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: EC:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The signalling mechanism and cellular targets of the AT2 receptor are still unknown. We report that angiotensin II (Ang II) inhibits basal and atrial natriuretic peptide stimulated particulate guanylate cyclase (pGC) activity through AT2 receptors in rat adrenal glomerulosa and PC12W cells. This inhibition is blocked by the phosphotyrosine phosphatase (PTPase) inhibitor orthovanadate but not by the Ser/Thr phosphatase inhibitor okadaic acid, suggesting the involvement of a PTPase in this process. Moreover, Ang II induces a rapid, transient and orthovanadate sensitive dephosphorylation of phosphotyrosine containing proteins in PC12W cells. Our findings suggest that AT2 receptors signal through stimulation of a PTPase and that this mechanism is implicated in the regulation of pGC activity. This observation is also the first example of hormonal inhibition of basal pGC activity.
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PMID:The angiotensin AT2 receptor stimulates protein tyrosine phosphatase activity and mediates inhibition of particulate guanylate cyclase. 134 47

To evaluate an interaction between vasoconstrictive (Ang II) and vasodilating (ANP) peptides, we examined the effect of Ang II on ANP-induced accumulation of cGMP in cultured glomerular mesangial cells. ANP rapidly increased intracellular cGMP levels, with a peak stimulation at one minute in the absence of IBMX and at ten minutes in the presence of IBMX. The ANP-induced cGMP accumulation was significantly inhibited when the cells were treated with Ang II simultaneously with ANP for one minute in the absence of IBMX. This inhibitory effect of Ang II was completely abolished by IBMX and significantly reduced in calcium-free media or by W7, but not affected by H7. Similar inhibitory effect was observed when cells were treated with A23187 but not with TPA for one minute. In the presence of IBMX, Ang II inhibited ANP-induced cGMP accumulation when cells were treated with Ang II for 15 minutes prior to the stimulation by ANP. This inhibition by Ang II was blocked by H7. ANP-induced increase in particulate guanylate cyclase activity was significantly reduced in the cells treated with Ang II or TPA. This reduction of enzyme activity was also prevented by H7. These results indicate that Ang II inhibits ANP-induced cGMP accumulation in cultured glomerular mesangial cells through at least two mechanisms; one is the activation of calcium-dependent, calmodulin-stimulated cyclic nucleotide phosphodiesterase in the initial phase, and the other is the inhibition of guanylate cyclase resulting from protein kinase C activation in the maintenance phase.
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PMID:Dual mechanism of angiotensin II inhibits ANP-induced mesangial cGMP accumulation. 171 65

Angiotensin II (Ang II) receptors, estimated by the specific binding of the peptide Ang II receptor antagonist [125I] [Sar1,Ile8]Ang II, are localized on multiple ovarian structures, including follicular granulosa cells. Using the Ang II receptor subtype-selective nonpeptide antagonists, DuP 753 [selective for the type 1 Ang II (AT1) receptor] and PD 123319 [selective for the type 2 Ang II (AT2) receptor], we show that follicular granulosa cells, in vivo and in vitro, exclusively express the AT2 receptor. To understand the function of Ang II in ovarian follicles, we compared the biochemical properties and transmembrane signaling pathways of the granulosa cell AT2 receptor with those properties generally associated with Ang II receptors found in the adrenal zona glomerulosa, where the AT1 receptor predominates. The mol wt of the granulosa cell AT2 receptor (approximately 79,000), estimated by affinity cross-linking studies, is similar to that of the adrenal zona glomerulosa Ang II receptor. Like the adrenal zona glomerulosa Ang II receptor, binding inhibition studies show that the granulosa cell AT2 receptor binds Ang II and Ang III with high affinity (IC50, approximately 0.5 nM for both peptides), but not Ang-(1-7) (IC50, approximately 0.5 microM) or Ang-(1-5) (IC50, greater than 10 microM). However, unlike the adrenal zona glomerulosa Ang II receptor, the granulosa cell AT2 receptor does not undergo agonist-induced endocytosis. Further, Ang II does not affect basal or stimulated inositol phosphate production, intracellular Ca2+ mobilization, or adenylyl cyclase or guanylyl cyclase activity in granulosa cells. The granulosa cell AT2 receptor does not appear to directly interact with guanine nucleotide binding regulatory proteins, since agonist dissociation from the AT2 receptor is unaffected by the GTP analog guanosine 5'-O-(3-thiotriphosphate); in contrast, the AT1 receptor appears to directly interact with guanine nucleotide binding regulatory protein, because agonist dissociation from the AT1 receptor is stimulated by guanosine 5'-O-(3-thiotriphosphate). These studies clearly demonstrate that the granulosa cell AT2 receptor is functionally distinct from the well characterized adrenal zona glomerulosa Ang II receptor. The exclusive presence of the AT2 receptor on the granulosa cell makes it an ideal cell type for studying the potential, but as yet unknown, function of this receptor.
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PMID:Biochemical properties of the ovarian granulosa cell type 2-angiotensin II receptor. 184 6

Atrial natriuretic factor (ANF) and angiotensin II (Ang II) appear to act as physiological antagonists in the regulation of blood pressure and fluid homeostasis. After 18 h incubation in cultured vascular smooth muscle cells, Ang II (10(-8) mol/l) induced down-regulation of ANF receptors (reduced by 60% of total binding capacity) that was inhibited by Sar1-Ile8-Ang II (10(-7) mol/l), whereas ANF (10(-8), 10(-7) mol/l) was not able to affect Ang II receptors. The down-regulation provoked by Ang II was associated with an enhancement of ANF-stimulated cyclic (c) GMP formation and was confined to the non-guanylate cyclase-coupled ANF receptor subtype. This suggests that the decrease in ANF receptors elicited by Ang II and the paradoxical increase in the biological activity of ANF may represent a mechanism that represses excessive or long-term pressor effects of Ang II.
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PMID:Interaction between atrial natriuretic factor and angiotensin II receptors in the regulation of blood pressure. 285 37

Ever since the identification of two distinct Ang II receptor subtypes, the function of the AT2 receptor has been a subject of debate. As opposed to the AT1 subtype, this receptor does not interact with G-proteins in most cell lines and tissues. We show here that, in intact PC12W cells which express only AT2 receptors, Ang II significantly decreases basal and atrial natriuretic peptide (ANP)-stimulated cGMP concentration. This effect is mimicked by the AT2 selective agonist CGP 42112, and is not prevented by the AT1 selective antagonist losartan, indicating that this is an AT2 receptor mediated response. The lack of effect of the phosphodiesterase (PDE) inhibitor IBMX shows that this mechanism does not involve PDE stimulation. This is confirmed by the finding that neither Ang II or CGP 42112 affect the Ca++/calmodulin dependent cGMP PDE activity. Furthermore Ang II and CGP 42112 have no effect on nitroprusside-stimulated cGMP levels in these cells, thus ruling out interactions between the AT2 receptor and soluble guanylate cyclase. These data indicate that the AT2 receptor mediated decrease of cGMP is due to the selective inhibition of particulate guanylate cyclase (pGC) activity. In an accompanying paper we report that interaction of Ang II with the AT2 receptor in the same cells results in the stimulation of phosphotyrosine phosphatase (PTPase) activity. Interestingly, the PTPase inhibitors sodium orthovanadate and phenylarsine oxyde, but not the Ser/Thr phosphatase inhibitor okadiac acid, inhibitthe Ang II and CGP 42112 induced decreases in cellular cGMP concentration. These findings suggest that stimulation of PTPase activity may be involved in the regulation of pGC activity via AT2 receptors.
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PMID:Angiotensin AT2 receptor mediated inhibition of particulate guanylate cyclase: a link with protein tyrosine phosphatase stimulation? 752 2

We previously reported that angiotensin II (Ang II) increases cGMP content through a new Ang II receptor subtype that is distinct from both the AT1 and AT2 subtypes in differentiated Neuro-2A cells. In this study, the mechanism of the Ang II-stimulated cGMP increase was investigated in comparison with bradykinin- and atrial natriuretic factor (ANF)-stimulated cGMP increases in differentiated Neuro-2A cells. Ang II increased cGMP in differentiated Neuro-2A cells rapidly, with a maximal effect in 30 sec and a return to basal levels in 60 sec. Removal of extracellular Ca2+ or pretreatment with a membrane-permeable Ca2+ chelator [1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetraacetoxymethyl ester] attenuated Ang II-stimulated cGMP accumulation. Both the time course and Ca2+ dependency of the effect of Ang II were similar to those of the effect of bradykinin, which activates soluble guanylyl cyclase, but distinct from those of the effect of ANF, which activates particulate guanylyl cyclase. Methylene blue, an inhibitor of soluble guanylyl cyclase, attenuated the effects of Ang II and bradykinin but not that of ANF. LaCl3, a nonspecific Ca2+ blocker, prevented Ang II-stimulated cGMP accumulation. L-type Ca2+ channel blockers, nifedipine and diltiazem, or an N-type Ca2+ channel blocker, omega-conotoxin, failed to inhibit the effect of Ang II. Ang II had no effect on formation of 1,4,5-inositol trisphosphate or cAMP content, whereas bradykinin stimulated 1,4,5-inositol trisphosphate formation in differentiated Neuro-2A cells. Further, the nitric oxide synthase inhibitors NG-monomethyl-L-arginine and NG-nitro-L-arginine attenuated Ang II- and bradykinin-stimulated elevation of cGMP content but not that stimulated by ANF. The Ca2+ ionophore A23187 also stimulated cGMP formation and the effect was inhibited by the nitric oxide synthase inhibitors. These results indicate that the newly found Ang II receptor mediates cGMP formation through activation of soluble guanylyl cyclase and that the activation is mediated by nitric oxide, which is increased by Ca2+ influx via an ion channel distinct from the L-type and N-type Ca2+ channels.
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PMID:New signaling mechanism of angiotensin II in neuroblastoma neuro-2A cells: activation of soluble guanylyl cyclase via nitric oxide synthesis. 768 50

Most of angiotensin II's (Ang II) documented effects have been attributed to the interaction of this peptide with a G-protein coupled receptor termed AT1. The role and the signalling mechanisms of the more recently characterized AT2 receptor, which does not appear to interact with G-proteins, are however still unclear. We report here that this receptor mediates the rapid dephosphorylation of tyrosine residues of specific proteins in the 60 to 150 KDa range in PC12W cells which express only AT2 receptors. We further characterized this phosphatase activity using the synthetic substrate para-nitrophenyl phosphate. Dephosphorylation of this substrate in response to Ang II is not affected by Ser/Thr phosphatase inhibitors, but is completely prevented by the protein tyrosine phosphatase (PTPase) inhibitor sodium orthovanadate. This effect is mimicked by the AT2 selective agonist CGP42112 and is not affected by the AT1 antagonist losartan, In contrast to the recently reported PTPase stimulation by somatostatin and dopamine, PTPase stimulation by Ang II is not affected by the guanyl nucleotides GTP gamma S and GDP beta S. Moreover, depletion of solubilized membrane preparations from G-proteins by lectin affinity chromatography does not alter Ang II stimulation of the measured PTPase activity. These findings indicate that Ang II stimulates a PTPase activity through AT2 receptors via G-protein independent pathways. This signalling mechanism may be involved in AT2 receptor mediated actions of Ang II such as particulate guanylate cyclase inhibition, modulation of T-type Ca++ channels and regulation of cell proliferation and differentiation.
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PMID:Angiotensin II stimulates protein tyrosine phosphatase activity through a G-protein independent mechanism. 795 93

The effects of somatostatin (ST) on the regulation of the glomerular filtration rate have not been extensively studied. The present experiments were designed to analyze this possible relationship. ST alone did not modify the planar cell surface area (PCSA) of cultured rat mesangial cells (CRMC), but it prevented and reversed the reduction in PCSA induced by 10 nM angiotensin II (Ang II) in a dose- and time-dependent manner. ST (1 microM) completely prevented and reversed the increase in the myosin light chain phosphorylation induced by 10 nM Ang II. Incubation with pertussis toxin (PT, 0.5 micrograms/ml) inhibited the effect of ST on the Ang II-dependent changes in PCSA, but this effect was not inhibited by the blockade of the vasodilatory prostaglandins (indomethacin, 10 microM) or nitric oxide (L-N-methyl-arginine, 0.2 mM) synthesis. 2',5'-dideoxyadenosine (DDA, 0.1 mM), an adenylate cyclase blocker, and methylene blue (MB, 30 microM), a soluble guanylate cyclase blocker, did not interfere with the ST inhibitory effect on the Ang II-dependent reduction in PCSA of rat mesangial cells. ST also blocked the reduction in PCSA induced by phorbol myristate acetate (PMA, 300 nM). ST was also able to prevent and revert the Ang II dependent reduction in glomerular cross-sectional area of isolated rat glomeruli, also in a dose- and time-dependent fashion. Finally, intravenous administration of ST (200 ng/kg body wt as a bolus plus a continuous injection of 25 ng/min/kg body wt) partially blocked the reduction in GFR (measured as CIn) and RPF (measured as CPAH) and the increase in filtration fraction induced by the intravenous administration of Ang II (1.7 micrograms/min/kg body wt) in anesthetized rats. In summary, these results suggest that ST could antagonize the renal actions of Ang II, increasing the GFR and RPF decreased by Ang II, and this effect could be dependent, at least partially, on a direct relaxing effect of ST on mesangial cells.
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PMID:Somatostatin antagonizes angiotensin II effects on mesangial cell contraction and glomerular filtration. 809 76

To test the hypothesis that the function of glomerular mesangial cells is impaired in diabetes, we examined the responsiveness of mesangial cells cultured under high concentrations of glucose to atrial natriuretic peptide (ANP1) and angiotensin II (Ang II). The ANP-induced accumulation of cGMP was enhanced in mesangial cells cultured under high glucose conditions, possibly due to the activation of particulate guanylate cyclase. Ang II action in mesangial cells was evaluated by measuring the ability of Ang II to inhibit ANP-induced cGMP accumulation through both activating phosphodiesterase (initial phase) and inhibiting guanylate cyclase (maintenance phase). The inhibition of both ANP-induced cellular cGMP accumulation and particulate guanylate cyclase activity by Ang II was significantly reduced in mesangial cells cultured under high concentrations of glucose. Moreover, in the cells exposed to high concentrations of glucose, both basal and Ang II-stimulated levels of inositol 1,4,5-trisphosphate (IP3) were significantly reduced. These results indicate that, in high glucose conditions, the actions of ANP and Ang II are modulated differently, resulting in the impairment of contractile responsiveness of mesangial cells.
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PMID:Alteration of mesangial response to ANP and angiotensin II by glucose. 823 Oct 24

This study tests the hypothesis that the control of vascular smooth muscle cell (VSMC) apoptosis is regulated by the antagonistic balance between vasoactive substances such as NO and angiotensin II (Ang II). Moreover, it is postulated that the cellular signaling pathways involved in regulating vessel tone are also coupled to the regulation of programmed cell death. Using an in vitro model system, we documented that the addition of NO donor molecules S-nitroso-N-acetylpenicillamine or sodium nitroprusside to VSMC dose-dependently induced apoptosis as documented by DNA laddering and quantified by analysis of cellular chromatin morphology. The mediator role of the guanylate cyclase signaling pathway in NO-induced apoptosis was evidenced by (1) induction of apoptosis by the 8-bromo-cGMP analogue, (2) potentiation of NO-induced apoptosis by cGMP-specific phosphodiesterase inhibition, and (3) the prevention of NO-induced apoptosis by the inhibition of the cGMP-dependent protein kinase 1 alpha. In contrast, Ang II directly antagonized NO donor- and cGMP analogue-induced apoptosis via activation of the type I Ang II receptor. These findings suggest that the countervailing balance between NO and Ang II may determine the overall cell population within the vessel wall by regulating genetic programs determining cell death as well as cell growth.
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PMID:Vasoactive substances regulate vascular smooth muscle cell apoptosis. Countervailing influences of nitric oxide and angiotensin II. 883 98


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