Molecular Mechanisms of Go Signaling

Jiang, Meisheng; Bajpayee, Neil S.

doi:10.1159/000186688

Cited by 110 publications

(121 citation statements)

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“…Further study is required to determine whether the inhibitory effects of G z and G o2 on insulin secretion occur through additive and/or independent mechanisms. The α subunits of the PTX-sensitive subfamily of G proteins are highly homologous to each other (12). Although G i/o proteins can elicit similar signaling responses in cells, their functional overlap in the body remains to be elucidated.…”

Section: Resultsmentioning

confidence: 99%

“…The nonsensory PTX-sensitive G i /G o G proteins encompass three G i 's (G i1 , G i2 , and G i3 ), and two G o 's (G o1 and G o2 ). The α subunits of G i and G o display extensive homology and are functionally similar as they can be activated by the same or similar receptors and appear to signal to partially overlapping sets of effectors (12). This has raised questions whether the individual G i and G o proteins function distinctively between different receptors and effectors or whether they are simply isoforms of one another.…”

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confidence: 99%

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Augmented glucose-induced insulin release in mice lacking G _o2 , but not G _o1 or G _i proteins

Wang

Park

Bajpayee

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Insulin secretion by pancreatic β cells is a complex and highly regulated process. Disruption of this process can lead to diabetes mellitus. One of the various pathways involved in the regulation of insulin secretion is the activation of heterotrimeric G proteins. Bordetella pertussis toxin (PTX) promotes insulin secretion, suggesting the involvement of one or more of three G i and/or two G o proteins as suppressors of insulin secretion from β cells. However, neither the mechanism of this inhibitory modulation of insulin secretion nor the identity of the G i/o proteins involved has been elucidated. Here we show that one of the two splice variants of G o , G o2 , is a key player in the control of glucose-induced insulin secretion by β cells. Mice lacking G o2 α, but not those lacking α subunits of either G o1 or any G i proteins, handle glucose loads more efficiently than wild-type (WT) mice, and do so by increased glucose-induced insulin secretion. We thus provide unique genetic evidence that the G o2 protein is a transducer in an inhibitory pathway that prevents damaging oversecretion of insulin.D iabetes mellitus is characterized by abnormalities in insulin secretion that may be either a primary defect, as seen in type I diabetes, or a secondary defect, where secretion is inadequate to overcome primary insulin resistance seen in type II diabetes. In either case, individuals are hyperglycemic. Insulin is the master controller of glucose metabolism, and its release from β cells is tightly regulated. Many factors, including hormones, neuropeptides, and neurotransmitters regulate insulin secretion by activating heterotrimeric G proteins, which can control the output of insulin in response to physiological demands (1, 2). Activation of pathways mediated by G s and/or G q/11 stimulates insulin release from β cells (3, 4). The involvement of G i /G o proteins as inhibitors of insulin secretion from β cells was originally uncovered in studies on the Bordetella pertussis toxin (PTX) in animals and cells (5, 6). Previously called islet-activating protein (IAP), PTX was shown to lower glucose levels in the bloodstream by increasing insulin secretion from β cells (7). The enhanced secretion resulted from the removal of tonic inhibition exerted by neurotransmitters/hormones, including adrenaline (8), galanin (9), and ghrelin (10). PTX catalyzes the ADP ribosylation of a carboxyl-terminal cysteine present in the α subunits of the G protein subgroup now referred to as G i /G o (11). This event causes these G proteins to become uncoupled from receptors and thereby disrupts the signal transduction process. The nonsensory PTX-sensitive G i /G o G proteins encompass three G i 's (G i1 , G i2 , and G i3 ), and two G o 's (G o1 and G o2 ). The α subunits of G i and G o display extensive homology and are functionally similar as they can be activated by the same or similar receptors and appear to signal to partially overlapping sets of effectors (12). This has raised questions whether the individual G i and G o proteins function dis...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Augmented glucose-induced insulin release in mice lacking G _o2 , but not G _o1 or G _i proteins

Wang

Park

Bajpayee

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…G-protein sub-units have been reported to act directly without the involvement of second messengers in other systems (e.g. Dascal, 2001;Jiang and Bajpayee, 2009;Soejima and Noma, 1984;Wickman et al, 1994). As DPKQDFMRFamideinduced contractions are completely abolished by nifedipine and nicardipine and by lowering extracellular Ca 2+ concentration (Clark et al, 2008), they appear to require Ca 2+ influx through L-type channels associated with the sarcolemma, which have been shown to be present in body wall muscles of Drosophila larvae (Gielow et al, 1995).…”

Section: Research Articlementioning

confidence: 99%

Mode of Action of aDrosophilaFMRFamide in Inducing Muscle Contraction

Milakovic

Ormerod

Klose

et al. 2014

Journal of Experimental Biology

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Drosophila melanogaster is a model system for examining the mechanisms of action of neuropeptides. DPKQDFMRFamide was previously shown to induce contractions in Drosophila body wall muscle fibres in a Ca 2+ -dependent manner. The present study examined the possible involvement of a G-protein-coupled receptor and second messengers in mediating this myotropic effect after removal of the central nervous system. DPKQDFMRFamide-induced contractions were reduced by 70% and 90%, respectively, in larvae with reduced expression of the Drosophila Fmrf receptor (FR) either ubiquitously or specifically in muscle tissue, compared with the response in control larvae in which expression was not manipulated. No such effect occurred in larvae with reduced expression of this gene only in neurons. The myogenic effects of DPKQDFMRFamide do not appear to be mediated through either of the two Drosophila myosuppressin receptors (DmsR-1 and DmsR-2). DPKQDFMRFamide-induced contractions were not reduced in Ala1 transgenic flies lacking activity of calcium/calmodulin-dependent protein kinase (CamKII), and were not affected by the CaMKII inhibitor KN-93. Peptide-induced contractions in the mutants of the phospholipase C-β (PLCβ) gene (norpA larvae) and in IP 3 receptor mutants were similar to contractions elicited in control larvae. The peptide failed to increase cAMP and cGMP levels in Drosophila body wall muscles. Peptide-induced contractions were not potentiated by 3-isobutyl-1-methylxanthine, a phosphodiesterase inhibitor, and were not antagonized by inhibitors of cAMP-dependent or cGMPdependent protein kinases. Additionally, exogenous application of arachidonic acid failed to induce myogenic contractions. Thus, DPKQDFMRFamide induces contractions via a G-protein coupled FMRFamide receptor in muscle cells but does not appear to act via cAMP, cGMP, IP 3 , PLC, CaMKII or arachidonic acid.

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“…Pancreatic islets are highly innervated, and activation of pancreatic nerves is sufficient to influence islet function (15). G o was originally identified as the "other" PTXsensitive G protein in the brain and is highly expressed in the CNS and endocrine cells (41). Logically, antagonizing the G s pathway by suppressing adenylyl cyclase (AC) activity might be a mechanism for galanin receptor-G o protein-mediated signaling in cells.…”

Section: Loss Of G O 2α Blunts the Hyperglycemic Effect Of Galanin Inmentioning

confidence: 99%

G _o 2 G protein mediates galanin inhibitory effects on insulin release from pancreatic β cells

Tang

Wang

Park

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The neuropeptide galanin regulates numerous physiological activities in the body, including feeding and metabolism, learning and memory, nociception and spinal reflexes, and anxiety and related behaviors. Modulation of blood glucose levels by suppressing insulin release was the first reported activity for galanin. This inhibition was mediated by one or more pertussis toxin-sensitive G proteins of the G i/o subfamily. However, the molecular identities of the specific G protein(s) and intracellular effectors have not been fully revealed. Recently, we demonstrated that mice lacking G o 2, but not other members of the G i/o protein family, secrete more insulin than controls upon glucose challenge, indicating that G o 2 is a major transducer for the inhibitory regulation of insulin secretion. In this study, we investigated galanin signaling mechanisms in β cells using cell biological and electrophysiological approaches. We found that islets lacking G o 2, but not other G i/o proteins, lose the inhibitory effect of galanin on insulin release. Potentiation of ATPsensitive potassium (K ATP ) and inhibition of calcium currents by galanin were disrupted by anti-G o 2α antibodies. Galanin actions on K ATP and calcium currents were completely lost in G o 2 −/− β cells. Furthermore, the hyperglycemic effect of galanin is also blunted in G o 2 −/− mice. Our results demonstrate that G o 2 mediates the inhibition of insulin release by galanin by regulating both K ATP and Ca 2+ channels in mice. Our findings provide insight into galanin's action in glucose homeostasis. The results may also be relevant to the understanding of galanin signaling in other biological systems, especially the central nervous system.G alanin, a 29-to 30-residue neuropeptide hormone initially discovered in porcine intestine (1), is distributed throughout the central and peripheral nervous systems and the intestinal neuroendocrine system of many mammalian species (2, 3). The first 15 N-terminal amino acids, which retain the biological activity of the full-length peptide hormone, are highly conserved, underscoring a physiological importance across species. Galanin coexpresses and colocalizes with many neurotransmitters (4) and functions as an inhibitory modulator.The biological effects of galanin are mediated by galanin receptors. Three types of galanin receptors (GalR1, GalR2, and GalR3) have been identified by molecular cloning and characterized pharmacologically in various species (5-8). All three subtypes of galanin receptors are members of the GTP-binding protein-coupled receptor (GPCR) superfamily. The three galanin receptors exhibit overlapping but distinctive patterns of expression in the central nervous system and periphery. The distinct distribution patterns of receptors support the notion that each receptor mediates some unique physiological function in the body.Physiological Effects of Galanin. The biological activity of galanin has been studied intensively in the central and peripheral nervous systems, as well as in the pituitary and the endoc...

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Molecular Mechanisms of Go Signaling

Cited by 110 publications

References 185 publications

Augmented glucose-induced insulin release in mice lacking G _o2 , but not G _o1 or G _i proteins

Augmented glucose-induced insulin release in mice lacking G _o2 , but not G _o1 or G _i proteins

Mode of Action of aDrosophilaFMRFamide in Inducing Muscle Contraction

G _o 2 G protein mediates galanin inhibitory effects on insulin release from pancreatic β cells

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Molecular Mechanisms of Go Signaling

Cited by 110 publications

References 185 publications

Augmented glucose-induced insulin release in mice lacking G o2 , but not G o1 or G i proteins

Augmented glucose-induced insulin release in mice lacking G o2 , but not G o1 or G i proteins

Mode of Action of aDrosophilaFMRFamide in Inducing Muscle Contraction

G o 2 G protein mediates galanin inhibitory effects on insulin release from pancreatic β cells

Contact Info

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Resources

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Augmented glucose-induced insulin release in mice lacking G _o2 , but not G _o1 or G _i proteins

Augmented glucose-induced insulin release in mice lacking G _o2 , but not G _o1 or G _i proteins

G _o 2 G protein mediates galanin inhibitory effects on insulin release from pancreatic β cells