophosphorylation, a proximal point in the insulin-sensitive cascade of signalling. Understanding the convergence and cross-talk of signals from the receptor tyrosine kinases and G-protein-coupled receptor pathways in physical, spatial and temporal contexts will remain a major challenge of cell biology.
3
Abid, Hasnat Ali, Asuka Inoue, and Caroline M. Gorvin. "Heterogeneity of G protein activation by the calcium-sensing receptor." Journal of Molecular Endocrinology 67, no. 2 (August 1, 2021): 41–53. http://dx.doi.org/10.1530/jme-21-0058.
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The calcium-sensing receptor (CaSR) is a G protein-coupled receptor that plays a fundamental role in extracellular calcium (Ca2+e) homeostasis by regulating parathyroid hormone release and urinary calcium excretion. The CaSR has been described to activate all four G protein subfamilies (Gαq/11, Gαi/o, Gα12/13, Gαs), and mutations in the receptor that cause hyper/hypocalcaemia, have been described to bias receptor signalling. However, many of these studies are based on measurements of second messengers or gene transcription that occurs many steps downstream of receptor activation and can represent convergence points of several signalling pathways. Therefore, to assess CaSR-mediated G protein activation directly, we took advantage of a recently described NanoBiT G protein dissociation assay system. Our studies, performed in HEK293 cells stably expressing CaSR, demonstrate that Ca2+e stimulation activates all Gαq/11 family and several Gαi/o family proteins, although Gαz was not activated. CaSR stimulated dissociation of Gα12/13 and Gαs from Gβ-subunits, but this occurred at a slower rate than that of other Gα-subunits. Investigation of cDNA expression of G proteins in three tissues abundantly expressing CaSR, the parathyroids, kidneys and pancreas, showed Gα11, Gαz, Gαi1 and Gα13 genes were highly expressed in parathyroid tissue, indicating CaSR most likely activates Gα11 and Gαi1 in parathyroids. In kidney and pancreas, the majority of G proteins were similarly expressed, suggesting CaSR may activate multiple G proteins in these cells. Thus, these studies validate a single assay system that can be used to robustly assess CaSR variants and biased signalling and could be utilised in the development of new pharmacological compounds targeting CaSR.
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Liu, Ying, Yang Yang, Richard Ward, Su An, Xiao-Xi Guo, Wei Li, and Tian-Rui Xu. "Biased signalling: the instinctive skill of the cell in the selection of appropriate signalling pathways." Biochemical Journal 470, no. 2 (August 20, 2015): 155–67. http://dx.doi.org/10.1042/bj20150358.
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GPCRs (G-protein-coupled receptors) are members of a family of proteins which are generally regarded as the largest group of therapeutic drug targets. Ligands of GPCRs do not usually activate all cellular signalling pathways linked to a particular seven-transmembrane receptor in a uniform manner. The fundamental idea behind this concept is that each ligand has its own ability, while interacting with the receptor, to activate different signalling pathways (or a particular set of signalling pathways) and it is this concept which is known as biased signalling. The importance of biased signalling is that it may selectively activate biological responses to favour therapeutically beneficial signalling pathways and to avoid adverse effects. There are two levels of biased signalling. First, bias can arise from the ability of GPCRs to couple to a subset of the available G-protein subtypes: Gαs, Gαq/11, Gαi/o or Gα12/13. These subtypes produce the diverse effects of GPCRs by targeting different effectors. Secondly, biased GPCRs may differentially activate G-proteins or β-arrestins. β-Arrestins are ubiquitously expressed and function to terminate or inhibit classic G-protein signalling and initiate distinct β-arrestin-mediated signalling processes. The interplay of G-protein and β-arrestin signalling largely determines the cellular consequences of the administration of GPCR-targeted drugs. In the present review, we highlight the particular functionalities of biased signalling and discuss its biological effects subsequent to GPCR activation. We consider that biased signalling is potentially allowing a choice between signalling through ‘beneficial’ pathways and the avoidance of ‘harmful’ ones.
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Ward, Richard J., John D. Pediani, Kaleeckal G. Harikumar, Laurence J. Miller, and Graeme Milligan. "Spatial intensity distribution analysis quantifies the extent and regulation of homodimerization of the secretin receptor." Biochemical Journal 474, no. 11 (May 24, 2017): 1879–95. http://dx.doi.org/10.1042/bcj20170184.
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Previous studies have indicated that the G-protein-coupled secretin receptor is present as a homodimer, organized through symmetrical contacts in transmembrane domain IV, and that receptor dimerization is critical for high-potency signalling by secretin. However, whether all of the receptor exists in the dimeric form or if this is regulated is unclear. We used measures of quantal brightness of the secretin receptor tagged with monomeric enhanced green fluorescent protein (mEGFP) and spatial intensity distribution analysis to assess this. Calibration using cells expressing plasma membrane-anchored forms of mEGFP initially allowed us to demonstrate that the epidermal growth factor receptor is predominantly monomeric in the absence of ligand and while wild-type receptor was rapidly converted into a dimeric form by ligand, a mutated form of this receptor remained monomeric. Equivalent studies showed that, at moderate expression levels, the secretin receptor exists as a mixture of monomeric and dimeric forms, with little evidence of higher-order complexity. However, sodium butyrate-induced up-regulation of the receptor resulted in a shift from monomeric towards oligomeric organization. In contrast, a form of the secretin receptor containing a pair of mutations on the lipid-facing side of transmembrane domain IV was almost entirely monomeric. Down-regulation of the secretin receptor-interacting G-protein Gαs did not alter receptor organization, indicating that dimerization is defined specifically by direct protein–protein interactions between copies of the receptor polypeptide, while short-term treatment with secretin had no effect on organization of the wild-type receptor but increased the dimeric proportion of the mutated receptor variant.
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Europe-Finner, G. N., E. Cartwright, J. Bellinger, H. J. Mardon, D. H. Barlow, and A. López Bernal. "Identification of Gαs messenger ribonucleic acid splice variants in human granulosa cells." Journal of Molecular Endocrinology 18, no. 1 (February 1997): 27–35. http://dx.doi.org/10.1677/jme.0.0180027.
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ABSTRACT Granulosa cells are essential for follicular development and corpus luteum formation and their functions are regulated by gonadotrophins through G protein-coupled receptors. The dominant second messenger pathway involves the stimulation of cyclic AMP formation by Gαs-linked receptors. In this paper we have investigated the expression of Gαs mRNA splice variants in relation to expression of Gαs protein isoforms in granulosa cells obtained from patients undergoing in vitro fertilization. We have carried out ribonuclease protection assays using cRNA riboprobes which are capable of detecting all Gαs mRNA isoforms as well as quantifying total amounts of Gαs mRNA. Granulosa cells express the message for Gαs-Large and Gαs-Small and the presence of two distinct protein products was confirmed by immunoblotting using the antibody RM/1. Moreover, the data show that a significant fraction of Gαs-Large and Gαs-Small mRNAs contain an extra CAG codon. This should generate proteins with an extra serine residue, resulting in Gαs variants with the consensus sequence of a protein kinase C phosphorylation site. These results highlight the possible interaction between different signalling pathways in the control of cAMP production and the need to investigate the relationship between Gαs variants and different adenylyl cyclase isozymes in patients with normal and abnormal ovarian function.
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Triest, Sarah, Alexandre Wohlkönig, Els Pardon, and Jan Steyaert. "Production, crystallization and preliminary X-ray diffraction of the Gαs α-helical domain in complex with a nanobody." Acta Crystallographica Section F Structural Biology Communications 70, no. 11 (October 25, 2014): 1504–7. http://dx.doi.org/10.1107/s2053230x14020962.
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GPCR–G-protein complexes are one of the most important components of cell-signalling cascades. Extracellular signals are sensed by membrane-associated G-protein-coupled receptors (GPCRs) and transducedviaG proteins towards intracellular effector molecules. Structural studies of these transient complexes are crucial to understand the molecular details of these interactions. Although a nucleotide-free GPCR–G-protein complex is stable, it is not an ideal sample for crystallization owing to the intrinsic mobility of the Gαs α-helical domain (AHD). To stabilize GPCR–G-protein complexes in a nucleotide-free form, nanobodies were selected that target the flexible GαsAHD. One of these nanobodies, CA9177, was co-crystallized with the GαsAHD. Initial crystals were obtained using the sitting-drop method in a sparse-matrix screen and further optimized. The crystals diffracted to 1.59 Å resolution and belonged to the monoclinic space groupP21, with unit-cell parametersa= 44.07,b= 52.55,c= 52.66 Å, α = 90.00, β = 107.89, γ = 90.00°. The structure of this specific nanobody reveals its binding epitope on GαsAHD and will help to determine whether this nanobody could be used as crystallization chaperone for GPCR–G-protein complexes.
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Wang, Qiuling, Weiwei Xiao, Yang Li, Zhenying Liu, Huafeng Li, Jinhuan Wang, Yuan Hu, Qingjie Xue, and Daping Wang. "Signaling of ghrelin at GHSR1b and OX1R receptor heterodimers." Molecular Biology of the Cell, October 10, 2019, mbc.E19–06–0326. http://dx.doi.org/10.1091/mbc.e19-06-0326.
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Growth hormone receptor 1b (GHSR1b) and orexin type 1 receptor (OX1R) have many similar characteristics in terms of their functions and body distribution and are involved in various physiological functions. In this study, we explored the possibility of GHSR1b and OX1R dimerization. Bioluminescence (BRET), fluorescence resonance energy transfer (FRET) and coimmunoprecipitation (Co-IP) were used to analyse the formation of GHSR1b and OX1R heteromers in cells. We also explored their signal transduction pathway mechanism. The results showed that ghrelin could stimulate GHSR1b/OX1R heterodimer cellsto increase Gαs protein activation and induce downstream signalling pathway activity. GHSR1b/OX1R heteromers triggered ghrelin-induced Gαs/protein kinase A signalling pathway activity. Thus, GHSR1b can form a heterodimer with OX1R, leading to increased protein kinase A activity. At the same time, stimulation with orexinA did not alter G protein-coupled receptor (GPCR) interactions with Gα protein subunits. Moreover, ghrelin induced a significant increase in cell proliferation. These results suggest that heterodimers of ghrelin and GHSR1b/OX1R promote the upregulation of a Gαs-cAMP-cAMP-responsive element signalling pathway. The nature of this signalling pathway may have significant implications in regulating physiological functions.
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Roberts, Maxine J., Lauren T. May, Alastair C. Keen, Bonan Liu, Terrance Lam, Steven J. Charlton, Elizabeth M. Rosethorne, and Michelle L. Halls. "Inhibition of the Proliferation of Human Lung Fibroblasts by Prostacyclin Receptor Agonists is Linked to a Sustained cAMP Signal in the Nucleus." Frontiers in Pharmacology 12 (April 29, 2021). http://dx.doi.org/10.3389/fphar.2021.669227.
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Idiopathic pulmonary fibrosis is a chronic and progressive fibrotic lung disease, and current treatments are limited by their side effects. Proliferation of human lung fibroblasts in the pulmonary interstitial tissue is a hallmark of this disease and is driven by prolonged ERK signalling in the nucleus in response to growth factors such as platelet-derived growth factor (PDGF). Agents that increase cAMP have been suggested as alternative therapies, as this second messenger can inhibit the ERK cascade. We previously examined a panel of eight Gαs-cAMP-coupled G protein-coupled receptors (GPCRs) endogenously expressed in human lung fibroblasts. Although the cAMP response was important for the anti-fibrotic effects of GPCR agonists, the magnitude of the acute cAMP response was not predictive of anti-fibrotic efficacy. Here we examined the reason for this apparent disconnect by stimulating the Gαs-coupled prostacyclin receptor and measuring downstream signalling at a sub-cellular level. MRE-269 and treprostinil caused sustained cAMP signalling in the nucleus and complete inhibition of PDGF-induced nuclear ERK and fibroblast proliferation. In contrast, iloprost caused a transient increase in nuclear cAMP, there was no effect of iloprost on PDGF-induced ERK in the nucleus, and this agonist was much less effective at reversing PDGF-induced proliferation. This suggests that sustained elevation of cAMP in the nucleus is necessary for efficient inhibition of PDGF-induced nuclear ERK and fibroblast proliferation. This is an important first step towards understanding of the signalling events that drive GPCR inhibition of fibrosis.
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Tschaikner, Philipp M., Dominik Regele, Ruth Röck, Willi Salvenmoser, Dirk Meyer, Michel Bouvier, Stephan Geley, Eduard Stefan, and Pia Aanstad. "Feedback control of the Gpr161-Gαs-PKA axis contributes to basal Hedgehog repression in zebrafish." Development 148, no. 4 (February 15, 2021). http://dx.doi.org/10.1242/dev.192443.
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ABSTRACT Hedgehog (Hh) ligands act as morphogens to direct patterning and proliferation during embryonic development. Protein kinase A (PKA) is a central negative regulator of Hh signalling, and in the absence of Hh ligands, PKA activity prevents inappropriate expression of Hh target genes. The orphan G-protein-coupled receptor Gpr161 contributes to the basal Hh repression machinery by activating PKA. Gpr161 acts as an A-kinase-anchoring protein, and is itself phosphorylated by PKA, but the functional significance of PKA phosphorylation of Gpr161 in the context of Hh signalling remains unknown. Here, we show that loss of Gpr161 in zebrafish leads to constitutive activation of medium and low, but not maximal, levels of Hh target gene expression. Furthermore, we find that PKA phosphorylation-deficient forms of Gpr161, which we show directly couple to Gαs, display an increased sensitivity to Shh, resulting in excess high-level Hh signalling. Our results suggest that PKA feedback-mediated phosphorylation of Gpr161 may provide a mechanism for fine-tuning Gpr161 ciliary localisation and PKA activity.