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)

To better understand the molecular mechanisms that underlie the exaggerated bradykinin (BK)-stimulated release of Ins(1,4,5)P3 in fibroblasts from Alzheimer patients, the role of G-proteins, protein kinase C (PKC) and cyclic AMP in BK-induced Ins(1,4,5)P3 formation was determined. A role for G-proteins in the coupling of the BK receptor to intracellular signals was indicated by guanosine 5'-(3-O-thio)triphosphate (GTP gamma S) enhanced BK-stimulated Ins(1,4,5)P3 release. The coupling of G-proteins to Ins(1,4,5)P3 formation was sensitive to cholera toxin (CTX), but not pertussis toxin (PTX), and was not altered by PKC activation. The inhibition by CTX appeared to be secondary to its ability to increase cyclic AMP, because forskolin also inhibited the BK-mediated Ins (1,4,5)P3 release. Activation of PKC with TPA diminished the number of BK receptors by 33% and proportionally decreased BK-mediated Ins(1,4,5)P3 formation by 28%. The latter response was abolished by PKC inhibitors. Depletion of PKC by prolonged TPA treatment did not further alter the number of BK receptors but further decreased the Ins(1,4,5)P3 response by 65%. Thus, changes in PKC probably do not underlie the enhanced BK-induced Ins(1,4,5)P3 formation in AD fibroblasts, because both activation and depletion of the PKC diminished the Ins(1,4,5)P3 response.
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PMID:Regulation of bradykinin-induced Ins(1,4,5)P3 formation by protein kinase C in human fibroblasts. 889 Sep 34

Smooth muscle cell-like mesangial cells play an important role in the regulation of glomerular blood flow and are involved in renal inflammatory reactions, thereby interacting with circulating cells. The platelet products serotonin (5-HT) and ATP induce similar, e.g. mitogenic, effects in mesangial cells, but differentially activate and induce inflammation-related genes. To get an insight into intracellular signaling steps, a very early step in the signaling cascade, the biphasic Ca2+ signal elicited by 5-HT and ATP in rat mesangial cells was investigated. Both phases of the Ca2+ signal, release from internal stores as well as influx of extracellular Ca2+, were dependent on phospholipase C activation as shown by the specific inhibitor U73122 (complete inhibition at 10 microM U73122). There was no evidence for voltage-gated L-type channels in these cells, suggesting that Ca2+ influx was mediated by Ca2+ release-activated channels. The L-type channel blocker verapamil, however, dose-dependently (0.1-10 microM) and specifically inhibited 5-HT-elicited Ca2+ signals by interference with binding of 5-HT to 5-HT2A receptors. 5-HT-mediated Ca2+ release was reduced by 80% when protein kinase C was activated by the phorbolester TPA (0.1 microM). Interaction of 5-HT2A receptors with phospholipase C was also inhibited by genistein (30% at 5 microM; 100% at 50 microM), an inhibitor of tyrosine kinases. Binding of 5-HT to its receptor reduced subsequent ATP-mediated Ca2+ signaling. The cross talk between the receptors was sensitive to genistein. ATP-mediated Ca2+ signaling was attributed to different types of P2y receptors and/or multiple G-proteins coupled, because the signal was partially inhibited by pertussis toxin (50%). In accordance, modulation of the ATP-mediated signaling by phosphorylation was less tightly controlled than 5-HT-mediated Ca2+ release. These data indicate that although the Ca2+ responses elicited by the two stimuli are comparable, interactions between receptors, G-proteins and target enzymes are regulated differentially.
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PMID:Mechanisms of serotonin-induced Ca2+ responses in mesangial cells. 927 31

We have investigated the effect of IGF-II on glucose-induced insulin release in the pancreatic beta-cell. Introduction of IGF-II during perifusion of the cells with 20 mM glucose abolished glucose-induced insulin release. Concomitant addition of IGF-II with 20 mM glucose caused a complete inhibition of insulin release. In addition, IGF-II inhibited Ca(2+)-induced insulin release from electropermeabilized pancreatic beta-cells. IGF-II had no effect on K(+)-or tolbutamide-induced insulin release. However, IGF-II could suppress K(+)-stimulated insulin release when cells were pretreated with the protein phosphatase inhibitor okadaic acid. The inhibitory effect of IGF-II on insulin release was not associated with significant changes in membrane potential, activity of the voltage-gated L-type Ca(2+)-channel or cytoplasmic free Ca2+ concentration. Pretreatment of the cells with pertussis toxin or the phorbol ester TPA abolished the inhibitory action of IGF-II on insulin release. Hence, the molecular mechanism whereby activation of the IGF-II/M6P receptor by IGF-II inhibits glucose-stimulated insulin exocytosis in the pancreatic beta-cell involves pertussis toxin-sensitive G proteins and is dependent on PKC activity.
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PMID:Insulin-like growth factor II inhibits glucose-induced insulin exocytosis. 947 90

ATP-induced arachidonic acid (AA) release was studied in [3H]AA-prelabeled cultured astrocytes. To characterize the P2 purinoceptor-mediated effect of ATP, the subtype-specific agonists 2-methylthio ATP (2-MeSATP) and UTP were compared. ATP, UTP, or 2-MeSATP induced a dose-dependent increase of [3H]AA release, with EC50 values of 22.7 microM, 29.4 microM, and 1.68 microM, respectively; alpha,beta-methyleneATP and adenosine had no effect. The order of potency was ATP = UTP > or = 2-MeSATP, indicating that ATP interacted with both P2Y1 and P2Y2 receptors to mediate AA release in astrocytes. The effect of ATP, UTP, or 2-MeSATP was markedly inhibited by pretreatment of cells with pertussis toxin. Ca2+ ionophore-A23187 and PKC activator-TPA mimicked the effects of these three agonists to stimulate AA release. ATP, UTP, and 2-MeSATP induced a rapidly initial rise of [Ca2+]i and a sustained [Ca2+]i increase. The AA release was blocked in the external Ca2+ free in condition the sustained [Ca2+]i increase was abolished. Both A23187- and TPA-induced AA release were also blocked in this condition. Furthermore, inorganic Ca2+ channel blocker Co2+ inhibited ATP, UTP, or 2-MeSATP induced AA release as well. Long-term (24 h) treatment of cells with TPA resulted in an attenuation of three agonists, TPA or A23187 response. Similarly, ATP or TPA promoted AA release was inhibited by the mitogen-activated protein kinase (MAPK) cascade inhibitor PD 98059. ATP, TPA, or A23187 induced an increase in the activity and tyrosine phosphorylation of p42 MAPK, as well as a molecular weight shift, consistent with phosphorylation, of cytosolic phospholipase A2 (cPLA2). ATP- and TPA-stimulated activation of p42 MAPK activity and tyrosine phosphorylation were inhibited by long-term TPA treatment, while A23187-stimulated effects were completely blocked. Furthermore, tyrosine phosphorylation and activation of p42 MAPK and mobility shift of cPLA2 induced by A23187 were reversed in the absence of external Ca2+, suggesting the involvement of PKCalpha in MAPK activation and mobility shift of cPLA2. Taken together, ATP-stimulated AA release was secondary to the activation of P2Y1 and P2Y2 receptors/PLC pathway. Ca2+ and PKC interact to regulate this response. Elevation of intracellular Ca2+, the mechanism involving extracellular Ca2+ influx, might act partly through PKCalpha activation and in turn MAPK might be activated, leading to cPLA2 phosphorylation and AA release.
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PMID:ATP-induced arachidonic acid release in cultured astrocytes is mediated by Gi protein coupled P2Y1 and P2Y2 receptors. 951 68

The neuropeptide galanin is widely distributed in the gastrointestinal tract and exerts several inhibitory effects, especially on intestinal motility and on insulin release from pancreatic beta-cells. The presence of galanin fibres not only in the myenteric and submucosal plexus but also in the mucosa, prompted us to investigate the regulatory role of galanin, and its mechanism of action, on the secretion of the insulinotropic hormone glucagon-like peptide-1 (GLP-1). Rat ileal cells were dispersed through mechanical vibration followed by moderate exposure to hyaluronidase, DNase I and EDTA, and enriched for L-cells by counterflow elutriation. A 6- to 7-fold enrichment in GLP-1 cell content was registered after elutriation, as compared with the crude cell preparation (929 +/- 81 vs 138 +/- 14 fmol/10(6) cells). L-cells then accounted for 4-5% of the total cell population. Bombesin induced a time-(15-240 min) and dose- (0.1 nM-1 microM) dependent release of GLP-1. Glucose-dependent insulinotropic peptide (GIP, 100 nM), forskolin (10 microM) and the phorbol ester 12-0-tetradecanoylphorbol-13-acetate (TPA, 1 microM) each stimulated GLP-1 secretion over a 1-h incubation period. Galanin (0.01-100 nM) induced a dose-dependent inhibition of bombesin- and of GIP-stimulated GLP-1 release (mean inhibition of 90% with 100 nM galanin). Galanin also dose-dependently inhibited forskolin-induced GLP-1 secretion (74% of inhibition with 100 nM galanin), but not TPA-stimulated hormone release. Pretreatment of cells with 200 ng/ml pertussis toxin for 3 h, or incubation with the ATP-sensitive K+ channel blocker disopyramide (200 microM), prevented the inhibition by galanin of bombesin- and GIP-stimulated GLP-1 secretion. These studies indicate that intestinal secretion of GLP-1 is negatively controlled by galanin, that acts through receptors coupled to pertussis toxin-sensitive G protein and involves ATP-dependent K+ channels.
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PMID:Galanin inhibits glucagon-like peptide-1 secretion through pertussis toxin-sensitive G protein and ATP-dependent potassium channels in rat ileal L-cells. 961 55

The heparin-binding protein vascular endothelial growth factor (VEGF) is a highly specific growth factor for endothelial cells. VEGF binds to specific tyrosine kinase receptors, which mediate intracellular signaling. We investigated 2 hypotheses: (1) VEGF affects intracellular calcium [Ca2+]i regulation and [Ca2+]i-dependent messenger systems; and (2) these mechanisms are important for VEGF's proliferative effects. [Ca2+]i was measured in human umbilical vein endothelial cells using fura-2 and fluo-3. Protein kinase C (PKC) activity was measured by histone-like pseudosubstrate phosphorylation. PKC isoform distribution was observed with confocal microscopy and Western blot. Inhibition of PKC isoforms was assessed by specific antisense oligonucleotides (ODN) for the PKC isoforms. VEGF (10 ng/mL) induced a transient increase in [Ca2+]i followed by a sustained elevation. The sustained [Ca2+]i plateau was abolished by EGTA. Pertussis toxin also abolished the plateau phase, whereas the initial peak was not affected. The PKC isoforms alpha, delta, epsilon, and zeta were identified in endothelial cells. VEGF induced a translocation of PKC-alpha and PKC-zeta toward the nucleus and the perinuclear area, whereas cellular distribution of PKC-delta and PKC-epsilon was not influenced. Cell exposure to TPA led to a down-regulation of PKC-alpha and reduced the proliferative effect of VEGF. VEGF-induced endothelial cell proliferation also was reduced by the PKC inhibitors staurosporine and calphostin C. Specific down-regulation of PKC-alpha and PKC-zeta with antisense ODN reduced the proliferative effect of VEGF significantly. Our data show that VEGF induces initial and sustained Ca2+ influx. VEGF leads to the translocation of the [Ca2+]i-sensitive PKC isoform alpha and the atypical PKC isoform zeta. Antisense ODN for these PKC isoforms block VEGF-induced proliferation. These findings suggest that PKC isoforms alpha and zeta are important for VEGF's angiogenic effects.
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PMID:The proliferative effect of vascular endothelial growth factor requires protein kinase C-alpha and protein kinase C-zeta. 988 81

The aim of the present study was to examine the signaling pathways for a low dose of angiotensin II (ANG II) on Na+ uptake of primary cultured rabbit renal proximal tubule cells (PTCs) in hormonally defined serum-free medium. The results were as follows; ANG II (10(-11) M) stimulated the proliferation of PTCs. 10(-11) M ANG II stimulated Na+ uptake by 20%, whereas 10(-9) M ANG II inhibited it by 20% (p < 0.05). The stimulatory effect of 10(-11) M ANG II on Na+ uptake was inhibited by amiloride (10(-3) M) and by losartan (ANG II receptor subtype 1 antagonist, 10(-8) M) but not by PD123319 (ANG II receptor subtype 2 antagonist, 10(-8) M). Pertussis toxin (PTX, 50 ng/ml) prevented the ANG II-induced stimulation of Na+ uptake (p < 0.01). 8-Bromoadenosine 3', 5'-cyclic monophosphate (8-Br-cAMP, 10(-6) M) did not affect Na+ uptake. SQ 22536 (adenylate cyclase inhibitor, 10(-6) M) also did not change the ANG II-induced stimulation of Na+ uptake. ANG II did not stimulate cAMP production. In contrast, 12-O-tetradecanoylphorbol-13-acetate (TPA, 0.01 ng/ml) produced significant increase in Na+ uptake. When ANG II and TPA were added together to the PTCs, there was no additive effect on Na+ uptake. Staurosporine (calcium-dependant protein kinase C inhibitor, 10(-6) M) led to a complete inhibition of ANG II-induced stimulation of Na+ uptake. ANG II-treatment resulted in a 26% increase in total protein kinase C (PKC) activity. However, 10(-11) M ANG II did not change [Ca2+]i mobilization and [3H]-AA release while 10(-9) M ANG II increased both of them. In conclusion, the PTX-sensitive PKC pathway may be the main signaling cascade in the stimulatory effects of low dose of ANG II (10(-11) M) on Na+ uptake in the primary cultured rabbit renal proximal tubule cells in hormonally defined serum-free medium.
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PMID:A signaling pathway for stimulation of Na+ uptake induced by angiotensin II in primary cultured rabbit renal proximal tubule cells. 1008 51

The effects of extracellular adenosine 5'-triphosphate (ATP) on the delayed rectifier K+ current (IK) were studied in guinea-pig ventricular myocytes using the whole-cell voltage-clamp technique. ATP increased IK concentration dependently with a concentration eliciting a half-maximal response of 1.86 microM and a maximal increase of about 1.8-fold. The enhancement of IK developed slowly, the effect reaching a maximum in about 1.6 min after application of ATP. The rank order of agonist potency in enhancing IK was 2-methylthio-ATP>/= ATP>>alpha,beta-methylene-ATP. The ATP response was attenuated in guanosine 5'-O-(2-thiodiphosphate) (GDPbetaS)- loaded cells, but was not affected by pertussis toxin (PTX)-pre-treatment, indicating that a PTX-insensitive G protein is involved in the response. These features are consistent with operation of P2Y-type purinoceptors. ATP produced a further increase in IK stimulated maximally either by isoprenaline (1 microM) through protein kinase A (PKA) or by 12-O-tetradecanoylphorbol 13-acetate (TPA, 100 nM) through protein kinase C (PKC), while 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7, 10 microM) did not affect the ATP response, suggesting that PKA and PKC do not mediate the response. ATP irreversibly enhanced IK in cells loaded with adenosine 5'-O-(3-thiotriphosphate) (ATPgammaS, 5 mM) or okadaic acid (10 microM), a phosphatase inhibitor, suggesting that a phosphorylation step is present after the receptor stimulation. Genistein, an inhibitor of tyrosine phosphorylation, suppressed the ATP response significantly, while daidzein, an inactive analogue of genistein, had little effect on it, although both genistein or daidzein alone decreased IK. It is hypothesized that tyrosine phosphorylation plays a role in the signalling pathway involved in the enhancement of cardiac IK by P2Y-purinergic stimulation.
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PMID:On the mechanism of the enhancement of delayed rectifier K+ current by extracellular ATP in guinea-pig ventricular myocytes. 1008 39

The mechanism of arginine vasopressin (AVP)-induced arachidonic acid (AA) release was examined in the cardiac myoblast cell line, H9c2. Stimulation of cells with AVP induced dose-dependent AA release, and this effect was completely inhibited by the V1 receptor antagonist, d(CH)5[Tyr(Me)2]AVP. AVP also produced dose-dependent stimulation of inositol phosphate formation; this was not affected by pertussis toxin, indicating the presence of the V1 receptor/Gq protein/PLCbeta pathway in H9c2 cells. The concentration-response curves for these two effects of AVP overlapped. AVP induced a rapid increase in [Ca2+]i, followed by a sustained increase. The Ca2+ ionophore, A23187 or ionomycin, mimicked the effect of AVP, whereas the protein kinase C (PKC) activator, TPA, only induced a slight increase in AA release. Both the AVP- or A23187-stimulated AA release and the AVP-induced sustained [Ca2+]i increase were completely blocked in the absence of external Ca2+. The receptor-operated Ca2+ channel blocker, SKF 96365, and the inorganic Ca2+ channel blockers, Ca2+ and Ni2+, also inhibited the AVP-induced AA release. Western blots demonstrated expression of PKCalpha, betaI, epsilon, delta, and zeta in H9c2 cells; PKC inhibitors (staurosporine or Ro 31-8220) or down-regulation of PKCalpha, betaI, epsilon, and delta by long-term (24 h) TPA treatment caused a partial blockade of the AVP-induced response, whereas the A23187-induced AA release was unaffected by down-regulation of these isoforms. AVP-induced, but not A23187-induced, AA release was partially blocked by the p42 MAPK cascade inhibitor, PD 98059. AVP and TPA, but not A23187, induced an increase in activity and tyrosine phosphorylation of p42 MAPK, together with a molecular weight shift, consistent with phosphorylation, of cytosolic PLA2. AVP- or TPA-induced activation and tyrosine phosphorylation of p42 MAPK were completely blocked by down-regulation of PKCalpha, betaI, epsilon, and delta, but still occurred, together with the cytosolic PLA2 mobility shift, in the absence of external Ca2+. These results show that AVP-induced AA release in H9c2 cells is secondary to activation of the V1 receptor/Gq protein/PLCP pathway, leading to an influx of extracellular Ca2+ and activation of PKCalpha, betaI, epsilon, and delta. The influx of extracellular Ca2- and DAG act, respectively, through PKC-/MAPK-independent or PKC-dependent MAPK pathways to mediate AA release.
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PMID:Signal transduction of arginine vasopressin-induced arachidonic acid release in H9c2 cardiac myoblasts: role of Ca2+ and the protein kinase C-dependent activation of p42 mitogen-activated protein kinase. 1009 98

In Chinese hamster ovary (CHO) cells transfected with the cDNA for the dopamine D3 receptor, low concentrations of dopamine (IC50: 0.5 nM) counteracted the release of arachidonic acid (AA) induced by the protein kinase C activator TPA (maximal inhibition: 15% at 10 - 30 nM). The effect of dopamine -- which was antagonized by pretreatment with pertussis toxin (PTX) or by the dopamine receptor antagonist haloperidol -- was biphasic; thus, at increasing concentrations of dopamine (100 nM - 1 microM), AA levels approached baseline. The preferential dopamine D3 receptor ligand PNU-99194A displayed an effect similar to that of dopamine; thus, whereas low concentrations of PNU-99194A (IC50: 1.9 nM) reduced TPA-induced AA release (maximal inhibition: 15% at 30 - 100 nM), higher concentrations (> or =1 microM) were ineffective. When dopamine and PNU-99194A were administered together at concentrations yielding maximal inhibition of AA release, no additive effect was observed; moreover, a high concentration of dopamine counteracted the AA-reducing effect of a low concentration of PNU-99194A and vice versa. It is suggested that D3 receptors in transfected CHO cells may exert mainly an inhibitory, but also a stimulatory influence on TPA-induced AA release, and that PNU-99194A acts as an agonist in this system.
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PMID:Both dopamine and the putative dopamine D3 receptor antagonist PNU-99194A induce a biphasic inhibition of phorbol ester-stimulated arachidonic acid release from CHO cells transfected with the dopamine D3 receptor. 1020 43


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