Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0043167 (pertussis)
19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A novel pathway for physiological "cross-talk" between the insulin receptor and the regulatory Gi-protein has been demonstrated. We tested the hypothesis that a coupling defect between Gi and the insulin receptor is present in the liver of obese patients with and without type II diabetes. Insulin 1 x 10(-9) M (approximately ED50) and 1 x 10(-7) M (Max) inhibited pertussis toxin-catalyzed ADP ribosylation of Gi in human liver plasma membranes from lean and obese nondiabetic patients. However, 1 x 10(-7) M insulin was without effect in membranes from patients with type II diabetes. This coupling defect was not intrinsic to Gi, since Mg2+ and GTP gamma S inhibited pertussis toxin-catalyzed ADP ribosylation in both diabetic and nondiabetic patients. Binding of insulin of the alpha-subunit and activation of the tyrosine kinase intrinsic to the beta-subunit of the insulin receptor are not responsible for the coupling defect. 125I insulin binding is the same in obese patients with or without diabetes. Tyrosine kinase of the insulin receptor is decreased in diabetes. However, a monoclonal antibody to the insulin receptor (MA-20) at equimolar concentrations with insulin equally inhibits pertussis toxin-catalyzed ADP ribosylation of Gi without activating tyrosine kinase or insulin receptor autophosphorylation. Immunodetection of G-proteins suggested that Gi3 alpha was normal in diabetes and Gi1-2 alpha was decreased by 40% in the diabetic group as compared to the obese nondiabetic group but was normal when compared to the lean non diabetic group. We conclude that the novel pathway of insulin signaling involving the regulatory Gi proteins via biochemical mechanisms not directly involving the tyrosine kinase of the insulin receptor is altered in obese type II diabetes and offers a new target for the search of the mechanism(s) of insulin resistance.
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PMID:Guanine nucleotide binding regulatory proteins in liver from obese humans with and without type II diabetes: evidence for altered "cross-talk" between the insulin receptor and Gi-proteins. 820 Sep 11

Insulin has a paradoxical effect on a 41kDa Gi-like protein: Although insulin-treatment of rat adipocytes inhibited pertussis toxin-catalyzed ADP-ribosylation of a 41kDa G-protein in membranes in a dose-dependent manner, it simultaneously increased ADP-ribosylation of a 41kDa G-protein that co-immunoprecipitates with the insulin receptor (GIR41). The latter effect was insulin concentration- and time-dependent. The dose-dependent stimulatory effect of insulin on the autophosphorylation of the insulin receptor and on the ADP-ribosylation of the GIR41 in the insulin receptor immunoprecipitates closely paralleled each other. The time course of insulin-stimulated increase in the ADP-ribosylated GIR41, although rapid, was slower than the autophosphorylation of the receptor. The GIR41 is associated with and regulated by the insulin receptor further supporting an important role for this G-protein in modulating insulin action at the receptor level.
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PMID:Insulin stimulates association of a 41kDa G-protein (GIR41) with the insulin receptor. 821 41

Some functions of the insulin receptor (insR) are assumed to be mediated by pertussis toxin-sensitive Gi/G(o) proteins. Here we have located G-protein-activator domains in the cytoplasmic region of the human insR. We searched the sequence of insR and found three candidate regions at residues 1039-1061, 1147-1168 and 1325-1345, referred to as ISRP1, ISRP2 and ISRP3, respectively. Among them, the Gi/G(o)-activating function was observed only in peptide ISRP3. ISRP1 specifically activated Gs, whereas ISRP2 had no effect on G proteins. ISRP2 and ISRP3 contained five of six autophosphorylated tyrosine residues in insR. After tyrosine phosphorylation, ISRP2 showed specific Gi-activating function, and ISRP3 potentiated its ability and became capable of activating G proteins generally. This is the first study that specifies G-protein-activator domains in insR and describes their modification by autophosphorylation.
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PMID:GTP-binding protein-activator sequences in the insulin receptor. 813 61

The insulin receptor mediates a variety of cellular responses to insulin, including glucose transport, endocytosis, and cell proliferation. The role of the insulin receptor in mediating cellular motility has not, however, been extensively investigated. In this report, we demonstrate that chinese hamster ovary (CHO) cells that normally have low concentrations of insulin receptor display chemotaxis toward insulin after overexpression of the wild type human insulin receptor. Chemotaxis toward insulin proceeded through a pertussis toxin-sensitive pathway and required both tyrosine kinase activity and tyrosine autophosphorylation of the regulatory region of the beta-subunit. In contrast, the autophosphorylation sites in the carboxyl terminus of the receptor were not required for chemotactic activity. A mutation in the juxtamembrane region, which disabled tyrosine phosphorylation of the insulin receptor substrate-1 (IRS-1), also prevented the chemotactic response, suggesting a possible role for IRS-1 in chemotactic signaling. In the absence of insulin receptor, however, the presence of excess transfected IRS-1 was not sufficient to mediate chemotaxis toward insulin. These results demonstrate that the intact insulin receptor can stimulate a chemotactic signaling pathway and that this initial pathway more closely correlates with that for insulin-stimulated cell proliferation than for insulin-stimulated receptor endocytosis.
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PMID:Functional domains of the insulin receptor responsible for chemotactic signaling. 827 80

The platelet-activating factor (PAF) was seen to potently activate mitogen-activated protein (MAP) kinase and MAP kinase kinase through the cloned guinea pig PAF receptor stably expressed in Chinese hamster ovary (CHO) cells. Both 42- and 44-kDa MAP kinases were activated and tyrosine-phosphorylated in response to PAF. The PAF receptor also triggered the production of inositol phosphates and the release of arachidonic acid and inhibited cyclic AMP accumulation. Differential inhibitory effects of pertussis toxin (PTX) on these signals suggested that the PAF receptor couples to both PTX-sensitive and -insensitive G proteins in CHO cells. MAP kinase and MAP kinase activations were partially regulated by PTX-sensitive G proteins. The PAF receptor did not trigger any detectable increase in the GTP form of Ras under the conditions in which the human insulin receptor expressed in the same parent CHO cells potently increased the level. Since these agonists induced comparable MAP kinase activations through cognate receptors, Ras seems to play different roles in MAP kinase activation by the two different classes of receptors. The activation of MAP kinase by the cloned PAF receptor may explain part of the mechanisms underlying PAF-induced differentiation and proliferation in non-inflammatory cells.
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PMID:Transfected platelet-activating factor receptor activates mitogen-activated protein (MAP) kinase and MAP kinase kinase in Chinese hamster ovary cells. 829 89

Several groups have shown a relationship between the insulin receptor and inhibitory G proteins, G(i). An antisera, 8729, to a peptide sequence (KNNLKDCGLF) corresponding to the carboxyl termini of G(i)alpha subunits was used to investigate this relationship by immunoelectron microscopy. Rat adipocytes were incubated in the absence or presence of 100 ng/ml insulin for 1 h and fixed for immunoelectron microscopy. Insulin-treated adipocytes stained with 8729 were labeled at the cell surface at a much higher density than control adipocytes. Subcellular fractionation of insulin-treated and control cells was followed by PAGE and Western blots of the plasma membrane and low-density microsomes with 8729. The density of the bands did not change in response to insulin treatment. Antibodies to noncarboxyl terminus sequences of the alpha subunit were used for immunoelectron microscopy and no difference was noted between insulin-treated and control adipocytes. These results indicated that 8729 was detecting a conformational change in the structure of G(i)alpha subunit in the plasma membrane in response to insulin. This unmasking of the carboxyl terminus was also seen in response to treatment with phenylisopropyladenosine and prostaglandin E2. Pertussis toxin-catalyzed ADP ribosylation also unmasked the carboxyl terminus. In contrast, isoproterenol, an agonist of stimulatory G proteins (Gs), did not induce an unmasking of the carboxyl terminus. These results support the hypothesis that some of insulin's effects are mediated through G(i) proteins in adipocytes.
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PMID:Insulin induces an unmasking of the carboxyl terminus of G(i) proteins in rat adipocytes. 848 58

Human fat cells possess a multireceptor-linked H2O2-generating system that is activated by insulin. Previous studies revealed that manganese was the sole cofactor required for a hormonal regulation of NADPH-dependent H2O2 generation in vitro. In this report it is shown that the synergistic activation of NADPH-dependent H2O2 generation by Mn2+ and insulin was blocked by GDPbetaS (guanosine 5'-O-(2-thiodiphosphate)), pertussis toxin and COOH-terminal anti-Galphai1-2 or the corresponding peptide. Consistently, manganese could be replaced by micromolar concentrations of GTPgammaS (guanosine 5'-O-(3-thiotriphosphate)), which increased NADPH-dependent H2O2 generation by 20-40%. Insulin shifted the dose response curve for GTPgammaS to the left (>10-fold) and increased the maximal response. In the presence of 10 microM GTPgammaS, the hormone was active at picomolar concentrations, indicating that insulin acted via its cognate receptor. The insulin receptor and Gi were co-adsorbed on anti-Galphai and anti-insulin receptor beta-subunit (anti-IRbeta) affinity columns. Partially purified insulin receptor preparations contained Galphas, Galphai2, and Gbetagamma (but no Galphai1 or Galphai3). The functional nature of the insulin receptor-Gi2 complex was made evident by insulin's ability to modulate labeling of Gi by bacterial toxins. Insulin action was mimicked by activated Galphai, but not by Galphao or Gbetagamma, indicating that insulin's signal was transduced via Galphai2. Thus, NADPH oxidase is the first example of an effector system that is coupled to the insulin receptor via a heterotrimeric G protein.
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PMID:Insulin-induced activation of NADPH-dependent H2O2 generation in human adipocyte plasma membranes is mediated by Galphai2. 909 59

The present study was conducted to examine the ability of insulin receptor to activate the calcium signaling system in Chinese hamster ovary (CHO) cells expressing human insulin receptor (CHO-IR cells). In these cells, insulin evoked the elevation of cytoplasmic free calcium concentration, [Ca2+]c, measured by using fura-2. Insulin-induced increase in [Ca2+]c was blocked by reducing the extracellular calcium concentration to 1 microM or by adding nickel chloride, an inorganic inhibitor of calcium entry. Insulin did not elevate [Ca2+]c in parental CHO cells or in CHO cells expressing mutant insulin receptor lacking an ATP-binding site. When the transmembrane calcium current was measured by perforated whole-cell patch clamp, adding insulin to the bath solution markedly augmented the inward calcium current. In a cell-attached patch, a single channel activity appeared when insulin was included in the pipette. In contrast, insulin added outside the patch was ineffective. The current/voltage relationship demonstrated that insulin activated a voltage-independent calcium-permeable cation channel with a single-channel conductance of 10 pS. Exposing CHO-IR cells to pertussis toxin abolished the subsequent insulin effect on [Ca2+]c and activation of the calcium-permeable channel. Mastoparan activated the 10-pS calcium-permeable cation channel. In an inside-out patch, insulin activated the calcium-permeable channel when the bath solution contained both GTP and ATP. Nonhydrolyzable ATP could substitute for ATP. These results indicate that in CHO-IR cells, insulin elevates [Ca2+]c by activating the 10-pS calcium-permeable cation channel. Activation by the insulin receptor involves pertussis toxin-sensitive G protein.
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PMID:Activation of calcium-permeable cation channel by insulin in Chinese hamster ovary cells expressing human insulin receptors. 942 13

We present evidence that stimulation of the human beta-3 adrenergic receptor (AR), expressed in Chinese hamster ovary/K1 cells, specifically activates the mitogen-activated protein kinases extracellular signal-regulated kinase (ERK)1 and 2, but not JNK or p38. The extent and kinetics of the ERK stimulation by the beta-3 AR are identical with those of the endogenic insulin receptor. However, insulin augments cellular proliferation, whereas beta-3 AR agonists inhibit proliferation due to the production of cyclic AMP. The pharmacological profile of the ERK activation by the beta-3 AR differs significantly from its activation of adenylyl cyclase. The order of potency and intrinsic activities of both natural ligands, norepinephrine and epinephrine, is inversed between both signaling pathways. In addition, BRL 37344 and propranolol, ligands that act as agonists in the stimulation of cyclase, act as antagonists for ERK activation. The activation of ERK1/2 is sensitive to pertussis toxin, suggesting that the beta-3 AR, in addition to its interaction with Gs, can couple to Gi/o. Furthermore, the activation of ERK by the beta-3 AR is sensitive to PD98059, wortmannin, and LY294002, indicating a crucial role for mitogen-activated protein kinase kinase and phosphatidylinositol-3 kinase (PI3K), respectively. A beta-3 AR-mediated stimulation of PI3K is confirmed by the observation that the selective agonist CGP 12177A specifically activates protein kinase B. As was observed for the activation of ERK, the activation of protein kinase B is inhibited by preincubation with pertussis toxin and PI3K inhibitors, suggesting that both are a consequence of a Gi/o-mediated activation of PI3K.
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PMID:Stimulation of the extracellular signal-regulated kinase 1/2 pathway by human beta-3 adrenergic receptor: new pharmacological profile and mechanism of activation. 992 16

Insulin action is initiated by binding to its cognate receptor, which then triggers multiple cellular responses by activating different signaling pathways. There is evidence that insulin receptor signaling may involve G protein activation in different target cells. We have studied the activation of G proteins in rat hepatoma (HTC) cells. We found that insulin stimulated binding of guanosine 5'-O-(3-thiotriphosphate) (GTP-gamma-35S) to plasma membrane proteins of HTC cells, in a dose-dependent manner. This effect was completely blocked by pertussis toxin treatment of the membranes, suggesting the involvement of G proteins of the G alpha i/G alpha o family. The expression of these G alpha proteins was checked by Western blotting. Next, we used blocking antibodies to sort out the specific G alpha protein activated by insulin stimulation. Anti-G alpha il,2 antibodies completely prevented insulin-stimulated GTP binding, whereas anti-G alpha o,i3 did not modify this effect of insulin on GTP binding. Moreover, we found physical association of the insulin receptor with G alpha il,2 by copurification studies. These results further support the involvement of a pertussis toxin-sensitive G protein in insulin receptor signaling and provides some evidence of specific association and activation of G alpha il,2 protein by insulin. These findings suggest that G alpha il,2 proteins might be involved in insulin action.
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PMID:Insulin activates G alpha il,2 protein in rat hepatoma (HTC) cell membranes. 1006 61


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