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)

In bovine adrenal zona fasciculata (AZF) cells, angiotensin II (AII) may stimulate depolarization-dependent Ca2+ entry and cortisol secretion through inhibition of a novel potassium channel (IAC), which appears to set the resting potential of these cells. Aspects of the signaling pathway, which couples AII receptors to membrane depolarization and secretion, were characterized in patch clamp and membrane potential recordings and in secretion studies. AII-mediated inhibition of IAC, membrane depolarization, and cortisol secretion were all blocked by the AII type I (AT1) receptor antagonist losartan. These responses were unaffected by the AT2 antagonist PD123319. Inhibition of IAC by AII was prevented by intracellular application of guanosine 5'-O-2-(thio)-diphosphate but was not affected by pre-incubation of cells with pertussis toxin. Although mediated through an AT1 receptor, several lines of evidence indicated that AII inhibition of IAC occurred through an unusual phospholipase C (PLC)-independent pathway. Acetylcholine, which activates PLC in AZF cells, did not inhibit IAC. Neither the PLC antagonist neomycin nor PLC-generated second messengers prevented IAC expression or mimicked the inhibition of this current by AII. IAC expression and inhibition by AII were insensitive to variations in intracellular or extracellular Ca2+ concentration. AII-mediated inhibition of IAC was markedly reduced by the non-hydrolyzable ATP analog adenosine 5'-(beta, gamma-imino)triphosphate and by the non-selective protein kinase inhibitor staurosporine. The protein phosphatase antagonist okadaic acid reversibly inhibited IAC in whole cell recordings. These findings indicate that AII-stimulated effects on IAC current, membrane voltage, and cortisol secretion are linked through a common AT1 receptor. Inhibition of IAC in AZF cells appears to occur through a novel signaling pathway, which may include a losartan-sensitive AT1 receptor coupled through a pertussis-insensitive G protein to a staurosporine-sensitive protein kinase. Apparently, the mechanism linking AT1 receptors to IAC inhibition and Ca2+ influx in adrenocortical cells is separate from that involving inositol trisphosphate-stimulated Ca2+ release from intracellular stores. AII-stimulated cortisol secretion may occur through distinct parallel signaling pathways.
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PMID:Losartan-sensitive AII receptors linked to depolarization-dependent cortisol secretion through a novel signaling pathway. 767 18

Angiotensin II (ANG II) receptors of the AT1 subtype are present on the apical and basolateral membranes of renal proximal tubule cells. Cells of the proximal tubulelike cell line, LLC-PK1/Cl4, were transfected with an expression plasmid containing cDNA encoding the rabbit AT1 ANG II receptor. In transfected cells, specific binding of 125I-ANG II was detected on both apical and basolateral membranes; wild-type LLC-PK1/Cl4 cells did not express ANG II receptors. In transfected cells, apical or basolateral ANG II increased both S6 kinase activity and incorporation of [3H]leucine. In cells pretreated with pertussis toxin, the stimulatory effect of apical or basolateral ANG II on [3H]leucine incorporation was abolished. In contrast, ANG II did not affect mitogenesis, determined by [3H]thymidine incorporation. Apical or basolateral ANG II (10(-6) M) stimulated phosphoinositide turnover by 13.4 +/- 4.4% (n = 8) and 16.3 +/- 4.2% (n = 9), respectively. The activity of protein kinase C, determined by phosphorylation of a specific protein kinase C peptide substrate, was also stimulated by ANG II in transfected cells. Apical or basolateral ANG II had no significant effect on cellular adenosine 3',5'-cyclic monophosphate levels. In permeabilized transfected cells, apical ANG II (10(-6) M) inhibited the phosphorylation of a specific peptide substrate of protein kinase A; lower apical concentrations or basolateral ANG II were without significant effect. These results indicate that AT1 ANG II receptors sort to both apical and basolateral membranes in renal epithelial cells and are coupled to activation of phospholipase C. ANG II stimulates protein synthesis by binding to either apical or basolateral receptors; this effect requires coupling to G proteins and may be mediated by activation of S6 kinase. Because high concentrations of ANG II exist in proximal tubule, binding to apical and basolateral receptors may regulate proximal tubule cell growth under physiological conditions.
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PMID:Signaling and growth responses of LLC-PK1/Cl4 cells transfected with the rabbit AT1 ANG II receptor. 773 40

Angiotensin II (Ang II) is an important regulator of proximal tubule salt and water reabsorption. Recent studies indicate that rabbit proximal tubule angiotensin II receptors are the type-1 (AT1R) subtype. We studied the effect of Ang II on proximal tubule receptor expression. Rabbits were treated with either angiotensin converting enzyme inhibitors or a low salt diet to modulate endogenous Ang II levels. In captopril-treated rabbits, liver and glomerular AT1R mRNA levels increased 242 +/- 125 and 141 +/- 60%, respectively (n = 6-7; P < 0.05), as determined by quantitative PCR. In contrast, proximal tubule AT1R mRNA levels decreased 40 +/- 11% (n = 6; P < 0.05). Binding of 125I Ang II to renal cortical basolateral membranes of captopril-treated rabbits decreased from 2.9 +/- 0.55 to 1.4 +/- 0.17 fmol/mg protein (n = 6; P < 0.025). In rabbits fed a sodium chloride-deficient diet for 4 wk, AT1R mRNA levels decreased 52 +/- 11% in liver and 43 +/- 7% in glomeruli (n = 4-5; P < 0.05), whereas they increased 141 +/- 85% (n = 5; P < 0.05) in proximal tubule. In basolateral membranes from rabbits on the sodium chloride-deficient diet, specific binding of 125I Ang II increased from 2.1 +/- 0.2 to 4.3 +/- 1.1 fmol/mg protein (n = 7; P < 0.05). To determine whether Ang II directly regulates expression of proximal tubule AT1 receptors, further studies were performed in cultured proximal tubule cells grown from microdissected S1 segments of rabbit proximal tubules and immortalized by transfection with a replication-defective SV40 vector. Incubation of these cells with Ang II (10(-11) to 10(-7) M) led to concentration-dependent increases in both AT1R mRNA levels and specific 125I Ang II binding. Pretreatment with pertussis toxin inhibited Ang II stimulation of AT1R mRNA. AT1R mRNA expression was decreased by either forskolin or a nonhydrolyzable cAMP analogue (dibutryl cAMP). Simultaneous Ang II administration overcame the inhibitory effect of forskolin but not dibutryl cAMP. These results indicate that proximal tubule AT1R expression is regulated by ambient Ang II levels, and Ang II increases AT1R mRNA at least in part by decreasing proximal tubule cAMP generation through a pertussis toxin-sensitive mechanism. Upregulation of proximal tubule AT1R by Ang II may be important in mediating enhanced proximal tubule sodium reabsorption in states of elevated systemic or intrarenal Ang II.
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PMID:Angiotensin II upregulates type-1 angiotensin II receptors in renal proximal tubule. 773 68

To identify the mechanisms of action of isoforms angiotensin II receptors (AT1A, AT1B, and AT2) and to overcome the difficulties encountered in attempts to purify the receptors, we have expression-cloned their cDNAs from bovine and rat sources and isolated human cDNA and rat and human genomic DNA. The AT1A and AT1B cDNAs were found to encode respective receptor proteins with 359 amino acid residues, whereas, AT2 encodes a 363 amino acid residue receptor protein. Both AT1 and AT2 were found to conform with the seven transmembrane receptor structural motif, but showed only 32% amino acid residue identity to each other. The AT1 receptor was shown to be coupled to, at least, three different G proteins activating phospholipase C, inhibiting adenylyl cyclase and opening an L-type Ca(2+)-channel, whereas, AT2 was found to inhibit a phosphotyrosine phosphatase activity without affecting guanylyl cyclase by a pertussis-toxin-sensitive, presumably G-protein-mediated mechanism.
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PMID:Angiotensin II receptors: cloning and expression. 774 65

The effects of angiotensin II (ANG II) on growth responses of primary cultures of bovine adrenal glomerulosa cells were studied to explore the mechanism(s) by which ANG II leads to hyperplasia and hypertrophy of the glomerulosa layer in sodium deficiency. ANG II did not increase [3H]thymidine incorporation during the first 5 days of culture, but mitogenic responses to ANG II became evident after longer periods of culture and were most prominent between 8 and 11 days after seeding. At this time, cell cycle analysis showed that ANG II increased the proportion of cells in the S phase and did not cause accumulation of cells in the G2 phase. Consistent with this finding, ANG II also stimulated proliferation of glomerulosa cells during treatment for 3 days in the presence of 1% serum. The mitogenic effect of ANG II was not inhibited by pretreatment with pertussis toxin and was mediated by AT1 receptors as indicated by its sensitivity to the subtype-selective antagonist DuP-753. Also, there was no emergence of AT2 receptors in glomerulosa cells during prolonged culture. These results indicate that intracellular mechanisms that mediate growth responses become more active during prolonged culture of glomerulosa cells. Thus, in addition to regulating the steroidogenic and secretory functions of the zona glomerulosa, ANG II exerts mitogenic actions that depend on the functional state of the glomerulosa cells.
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PMID:Growth responses to angiotensin II in bovine adrenal glomerulosa cells. 784 Jan 71

Angiotensin-II (AII), which stimulates steroidogenesis in bovine adrenocortical (BAC) cells through the phosphoinositides pathway, activates p42-p44 mitogen-activated protein kinases (MAPKs) after 5 min of treatment (EC50 = 0.1 nM). This activation is 1) completely inhibited by the AII receptor AT1 subtype antagonist Dup 753 (10 microM), but unaffected by the AT2 antagonist PD 123177; 2) not reproduced by the AT2 agonist CGP 42112A; 3) insensitive to pretreatment with pertussis toxin; and 4) abolished by a 48-h preexposure of the cells to the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA; 1 microM), which down-regulates protein kinase-C activity. Fibroblast growth factor-2, a potent mitogen for BAC cells, which acts through its tyrosine kinase receptor, also activates MAPK (EC50 = 0.3 in a TPA-insensitive manner, while exhibiting no detectable effect on BAC cell steroidogenesis. In contrast, ACTH, which stimulates steroidogenesis via cAMP and inhibits BAC cell proliferation, does not stimulate MAPK. Indeed, ACTH completely blocks (IC50 = 0.01 nM) the stimulation of MAPK by AII, fibroblast growth factor-2, or TPA. Therefore, bovine adrenocortical cells provide an example of positive and negative hormonal regulation of MAPK activity through a cross-talk between the inositide-, cAMP-, and growth factor-activated tyrosine kinase pathways.
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PMID:Hormonal regulation of mitogen-activated protein kinase activity in bovine adrenocortical cells: cross-talk between phosphoinositides, adenosine 3',5'-monophosphate, and tyrosine kinase receptor pathways. 786 5

Treatment of vascular smooth muscle cells (SMC) with angiotensin II (AII) leads to an increase in the tyrosine phosphorylation of multiple cellular substrates. Here, we have demonstrated that AII stimulates tyrosine phosphorylation of the focal adhesion-associated protein paxillin in rat aortic SMC. AII-induced phosphorylation of paxillin was detectable within 1 min and was sustained up to 60 min. Preincubation with the AT1-selective antagonist losartan abolished this response. The stimulatory effect of AII on paxillin tyrosine phosphorylation was observed only in aortic SMC and not in other target cells such as adrenal zona glomerulosa cells, chromaffin cells, or hepatocytes. The effect of AII was dependent on the activation of phospholipase C. Chelation of intracellular calcium completely inhibited the ability of AII to stimulate paxillin tyrosine phosphorylation, while selective inhibition of protein kinase C partially attenuated the response. In contrast, treatment of the cells with pertussis toxin had no effect on AII-induced paxillin tyrosine phosphorylation. These findings identify paxillin as a new substrate for AII-stimulated tyrosine phosphorylation and suggest a role for cytoskeleton-associated proteins in the growth response of aortic SMC.
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PMID:Angiotensin II stimulates tyrosine phosphorylation of the focal adhesion-associated protein paxillin in aortic smooth muscle cells. 787 4

Angiotensin II (AII) receptors are known to interact with two distinct guanine nucleotide binding proteins, Gq/11 and Gi, in rat adrenal glomerulosa cells to activate phospholipase C and to inhibit adenylate cyclase, respectively. However, in cultured bovine glomerulosa cells AII potentiates rather than inhibits the stimulatory effect of adrenocorticotropin (ACTH) on cAMP levels. This effect of AII was partially mimicked by phorbol 12-myristate 13-acetate (PMA) and was partially inhibited by staurosporine or depletion of protein kinase C but was unaffected by pertussis toxin treatment. No potentiation was detectable in disrupted cells or in membrane preparations. In intact glomerulosa cells, treatment with cyclosporin A or FK506 completely inhibited AII- or PMA-induced potentiation of cAMP production without affecting the response to ACTH. In COS-7 cells transfected with the rat AT1 receptor, AII caused 2-3-fold enhancement of the ACTH-induced cAMP response, an effect that was partially reproduced by PMA. These potentiating actions of AII and PMA were prevented by preincubation with cyclosporin A or FK506, and the latter effect was abolished by rapamycin. These results implicate the Ca2+- and calmodulin-dependent protein phosphatase, calcineurin, in AII-induced enhancement of adenylate cyclase activity in both adrenal glomerulosa and transfected COS-7 cells. The finding that AII enhances ACTH-stimulated production of cAMP by a second messenger-mediated mechanism that involves the participation of calcineurin reveals an additional mode of cross-talk between pathways activated by Ca(2+)-mobilizing and cAMP-generating receptors.
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PMID:Evidence for participation of calcineurin in potentiation of agonist-stimulated cyclic AMP formation by the calcium-mobilizing hormone, angiotensin II. 792 24

The relationship between angiotensin II-induced activation of G proteins and receptor internalization was analyzed by transiently expressing mutant and wild type cDNAs for the rat AT1a receptor in COS-7 cells. Pertussis toxin-sensitive G proteins did not appear to play a role in endocytosis since the receptor showed normal internalization kinetics in pertussis toxin-treated cells. Three deletion mutants of the third cytoplasmic loop revealed that the N-terminal part of this region is important for both receptor endocytosis and intracellular signaling. Three point mutations of Asp74, which has been implicated in signal transduction by the AT1a receptor, caused impaired G protein coupling and inositol phosphate responses. However, each of these mutants (D74N, D74H, and D74Y) showed markedly different internalization kinetics. The D74Y mutant showed the greatest impairment of internalization but retained the highest degree of inositol phosphate stimulation. In contrast, the D74N mutant, which showed the most impaired G protein coupling and inositol phosphate responses, had similar internalization kinetics to the wild type receptor. The combined mutant receptor containing the D74N substitution and deletion of residues 221-226 from the third cytoplasmic loop showed no G protein coupling or inositol phosphate response but was internalized about 60% as rapidly as the wild type receptor. These data demonstrate that endocytosis of the AT1 receptor is independent of agonist-activated signal transduction and indicate that receptor internalization and activation of phospholipase C have different structural requirements.
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PMID:Independence of type I angiotensin II receptor endocytosis from G protein coupling and signal transduction. 792 58

Angiotensin II (AII) reversibly modulates calcium current in isolated neonatal rat nodose ganglion cells by two different pathways. A maximum inhibitory effect of 43 +/- 6% (n = 25) of the peak calcium current at -10 mV was observed at 10 nM AII. The IC50 of the inhibitory response was 100 pM. Losartan, a specific antagonist for the AT1 type of AII receptor, abolished the AII-induced inhibition, as did preincubation with pertussis toxin (PTX). When omega-conotoxin GVIA (CTX) was added to the bath solution, AII produced no inhibition of the remaining calcium current, indicating that the AII inhibition was mediated through CTX-sensitive calcium channels. Reversible facilitation of calcium current was seen more rarely. The AII-induced facilitation was unaffected by losartan and PTX, indicating that the effect is mediated by a non-AT1 receptor and does not depend upon a PTX-sensitive G-protein. The facilitation is present when the CTX-sensitive current has been blocked and involves activation of a reserve pool of dihydropyridine (DHP)-sensitive channels. In general, a particular neuron exhibited either inhibition or facilitation. However, in some neurons both inhibition and facilitation could be demonstrated in the presence of the appropriate blocking agents.
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PMID:Dual effects of angiotensin II on calcium currents in neonatal rat nodose neurons. 796 6


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