Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

C-type natriuretic peptide (CNP) and brain natriuretic peptide (BNP) are members of the natriuretic peptide family, which have been shown to interact with ANP-C/ANF-R2 receptors in addition to ANP-B receptor subtypes. The present study was undertaken to investigate if the interaction of CNP and BNP with ANP-C receptors results in the inhibition of adenylyl cyclase activity. CNP and BNP inhibited adenylyl cyclase activity in heart and brain striatal membranes in a concentration dependent manner with an apparent Ki between 0.1 and 1.0 nM. Maximal inhibition observed in heart membranes were about 25% and 35% for BNP and CNP respectively, however the inhibitions in brain striatal membranes were smaller (approximately 20%). The inhibition was dependent on the presence of guanine nucleotides and was attenuated by pertussis toxin treatment. In addition, CNP inhibited the stimulatory effect of isoproterenol on adenylyl cyclase, whereas CNP as well as BNP showed an additive effect with the inhibitory response of angiotensin II on adenylyl cyclase activity. When the combined effect of C-ANF4-23/BNP, C-ANF4-23/CNP and BNP/CNP at optimal concentrations was studied together on adenylyl cyclase activity, the percent inhibition remained the same for C-ANF4-23 and BNP or C-ANF4-23 and CNP, however, an additive inhibitory effect was observed for BNP and CNP. These results suggest that CNP and BNP like C-ANF4-23 interact with ANP-C receptors and result in the inhibition of adenylyl cyclase activity. On the other hand, CNP and BNP interact with the ANP-C receptor, however, the interaction may be different sites or there may be two subpopulations of ANP-C receptors specific for each of the peptides. These results indicate that BNP and CNP, like ANP and C-ANF4-23, inhibit the adenylyl cyclase/cAMP signal transduction system through an inhibitory guanine nucleotide regulatory protein, by interacting with ANP-C receptor subtypes.
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PMID:C-type natriuretic peptide and brain natriuretic peptide inhibit adenylyl cyclase activity: interaction with ANF-R2/ANP-C receptors. 764 5

We have used the whole-cell patch-clamp technique to identify and characterize Cl- currents in a cell line derived from human peripheral airway epithelium (NCI-H-441-4). The permeability sequence and relative selectivity for different anions was Br- (1.4) approximately I- (1.3) > Cl- (1.0) > F- (0.6) > gluconate (0.4) > glutamate (0.2). The current-voltage relationship displayed rectification in the outward direction. Diphenylamine-2-carboxylate (10(-4) M) applied intracellularly blocked the outward-rectified current, while extracellularly applied diphenylamine-2-carboxylate had no effect on Cl- current. This current was also blocked by extracellularly applied 5-nitro-2-(3-phenylpropylamino)benzoate (NPPB), with an estimated IC50 of 15.2 microM. Dibutyryl-cyclic AMP (10(-4) M) increased outward current, whereas pretreatment with 100 ng/mL pertussis toxin almost completely abolished the Cl- current. Pertussis toxin inhibition of this current could be partially reversed by dialysis of the cell interior with the activated alpha i-2 subunit of Gi protein. This cell line provides an opportunity to study directly the regulation of Cl- channels in cells derived from the peripheral human lung airways.
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PMID:Whole-cell Cl- currents in a human peripheral airway epithelial cell line. 831 29

Natriuretic peptide receptor C (NPR-C) is a disulfide-linked homodimer with an approximately 440-amino acid extracellular domain and a 37-amino acid cytoplasmic domain; it functions in the internalization and degradation of bound ligand. The use of NPR-C-specific natriuretic peptide analogs has implicated this receptor in mediating the inhibition of adenylyl cyclase or activation of phospholipase C. In the present studies we have investigated the role of the cytoplasmic domain of NPR-C in signaling the inhibition of adenylyl cyclase. Polyclonal rabbit antisera were raised against a 37-amino acid synthetic peptide (R37A) corresponding to the cytoplasmic domain of NPR-C. Incubation of anti-R37A with rat heart particulate fractions blocked atrial natriuretic peptide-dependent inhibition of adenylyl cyclase. The cytoplasmic domain peptides R37A and TMC (10 residues of transmembrane domain appended on R37A) were equipotent in inhibiting adenylyl cyclase (Ki approximately 1 nM) in a GTP-dependent manner, whereas K37E (a scrambled peptide control for R37A) did not inhibit adenylyl cyclase activity. Prior incubation of membranes with pertussis toxin blocked R37A or TMC inhibition of cAMP production. Detergent solubilization of the rat heart particulate fraction destroyed natriuretic peptide inhibition of adenylyl cyclase, but TMC was able to inhibit cAMP production in a dose-dependent manner. Our results provide evidence that the 37-amino acid cytoplasmic domain of NPR-C is sufficient for signaling inhibition of adenylyl cyclase through a pertussis toxin-sensitive G protein.
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PMID:Cytoplasmic domain of natriuretic peptide receptor-C inhibits adenylyl cyclase. Involvement of a pertussis toxin-sensitive G protein. 870 17

1. Previous studies demonstrate that volume-sensitive chloride currents are distinctly activated in cervical cancer cells, but not in human papillomavirus (HPV)-immortalized and normal cervical cells. In the present study, the Na(+)-independent volume-activated transport of taurine in three cervical cell types was investigated. 2. Osmotic swelling of cervical cancer HT-3 cells suspended in Na(+)-free hypotonic medium led to increased membrane uptake of taurine. This taurine uptake was effectively blocked by various Cl- channel blockers with a similar potency in blocking volume-sensitive Cl- channels: 1,9-dideoxyforskolin > 5-nitro-2-(3-phenyl-propylamino)-benzoic acid (NPPB) > 4-acetamido-4'-isothiocyanastilbene-2,2'-disulphonic acid (SITS) > 4,4'-diisothio-cyanatostilbene-2,2-disulphonic acid (DIDS) > furosemide. The taurine influx was also abolished by pertussis toxin. In contrast, Na(+)-independent volume-activated taurine transport was not significantly activated in HPV-immortalized Z183A cells and in normal cervical cells. 3. Exposure of HT-3 cells to hypotonic medium also resulted in a marked increase in taurine efflux. The volume-activated taurine efflux was osmolarity dependent and the pattern of pharmacological inhibition by Cl- channel blockers was indistinguishable from that for taurine uptake. 4. These results suggest that volume-sensitive Cl- channels in HT-3 cells can mediate the transport of amino acids. In addition, the pertussis toxin-sensitive G-protein is linked with the activation of this transport mechanism.
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PMID:Volume-activated taurine transport is differentially activated in human cervical cancer HT-3 cells but not in human papillomavirus-immortalized Z183A and normal cervical epithelial cells. 940 59

In gastrointestinal smooth muscle, the neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) induce relaxation by interacting with VIP2/PACAP3 receptors coupled via Gs to adenylyl cyclase and with distinct receptors coupled via Gi1 and/or Gi2 to a smooth muscle endothelial nitric oxide synthase (eNOS). The present study identifies the receptor as the single-transmembrane natriuretic peptide clearance receptor (NPR-C). RT-PCR and Northern analysis demonstrated expression of the natriuretic peptide receptors NPR-C and NPR-B but not NPR-A in rabbit gastric muscle cells. In binding studies using 125I-labeled atrial natriuretic peptide (125I-ANP) and 125I-VIP as radioligands, VIP, ANP, and the selective NPR-C ligand cANP(4-23) bound with high affinity to NPR-C. ANP, cANP-(4-23), and VIP initiated identical signaling cascades consisting of Ca2+ influx, activation of eNOS via Gi1 and Gi2, stimulation of cGMP formation, and muscle relaxation. NOS activity and cGMP formation were abolished (93 +/- 3 to 96 +/- 2% inhibition) by nifedipine, pertussis toxin, the NOS inhibitor, NG-nitro-L-arginine, and the antagonists ANP-(1-11) and VIP-(10-28). NOS activity stimulated by all three ligands in muscle membranes was additively inhibited by Gi1 and Gi2 antibodies (82 +/- 2 to 84 +/- 1%). In reconstitution studies, VIP, cANP-(4-23), and guanosine 5'-O-(3-thiotriphosphate) stimulated NOS activity in membranes of COS-1 cells cotransfected with NPR-C and eNOS. The results establish a unique mechanism for G protein-dependent activation of a constitutive NOS expressed in gastrointestinal smooth muscle involving interaction of the relaxant neuropeptides VIP and PACAP with a single-transmembrane natriuretic peptide receptor, NPR-C.
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PMID:G protein-dependent activation of smooth muscle eNOS via natriuretic peptide clearance receptor. 984 98

X-ray microanalysis was used to investigate whether cAMP- and/or Ca2+-activated regulation of chloride and potassium efflux is expressed in primary cultures of sweat gland duct cells. The effects of extracellular UTP and ATP on the duct cells, and the signalling system involved in the response to ATP was also studied. Primary cultures from duct cells of human sweat glands responded to 1 microM carbachol, 2 microM of the Ca2+ ionophore A23187, or 5 mM 8-bromo-cAMP stimulation for 5 min, resulting in a decrease in cellular Cl and K concentrations. 50 microM 5-nitro-2-(3-phenylpropyl-amino)-benzoic acid (NPPB), a Cl- channel blocker, can inhibit the decrease in Cl concentration induced by cAMP. Extracellular (200 microM) ATP caused a decrease of Cl and K in cultured duct cells, while (200 microM and 2 mM) UTP was ineffective. Both the phosphoinositidase C inhibitor U73122 (10 microM) and the absence of extracellular Ca2+ abolished the ATP-induced decrease in Cl and K content. Alloxan (1.25 mM), an adenylate cyclase inhibitor, had an inhibitory effect on the response to ATP. The decrease in K, but not in Cl, content in the cells elicited by ATP was blocked by prior incubation with 100 ng/ml pertussis toxin, indicating the coupling of ATP to pertussis toxin-sensitive G-proteins. In conclusion, both Ca2+- and cAMP-dependent Cl- permeability is present in primary cultures from duct cells of human sweat gland. The response to ATP can be mediated both by Ca2+- and by cAMP-dependent pathways, and is coupled to pertussis toxin-sensitive G-proteins.
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PMID:Regulation of ion content in primary cultures from reabsorptive ducts of human sweat glands studied by X-ray microanalysis. 987 64

P2U/2Y-receptors elicit multiple signaling in Madin-Darby canine kidney (MDCK) cells, including a transient increase of [Ca2+]i, activation of phospholipases C (PLC) and A2 (PLA2), protein kinase C (PKC) and mitogen-activated protein kinase (MAPK). This study examines the involvement of these signaling pathways in the inhibition of Na+,K+,Cl- cotransport in MDCK cells by ATP. The level of ATP-induced inhibition of this carrier ( approximately 50% of control values) was insensitive to cholera and pertussis toxins, to the PKC inhibitor calphostin C, to the cyclic nucleotide-dependent protein kinase inhibitors, H-89 and H-8 as well as to the inhibitor of serine-threonine type 1 and 2A phosphoprotein phosphatases okadaic acid. ATP led to a transient increase of [Ca2+]i that was abolished by a chelator of Ca2+i, BAPTA. However, neither BAPTA nor the Ca2+ ionophore A231287, or an inhibitor of endoplasmic reticulum Ca2+-pump, thapsigargin, modified ATP-induced inhibition of Na+,K+, Cl- cotransport. An inhibitor of PLC, U73122, and an inhibitor of MAPK kinase (MEK), PD98059, blocked ATP-induced inositol-1,4, 5-triphosphate production and MAPK phosphorylation, respectively. However, these compounds did not modify the effect of ATP on Na+,K+, Cl- cotransport activity. Inhibitors of PLA2 (AACOCF3), cycloxygenase (indomethacin) and lypoxygenase (NDGA) as well as exogenous arachidonic acid also did not affect ATP-induced inhibition of Na+,K+,Cl- cotransport. Inhibition of the carrier by ATP persisted in the presence of inhibitors of epithelial Na+ channels (amiloride), Cl- channels (NPPB) and Na+/H+ exchanger (EIPA) and was insensitive to cell volume modulation in anisosmotic media and to depletion of cells with monovalent ions, thus ruling out the role of other ion transporters in purinoceptor-induced inhibition of Na+,K+,Cl- cotransport. Our data demonstrate that none of the known purinoceptor-stimulated signaling pathways mediate ATP-induced inhibition of Na+,K+,Cl- cotransport and suggest the presence of a novel P2-receptor-coupled signaling mechanism.
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PMID:ATP-induced inhibition of Na+, K+, Cl- cotransport in Madin-Darby canine kidney cells: lack of involvement of known purinoceptor-coupled signaling pathways. 991 50

-Natriuretic peptides suppress adrenergic neurotransmission by a mechanism sensitive to pertussis toxin, suggesting that GTP-binding proteins are involved in the response. The major GTP-binding proteins present in the pheochromocytoma (PC12) cells used in this report are Goalpha and Gialpha2. We tested the hypothesis that the more abundant GTP-binding protein, Goalpha, mediates natriuretic peptide effects in PC12 cells by selectively ablating Goalpha from the cells with antisense oligodeoxynucleotides. The results indicate that a selective ablation of Goalpha with this technique eliminated C-type natriuretic peptide (CNP) effects and suppressed dopamine efflux evoked by a depolarizing stimulus. However, the activation of guanylyl cyclase (GC) by CNP was sustained after the Goalpha ablation. Further, Nomega-nitro-L-arginine methyl ester suppressed evoked dopamine efflux equally in the presence and absence of Goalpha. These results suggest that CNP attenuates evoked catecholamine efflux from PC12 cells by a mechanism requiring Goalpha but independent of GC activation.
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PMID:C-type natriuretic peptide attenuates evoked dopamine efflux by influencing Goalpha. 993 Oct 92

Brain natriuretic peptide (BNP) gene expression and chronic activation of the sympathetic nervous system are characteristics of the development of heart failure. We studied the role of the beta-adrenergic signaling pathway in regulation of the human BNP (hBNP) promoter. An hBNP promoter (-1818 to +100) coupled to a luciferase reporter gene was transferred into neonatal cardiac myocytes, and luciferase activity was measured as an index of promoter activity. Isoproterenol (ISO), forskolin, and cAMP stimulated the promoter, and the beta(2)-antagonist ICI 118,551 abrogated the effect of ISO. In contrast, the protein kinase A (PKA) inhibitor H-89 failed to block the action of cAMP and ISO. Pertussis toxin (PT), which inactivates Galpha(i), inhibited ISO- and cAMP-stimulated hBNP promoter activity. The Src tyrosine kinase inhibitor PP1 and a dominant-negative mutant of the small G protein Rac also abolished the effect of ISO and cAMP. Finally, we studied the involvement of M-CAT-like binding sites in basal and inducible regulation of the hBNP promoter. Mutation of these elements decreased basal and cAMP-induced activity. These data suggest that beta-adrenergic regulation of hBNP is PKA independent, involves a Galpha(i)-activated pathway, and targets regulatory elements in the proximal BNP promoter.
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PMID:Isoproterenol and cAMP regulation of the human brain natriuretic peptide gene involves Src and Rac. 1082 15

Brain natriuretic peptide (BNP) gene expression accompanies cardiac hypertrophy and heart failure. The vasoconstrictor endothelin-1 (ET) may be involved in the development of these diseases. ET has also been shown to activate phospholipase A(2) (PLA(2)), and the resulting metabolites are important second messengers. We studied how ET and PLA(2) metabolites regulate BNP gene expression. The human BNP (hBNP) promoter (from -1818 to +100) coupled to a luciferase reporter gene was transferred into neonatal ventricular myocytes (NVMs), and luciferase activity was measured as an index of promoter activity. ET induced BNP mRNA in NVMs as assessed by Northern blot. It also stimulated the hBNP promoter, an effect completely inhibited by actinomycin D. To test the involvement of different PLA(2) isoforms, transfected cells were treated with various PLA(2) inhibitors before stimulation with ET. Only Ca(2+)-independent PLA(2) blockade prevented ET-stimulated hBNP promoter activity. The PLA(2) metabolite lysophosphatidic acid (LPA) also activated the hBNP promoter, but arachidonic acid itself did not. ET regulation of the hBNP promoter is pertussis toxin-sensitive. The nonreceptor tyrosine kinase Src and the small GTPase Rac mediate the effects of both ET and LPA in stimulation of the hBNP promoter. We studied the involvement of cis elements in ET-stimulated hBNP promoter activity. Deletion of BNP promoter sequences from -1818 to -408 and from -408 to -40 reduced the effect of ET by 60% and 80%, respectively. Moreover, ET-stimulated luciferase activity was reduced by 50% when the proximal GATA element was mutated. These data suggest that (1) ET activates the hBNP promoter through a transcriptional mechanism; (2) LPA, perhaps generated by iPLA(2), is involved in the effect of ET; (3) Src and Rac mediate ET and LPA stimulation of the hBNP promoter; and (4) ET regulation of the hBNP promoter targets both distal and proximal cis elements.
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PMID:Src and Rac mediate endothelin-1 and lysophosphatidic acid stimulation of the human brain natriuretic peptide promoter. 1123 Mar 22


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