Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Changes in cyclic nucleotide metabolism similar to those characteristic of the chronic forms of hypertension were observed in an acute neurogenic form of hypertension in rats produced by electrolytic lesions of the nucleus tractus solitarii. These changes that were evident 2 hr after the lesions were made included decreased cyclic AMP levels in the heart, increased cGMP:cAMP ratio, cAMP phosphodiesterase (3':5'-cAMP 5'-nucleotidohydrolase, EC 3.1.4.17) and guanylyl cyclase (GTP pyrophosphate-lyase (cyclizing), EC 4.6.1.2) activities in the aorta and decreased snesitivity of adenylyl cyclase (ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1) in both the aorta and heart to stimulation by the beta-adrenergic stimulant isoproterenol. These changes appear to depend on catecholamine release and are not due to mechanical distortion secondary to the increased arterial pressure. These studies provide biochemical support to the concept that the sympathetic nervous system may play a critical role in the initiation of the hypertensive syndrome and that chronic hypertension could result from the fixation of the biochemical effects of increased sympathetic activity.
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PMID:Changes in cyclic nucleotide metabolism in aorta and heart of neurogenically hypertensive rats: possible trigger mechanism of hypertension. 23 70

At extremely low concentrations, in the picomole and the nanomole range, bradykinin produces contraction and relaxation of smooth muscle in the gastrointestinal and the urogenital tract. At the target organ, bradykinin interacts with discriminator proteins of the plasma membranes and triggers, via changes in certain membrane functions, its biological response:--The binding to the discriminator makes specific conformative and constitutional demands on the nonapeptide. The binding results from an angular conformation which exists in the solution. The complete sequence is responsible for this specific conformation. Consequently, the biological activity of partial sequences is low. The conformational analysis of analogues used in studies on the mechanism of action showed but slight differences from bradykinin. The interaction of these analogues with the discriminator protein is disturbed to a varying extent by modifications at positions 1, 5, 8 and 9 in the side chains. The affinity for the discriminator is affected, dependently on the respective configuration, by substitution on the beta-C atom in the two phenylalanine residues.--Bradykinin is not only bound to, but also degraded at, the plasma membranes of the rat uterus and duodenum. The bradykinin-degrading enzyme has been characterized as a kininase II with the aid of various inhibitors. The conformative and configurative prerequisites decisive for enzymatic degradation are others than those decisive for binding to the discriminator.--The changes in the activities of the membrane-bound adenylate and guanylate cyclases (produced by the bradykinin-discriminator complex) that take place at the rat duodenum and uterus in the presence of extracellular calcium ions contrast with each other: At the duodenum, the ratio between these two cyclic nucleotides is changed in favour of adenylate cyclase; and at the uterus, in favour of guanylate cyclase; Substances which increase or decrease the cAMP level may also potentiate or inhibit the relaxation of the duodenum. These bradykinin-induced changes in enzyme activity must be considered in connection with other effectors, e.g. prostaglandins and calcium ions.--The calcium-ion-dependence of the effect of bradykinin on the guinea-pig ileum and the rat uterus indicates the importance of these ions as additional second messengers. Bradykinin stimulates the influx of calcium ions into the ileum; it is ineffective if no extracellular calcium ions into the ileum; it is ineffective if no extracellular calcium ions are available. It seems that intracellular and membranal calcium is mobilized in the uterus, which is evidenced by results from experiments with EGTA on the isolated organ and by the release of calcium from plasma membranes after application of bradykinin. It is assumed that the observed changes in membrane functions are induced by the peptide-discriminator complex simultaneously and not in the form of a causal chain.
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PMID:[On the mode of action of bradykinin on smooth muscle (author's transl)]. 39 90

The 130 kDa atrial natriuretic factor receptor (ANF-R1) purified from bovine adrenal zona glomerulosa is phosphorylated in vitro by serine/threonine protein kinases such as cAMP-, cGMP-dependent and protein kinase C. This phosphorylation is independent of the presence of ANF (99-126) and there is no detectable intrinsic kinase activity associated with the ANF-R1 receptor or with its activated form. In bovine adrenal zona glomerulosa cells, TPA (phorbol ester) induces a marked inhibition of the ANF-stimulated cGMP accumulation as well as of the membrane ANF-sensitive guanylate cyclase catalytic activity without any change in the binding capacity or affinity for 125I-ANF. However, we have demonstrated a significant 32P incorporation in the ANF-R1 receptor of the TPA-treated cells. The effect of TPA on the zona glomerulosa ANF-R1 receptors was abolished by calphostin C, a specific protein kinase C inhibitor. Altered ANF actions due to blunted response of guanylate cyclase to ANF could be a consequence of the ANF receptor phosphorylation by excessive activity of protein kinase C and might be involved in the pathogenesis of hypertension.
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PMID:Phosphorylation of atrial natriuretic factor R1 receptor by serine/threonine protein kinases: evidences for receptor regulation. 128 Mar 21

Mesangial cells possess a variety of receptors for hormones and autacoids. They are also equipped with ectoenzymes whose function may be to control the availability of autacoids and hormones at their receptor sites. Several examples are considered. Receptors for angiotensin II (AII) are present both on murine and human mesangial cells. One single group of receptors has been demonstrated in each of these preparations. Mesangial cell AII receptors are linked to phospholipase C via a G protein. They belong to the AT1 subtype because (125I)AII is displaced from its binding sites preferentially by AT1 antagonists such as DUP 753 and EXP 3,174, whereas AT2 antagonists are much less potent. AT1 antagonists suppress the biological effects of AII in mesangial cells, including the stimulation of intracellular calcium concentration and the increase of prostaglandin synthesis and of (3H)leucine incorporation. Mesangial cells also have receptors for atrial natriuretic factor, but the distribution between B receptors with guanylate cyclase activity and clearance (C) receptors varies with the species. Both types are present in murine mesangial cells, whereas only C receptors are found in human mesangial cells. In contrast, human epithelial cells possess both B and C receptors. Ecto-5'-nucleotidase activity results in the production of adenosine, which acts on mesangial cells through A1 and A2 receptors. This enzyme is markedly induced in rat mesangial cells by interleukin-1, whose effect is mediated in part by prostaglandin E2 and cAMP. Various other cAMP-stimulating agents also induce 5'-nucleotidase expression in rat mesangial cells. Ectopeptidases are present in all glomerular cell types but essentially in epithelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cell surface receptors and ectoenzymes in mesangial cells. 131 10

Atrial natriuretic peptide (ANP) has been shown to affect water and ion transport and specific ANP binding has been identified in several secretory tissues. ANP commonly acts via stimulation of membrane-bound particulate guanylate cyclase with the production of cyclic guanosine monophosphate (cGMP). We questioned whether ANP played a role in the complex cyclic transformation of the endometrium into a secretory tissue, and whether its action was cGMP mediated. Endometrium was obtained by biopsy in regularly menstruating women and stromal cells were isolated and cultured for use in this study. ANP competitive binding assays were performed using 125I-labeled ANP (0.1 nmol/L) and increasing concentrations of unlabeled ANP (0-1000 nmol/L). Optimal binding was obtained after 3-h incubation at 4 C and binding characteristics, including dissociation constant and binding site quantity, were estimated by Scatchard analysis. Specific, high affinity (dissociation constant, 0.078 +/- 0.004 nmol/L) and low capacity (4,877 +/- 1,951 binding sites/cell) ANP binding was identified, with nonspecific binding representing less than or equal to 16% of total binding. Evaluation of ANP-stimulated cyclic nucleotide production revealed an increase in cGMP production, with a 7-fold increase at 1000 nmol/L ANP, and no effect on cAMP production. In conclusion, we have identified specific high affinity receptors for ANP in human endometrial cells, suggesting a role for ANP in endometrial cell function and/or development mediated via cGMP production. We propose that ANP may affect local salt and water metabolism, may be involved in the secretory evolution of glandular and stromal cells, and may further facilitate endometrial development via modulation of local vascular tone and endothelial permeability.
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PMID:Atrial natriuretic peptide receptors in human endometrial stromal cells. 132 28

Atrial natriuretic peptide (ANP) and endothelin-1 (ET-1) are vasoactive peptides produced in cells of the cardiovascular system. We examined the effects of ANP on ET-1 transcription, production (translation), and secretion in cultured bovine aortic endothelial cells (BAEC). ANP and C-ANP 4-23 (a specific ligand for the C or non-guanylate cyclase receptor) equipotently inhibited the synthesis of prepro-ET-1 and ET-1 proteins in BAEC by at least 50%. Both of these forms of ANP and another C receptor specific ligand, nanopiperazine ANP (11-15)-NH2, inhibited ET-1 secretion by as much as 55%. LY 83583, an inhibitor of ANP-induced cGMP generation, failed to reverse the ANP-induced inhibition of ET-1 secretion. This further indicated that the guanylate cyclase-linked B receptor is not involved. The decreased ET-1 secretion caused by C-ANP 4-23 was reversed by 8-bromo-cAMP or amiloride, which prevents ANP-induced inhibition of cAMP. We also found that ANP and C-ANP 4-23 augmented ET-1 mRNA levels in BAEC by prolonging the mRNA half-life. ANP or cycloheximide comparably inhibited ET-1 translation while increasing ET-1 mRNA levels, suggesting that the two events are related. These results indicate that ANP inhibits ET-1 protein production and secretion while stabilizing the ET-1 mRNA. The effects of ANP are mediated through the C receptor and are probably the result of ANP inhibiting the generation of cAMP. These findings suggest a potentially important new function for this receptor to mediate, in part, the interactions of ANP and ET in the vasculature.
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PMID:Atrial natriuretic peptide inhibits the production and secretion of endothelin from cultured endothelial cells. Mediation through the C receptor. 132 35

After the description in the past 5 years of BNP and CNP, interest in the natriuretic peptide family has dramatically increased. Molecular characterization of the receptors for this hormone family has identified a heterogeneity in the receptor subtypes not previously alluded to by pharmacological or biochemical studies. Much has been published on the physiology of ANP, but the major roles for BNP and CNP remain to be elucidated. Some experiments indicate that ANP and BNP may act synergistically, especially during cardiac stress; however, the high level of structural diversity of BNP among species and the ability of porcine BNP, but not human BNP, to activate human NPR-B suggest that an as yet unidentified receptor may exist that specifically recognizes BNP. Localization studies have implied that CNP is the most prominent neuropeptide in the natriuretic peptide family, and the restriction of its receptor, NPR-B, to the nervous system suggests that CNP and NPR-B may act in the brain to coordinate the central aspects of body fluid homeostasis. Of the three known NPRs, two, NPR-A and NPR-B, are capable of synthesizing their own second messenger, cGMP. The domain within these receptors that has high homology to protein kinases has been demonstrated to be essential for regulating this activity. No kinase activity has been measured in these proteins, but it is possible that this region is important for ATP regulation of guanylyl cyclase activity. This possibility raises interesting parallels with receptor-mediated cAMP signaling within cells. Seven transmembrane receptors, once activated by ligand, associate with G proteins to affect the activity of adenylyl cyclase.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Molecular biology of the natriuretic peptides and their receptors. 132 79

Intracellular injection of cAMP or cGMP into retinal horizontal cells blocked the gap junctions between the cells. Similar results were obtained when L-arginine was injected into the cells. L-Arginine is a substrate of nitric oxide (NO) which is believed to activate soluble guanylate cyclase to produce cGMP. The endothelium-derived relaxing factor (EDRF) in the blood vessels has been identified as NO. With respect to the nervous systems, production of NO and its synthase have been found in the brain, and NO has been discussed in relation to such phenomena as synaptic plasticity, long-term potentiation, and development. The decoupling effect of L-arginine suggests the presence of the L-arginine: NO: cGMP pathway in the retina as well. Before injection of cAMP, cGMP or L-arginine, the applied current leaked through the gap junctions. After the injection, the horizontal cells could be easily polarized by intracellular current injection, and the synaptic mechanisms were analyzed by measuring I-V curves. In luminosity-type (H1) horizontal cells, the reversal potential of light responses was estimated at about 0 mV. In addition, conductance decreases were detected during illumination. These findings support the widely accepted hypothesis that glutamate is released from the photoreceptors in darkness. In chromaticity-type cells (H2 and H3 cells), the reversal potentials of light responses were about 0 mV, suggesting that the ionic mechanisms of synaptic transmission are common among horizontal cell types.
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PMID:[Intracellular messengers and their roles in retinal gap junctions]. 132

Heat-stable enterotoxins activate guanylate cyclase, whereas heat-labile enterotoxins stimulate adenylate cyclase. Both classes of toxins cause secretory diarrhea at least in part by stimulating Cl- secretion in the intestine. The mechanism for regulation of Cl- secretion by guanosine 3',5'-cyclic monophosphate (cGMP) was investigated using cultured T84 intestinal cells as a model for intestinal crypt cells. Escherichia coli heat-stable enterotoxin (ST) markedly stimulated cGMP production in T84 cells. Cl- secretion across T84 cell monolayers cultured on permeable filters was stimulated by E. coli ST, cholera toxin, or 8-BrcAMP, but 8-BrcGMP was ineffective. cGMP analogues that are known to be potent and specific activators of cGMP-dependent protein kinase (cG-kinase) also had little effect on 36Cl- uptake by T84 cells cultured in plastic dishes. E. coli ST, forskolin, cholera toxin, or membrane-permeant cAMP analogues markedly increased 36Cl- uptake into T84 cells. The general protein kinase inhibitor, staurosporine, inhibited the stimulation of Cl- permeability elicited by E. coli ST, vasoactive intestinal peptide (VIP), or 8-BrcAMP. DEAE-Sephacel chromatography revealed a predominant type II isoform of cAMP-dependent protein kinase (cA-kinase) in T84 cells, whereas little or no cytosolic cG-kinase activity was found. Treatment of T84 cells with E. coli ST or VIP resulted in an increase in the cA-kinase activity ratio (-cAMP/+cAMP) if the cytosolic enzyme was assayed at reduced temperature (on ice).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Stimulation of intestinal Cl- transport by heat-stable enterotoxin: activation of cAMP-dependent protein kinase by cGMP. 132 20

Recently we reported the presence of both the guanylyl cyclase-linked (116 kDa) and the ANF-C (66 kDa) atrial natriuretic peptide receptors in the rat liver. Since ANF 103-125 (atriopeptin II) stimulates cGMP production in livers and because cGMP has previously been shown to mimic the actions of cAMP in regulating hepatic carbohydrate metabolism, studies were performed to investigate the effects of atriopeptin II on hepatic glycolysis and gluconeogenesis. Additionally, employing analogs of atrial natriuretic hormone [des-(Q116, S117, G118, L119, G120) ANF 102-121 (C-ANF) and des-(C105,121) ANF 104-126 (analog I)] which bind only the ANF-C receptors, the role of the ANF-C receptors in the hepatic actions of atriopeptin II was evaluated. In perfused livers of fed rats atriopeptin II, but not C-ANF and analog I, inhibited hepatic glycolysis and stimulated glucose production. Moreover, analog I did not alter the ability of atriopeptin II to inhibit hepatic glycolysis. Atriopeptin II, but not C-ANF and analog I, also stimulated cGMP production in perfused rat livers. Furthermore, while atriopeptin II inhibited the activity ratio of pyruvate kinase by 30%, C-ANF did not alter hepatic pyruvate kinase activity. Finally, in rat hepatocytes, atriopeptin II stimulated the synthesis of [14C]glucose from [2-14C]pyruvate by 50% and this effect of atriopeptin II was mimicked by the exogenously supplied cGMP analog, 8-bromo cGMP. Thus atriopeptin II increases hepatic gluconeogenesis and inhibits glycolysis, in part by inhibiting pyruvate kinase activity, and the effects of atriopeptin II are mediated via activation of guanylyl cyclase-linked ANF receptors which elevate cGMP production.
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PMID:Regulation of hepatic glycolysis and gluconeogenesis by atrial natriuretic peptide. 132 63


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