Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P19086 (Galphaz)
 110 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bradykinin triggered intracellular Ca mobilizations and ionic conductance changes were studied in the neuroblastoma x glioma hybrid cell line NG108-15 using Ca-sensitive fluorescent indicator fura-2 under patch pipette whole cell voltage clamp condition. The time course of outward current induced by bradykinin was closely related to the time-course of [Ca2+]i change. Following application of bradykinin, [Ca2+]i increased transiently and then decreased below the basal level before bradykinin application. The inward currents activated by step-depolarization were suppressed after bradykinin application, but the time-course of the suppression did not go in parallel with the [Ca2+]i changes: the suppression started before the [Ca2+]i change emerged and outlasted the phase of [Ca2+]i increase. Both transient type and long-lasting type Ca current were suppressed by bradykinin. [Ca2+]i increase induced by high potassium depolarization was suppressed by bradykinin. Pertussis toxin did not affect the Ca transient nor the suppression of Ca channel induced by bradykinin. Our results suggest that the modifications of ionic channels by bradykinin could be through the other mechanisms than the well established activation of the G-protein leading to the IP3 mechanisms and that the bradykinin receptor might couple with the pertussis toxin-insensitive G protein which regulates the calcium channels.
 ...
PMID:Mobilization of intracellular Ca2+ and suppression of inward currents in a neuronal hybrid cell line triggered by bradykinin. 196 37

Several classes of growth factors can be distinguished that act through different signal transduction pathways. One class is constituted by the peptide growth factors that bind to receptors with ligand-dependent protein tyrosine kinase activity. Another class of mitogens activates a phosphoinositide-specific phospholipase C via a receptor-linked G protein. An intriguing member of this class is lysophosphatidic acid (LPA). LPA mitogenicity is not dependent on other mitogens and is blocked by pertussis toxin. LPA evokes at least three separate signalling cascades: (i) activation of a pertussis toxin-insensitive G protein mediating phosphoinositide hydrolysis; (ii) release of arachidonic acid in a GTP-dependent manner, but independent of prior phosphoinositide hydrolysis; and (iii) activation of a pertussis toxin-sensitive Gi protein mediating inhibition of adenylate cyclase. The peptide bradykinin mimics LPA in inducing responses (i) and (ii), but fails to activate Gi and to stimulate DNA synthesis. Our results suggest that the mitogenic action of LPA occurs through Gi or a related pertussis toxin substrate and that, unexpectedly, the phosphoinositide hydrolysis pathway is neither required nor sufficient, by itself, for mitogenesis.
 ...
PMID:Growth factor-like action of lysophosphatidic acid: mitogenic signalling mediated by G proteins. 211 27

Recently, a cDNA coding for a novel G protein alpha-subunit, Gz-alpha, was isolated from a human retinal cDNA library and shown by Northern blot analysis to be expressed at high levels in neural tissues. We have prepared affinity-purified antibodies specifically directed against synthetic Gz-alpha peptides and employed immunohistochemical methods to map the localization of Gz-alpha in human, bovine, and murine retina and brain. By light microscopy, Gz-alpha was localized to the cytoplasm of neurons, with predominant reactivity in ganglion cells of the retina, Purkinje cells of the cerebellum, and most neurons of the hippocampus and cerebral cortex. Reactivity was confined to perikaryon, dendrites, and a very short segment of proximal axons, except for the retinal ganglion cells, in which the axons in the nerve fiber layer showed intense Gz-alpha immunoreactivity proximal to the lamina cribrosa. Pre-embedding immunoelectron microscopy demonstrated the presence of focal Gz-alpha immunoreactivity on the nuclear membranes, endoplasmic reticulum, and plasma membranes of Purkinje cell perikarya and in association with microtubules in their proximal dendrites. Subcellular fractionation studies confirmed the association of Gz-alpha with plasma and intracellular membranes. The localization of Gz-alpha and its unique amino acid sequence suggest that it may have a specialized function in neural tissues.
 ...
PMID:Novel localization of a G protein, Gz-alpha, in neurons of brain and retina. 211 45

We have recently demonstrated the presence in the rat Leydig cells of a corticotropin releasing factor (CRF) receptor and an inhibitory action of the peptide on human chorionic gonadotropin (hCG)-induced cAMP generation and steroidogenesis. The inhibitory action of CRF was unaffected by pertussis toxin and was completely reversed by 8-bromo-cAMP (Ulisse, S., Fabbri, A., and Dufau, M. L. (1989) J. Biol. Chem. 264, 2156-2163). In this study, we have evaluated the participation of protein kinase C in CRF action in the Leydig cells and the level of the gonadotropin signal pathway affected by CRF. Binding of 125I-labeled ovine CRF to Leydig cell membranes was reduced by GTP and guanyl-5'-yl imidodiphosphate (Gpp(NH)p), in a dose-dependent manner. Phorbol 12-myristate 13-acetate, like CRF, caused time-dependent inhibition of hCG-induced cAMP generation and steroidogenesis. This inhibitory action was reversed by 8-bromo-cAMP. Both CRF and 12-O-tetradecanoylphorbol-13-acetate did not affect 125I-hCG binding. No additive effects of CRF and the phorbol ester were observed in these studies. CRF caused a rapid translocation of protein kinase C in Leydig cells. Preincubation of cells with protein kinase C inhibitors or TPA-induced depletion of protein kinase C prevented the inhibitory actions of CRF and TPA. CRF and TPA were able to inhibit the stimulation of cAMP and testosterone production by cholera toxin and forskolin. Adenylate cyclase stimulation by Gpp(NH)p, luteinizing hormone + Gpp(NH)p, and NaF in crude membranes or by forskolin and manganese in solubilized membranes, prepared from CRF- and TPA-treated cells, was also markedly inhibited. We conclude that CRF receptors interact with a pertussis toxin-insensitive G protein (possibly Gp) in the Leydig cell and that the inhibitory action of CRF on Leydig cell function is exerted mainly on the catalytic subunit of adenylate cyclase through a direct or indirect action of protein kinase C.
 ...
PMID:A novel mechanism of action of corticotropin releasing factor in rat Leydig cells. 215 73

Quiescent cultures of Swiss 3T3 cells can be stimulated to recommence DNA synthesis by polypeptide growth factors, neuropeptides, and various pharmacologic agents that act via multiple signal transduction pathways. Neuropeptides of the bombesin family provide potent mitogens to elucidate these pathways. These peptides bind to specific receptors that have been characterized by radioligand binding and sensitivity to antagonists and identified as glycoproteins with a Mr of 75,000-85,000 by chemical cross-linking. After binding, bombesin elicits a cascade of early molecular events including stimulation of phosphorylation of the acidic Mr 80,000 cellular protein, which is a major substrate of protein kinase C; Ca2+ mobilization mediated by Ins(1,4,5)P3, Na+ and K+ fluxes, transmodulation of EGF receptor, enhancement of cAMP accumulation, and expression of the proto-oncogenes c-fos and c-myc. Studies using membrane preparations and permeabilized 3T3 cells indicate that G proteins play a role in the transduction of the mitogenic signal triggered by the binding of bombesin to its receptor. A pertussis toxin-insensitive G protein couples the bombesin receptor to the generation of a signal that activates protein kinase C, whereas a pertussis toxin-sensitive G protein mediates cross-talk between transmembrane signaling pathways. Bombesin-mediated mitogenesis can be blocked by different antagonists and by interrupting the signal-transduction process at various postreceptor levels. Thus, prolonged treatment with vasopressin causes heterologous desensitization to the mitogenic action of bombesin. This mitogenic block is mediated by uncoupling the receptor from its signaling system. Loss of responsiveness to bombesin-stimulated DNA synthesis is also induced by down-regulation of protein kinase C.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Bombesin stimulation of mitogenesis. Specific receptors, signal transduction, and early events. 217 58

Rat Leydig cells possess functional high affinity receptors for corticotropin-releasing factor (CRF). CRF inhibited human chorionic gonadotropin (hCG)-induced androgen production in cultured fetal and adult Leydig cells in a dose-dependent manner, but it had no effect on basal testosterone secretion. Comparable inhibitory effects of CRF were observed in the presence or absence of 3-isobutyl-1-methylxanthine. CRF treatment caused a marked reduction of steroid precursors of the androgen pathway (from pregnenolone to testosterone) during gonadotropin stimulation, but it did not influence their basal levels. The inhibitory action of CRF on hCG-induced steroidogenesis was fully reversed by 8-bromo-cAMP but was not affected by pertussis toxin. The action of CRF was rapid; and it was blocked by coincubation with anti-CRF antibody. CRF caused no changes in hCG binding to Leydig cells, and in contrast to other target tissues, CRF did not stimulate cAMP production, indicating that CRF receptors are not coupled to Gs in Leydig cells. These studies have demonstrated that CRF-induced inhibition of the acute steroidogenic action of hCG is exerted at sites related to receptor/cyclase coupling or cAMP formation. The inhibitory effects of CRF in the Leydig cell do not occur through the Gi unit of adenylate cyclase, but could involve pertussis toxin-insensitive G protein(s). These observations demonstrate that CRF has a novel and potent antireproductive effect at the testicular level. Since CRF is synthesized in the testis and is present in Leydig cells, it is likely that locally produced CRF could exert negative autocrine modulation on the stimulatory action of luteinizing hormone on Leydig cell function.
 ...
PMID:Corticotropin-releasing factor receptors and actions in rat Leydig cells. 246 87

Lysophosphatidate (LPA), the simplest natural phospholipid, is highly mitogenic for quiescent fibroblasts. LPA-induced cell proliferation is not dependent on other mitogens and is blocked by pertussis toxin. LPA initiates at least three separate signaling cascades: activation of a pertussis toxin-insensitive G protein mediating phosphoinositide hydrolysis with subsequent Ca2+ mobilization and stimulation of protein kinase C; release of arachidonic acid in a GTP-dependent manner, but independent of prior phosphoinositide hydrolysis; and activation of a pertussis toxin-sensitive Gi protein mediating inhibition of adenylate cyclase. The peptide bradykinin mimics LPA in inducing the first two responses but fails to activate Gi and to stimulate DNA synthesis. Our data suggest that the mitogenic action of LPA occurs through Gi or a related pertussis toxin substrate and that the phosphoinositide hydrolysis-protein kinase C pathway is neither required nor sufficient, by itself, for mitogenesis. The results further suggest that LPA or LPA-like phospholipids may have a novel role in G protein-mediated signal transduction.
 ...
PMID:Lysophosphatidate-induced cell proliferation: identification and dissection of signaling pathways mediated by G proteins. 255 6

Ca2+-mobilizing agonists stimulate phospholipase C-mediated phosphatidylinositol 4,5-bisphosphate hydrolysis and inositol trisphosphate (IP3) formation in pulmonary as well as in peripheral vascular endothelial cells (EC). In general, it is believed that receptor-phospholipase C interactions involve a guanine nucleotide regulatory (G) protein. This interaction can be inhibited by Bordetella pertussis toxin in certain cells. Here we report that pertussis toxin catalyzes the [32P]ADP ribosylation of a Mr = 41,000 protein in human umbilical vein EC. However, prior EC treatment with pertussis toxin (250 ng/ml for 20 h) does not inhibit thrombin-induced Ca2+ flux or IP3 formation, despite markedly attenuating the radiolabeling of the Mr = 41,000 protein (less than 5% control). Treatment of digitonin-permeabilized human umbilical vein EC with GTP gamma S, a stable GTP analog, or AIF4-, but not with GDP beta S, stimulates IP3 accumulation. However, GDP beta S inhibits GTP gamma S-induced IP3 accumulation. Although thrombin alone is not very effective in elevating IP3 levels in permeabilized EC, thrombin and GTP gamma S act in a synergistic fashion to increase IP3 accumulation. Overall, these observations are interpreted to indicate that a pertussis toxin-insensitive G protein is a key intermediate in the signaling pathway linking thrombin receptors to phospholipase C in human umbilical vein EC.
 ...
PMID:GTP gamma S increases thrombin-mediated inositol trisphosphate accumulation in permeabilized human endothelial cells. 255 82

The role of guanine nucleotide-binding proteins (G proteins) in the cAMP-dependent action of serotonin (5-HT) and the antagonistic action of the neuropeptide Phe-Met-Arg-Phe-NH2 (FMRF-amide), mediated by the lipoxygenase metabolites of arachidonic acid, was investigated in Aplysia sensory neurons. Intracellular injection of guanosine 5'-[gamma-thio]triphosphate (GTP[gamma-S]) mimics the hyperpolarizing action of FMRF-amide due to activation of the S K+ current and alters the transient response to FMRF-amide into an irreversible (or only partially reversible) response. At higher concentrations, GTP[gamma-S] occludes the response to FMRF-amide. Injection of activated pertussis toxin inhibits the response to FMRF-amide but not to 5-HT. Injection of guanosine 5'-[beta-thio]diphosphate inhibits the response to FMRF-amide by approximately equal to 50% and completely blocks the response to 5-HT. Three lines of evidence suggest that the FMRF-amide-activated G protein is involved at an early stage of the arachidonic acid cascade, prior to the release of arachidonate. (i) Pertussis toxin injection blocks the hyperpolarizing response to FMRF-amide but not to exogenously applied arachidonic acid. (ii) Two blockers of the arachidonic acid cascade inhibit the hyperpolarizing responses to both FMRF-amide and GTP[gamma-S] (and unmask a 5-HT-like depolarizing response to the nucleotide). (iii) Concentrations of GTP[gamma-S] that alter the kinetics of the FMRF-amide response have no effect on the hyperpolarizing response to arachidonic acid. We conclude that a pertussis toxin-sensitive G protein most likely acts to couple the FMRF-amide receptor to phospholipase activation and arachidonic acid release, whereas a pertussis toxin-insensitive G protein couples the 5-HT receptor to adenylate cyclase.
 ...
PMID:Role of two different guanine nucleotide-binding proteins in the antagonistic modulation of the S-type K+ channel by cAMP and arachidonic acid metabolites in Aplysia sensory neurons. 284 23

The effects of the simple bioactive lipid mediator lysophosphatidic acid (LPA) on cAMP accumulation were investigated in cultured human airway smooth muscle cells (ASMC). Pretreatment of cells with LPA induced an increase in subsequent stimulation of cAMP accumulation by forskolin and by isoproterenol. When included during the assay of cAMP accumulation rather than as a pretreatment, LPA inhibited forskolin stimulation but enhanced isoproterenol stimulation. Both effects of LPA on forskolin stimulation were completely blocked by pertussis toxin treatment, whereas the effects on isoproterenol stimulation appeared relatively insensitive to pertussis toxin. The protein kinase C activator phorbol-12-myristate-13-acetate (PMA) sensitized forskolin stimulation to a similar extent as did LPA, and the combination of LPA plus PMA caused markedly more sensitization than either agent alone. In contrast, PMA inhibited isoproterenol stimulation and markedly decreased the sensitization induced by LPA. Serum also induced sensitization, and sensitization by LPA plus serum was no greater than that with LPA alone. LPA-induced sensitization appeared to be independent of protein kinase C activation because it was unchanged in cells treated to down-regulate protein kinase C. LPA also stimulated polyphosphoinositide hydrolysis, and this stimulation was partially inhibited by pertussis toxin treatment. These results suggest that LPA activates receptors coupled to both the pertussis toxin-sensitive G protein Gi and the pertussis toxin-insensitive G protein Gq. The complex effects of LPA, PMA, and pertussis toxin on cAMP accumulation in these cells are consistent with the expression of the type 2 isozyme of adenylyl cyclase in these cells.
 ...
PMID:Lysophosphatidic acid regulation of cyclic AMP accumulation in cultured human airway smooth muscle cells. 747 5


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>