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)

A linear decapeptide, [cyclohexylalanine 106]ANP-(105-114)NH2 (1), where ANP is atrial natriuretic peptide, was prepared by solid phase synthesis and purified by reverse-phase liquid chromatography. This novel peptide was found to bind to ANP receptors in rabbit lung membranes, to stimulate cGMP production in various tissues, and to fully relax precontracted rabbit aorta in a dose-dependent fashion. The potency of 1 in the various in vitro assays varies between one-twentieth and one-eightieth of the potency of the reference peptide, the 24-mer rat ANP-(103-126). The linear decapeptide 1, which encompasses amino acid residues from the rat ANP sequence (105-114), features a cyclohexylalanine residue instead of the phenylalanine 106 residue in the hormone sequence, a free sulfhydryl function at the N-terminal cysteine 105, and a carboxamide C terminus. Its disulfide dimer 6 was active in the rabbit aorta assay while the S-methyl cysteine 7 analogue was not active in the same assay at similar concentrations. The decapeptide 1 is of particular significance because it is the shortest analogue reported to date endowed with agonistic activity at the guanylate cyclase-coupled ANP receptor. In particular, it is interesting to compare its structure to the structures of other short linear analogues of ANP which are totally devoid of the ability to stimulate particulate guanylate cyclase activity.
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PMID:A synthetic linear decapeptide binds to the atrial natriuretic peptide receptors and demonstrates cyclase activation and vasorelaxant activity. 255 53

Binding of atrial natriuretic peptide (ANP) to rat submandibular gland and its effect on guanosine 3',5'-cyclic monophosphate (cGMP) formation and salivary secretion were investigated. Membranes rapidly and specifically bound 125I-ANP. Binding was inhibited by unlabeled ANP (IC50 approximately 1.6 nM), but not by atriopeptin I, other COOH- and NH2-terminal deleted ANP fragments, or agents such as pilocarpine or substance P. Scatchard analysis revealed a single class of high-affinity sites (dissociation constant 0.74 +/- 0.25 nM; maximal binding capacity 20.5 +/- 6.3 pmol/mg protein). Intravenous infusion of ANP with pilocarpine caused a significant dose-dependent increase in the levels of cGMP detected in plasma and saliva. Because salivary cGMP may have originated in plasma, the effect of ANP on cGMP formation was evaluated in dispersed cells. ANP evoked a concentration-dependent increase in both cGMP synthesis and secretion (EC50 approximately 1.7 x 10(-8) M). The atrial peptide did affect basal or l-isoproterenol-stimulated adenosine 3',5'-cyclic monophosphate synthesis in dispersed cells. When infused by itself and/or with pilocarpine, ANP did not alter the rate of spontaneous or pilocarpine-induced salivary flow, secretion of chloride, or protein release. The data demonstrate the presence of guanylate cyclase-coupled ANP receptors in submandibular gland; the atrial peptide, however, does not exert an effect of the secretory function of the gland.
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PMID:Atrial natriuretic peptide stimulates submandibular gland synthesis and secretion of cGMP. 255 37

Elevated concentrations of atrial natriuretic peptide reportedly mitigate acute renal failure in vivo and in the isolated perfused kidney (M. Nakamoto, J.I. Shapiro, P.F. Shanley, L. Chan & R.W. Shrier (1987) J. Clin. Invest. 80, 698-705; S.G. Shaw, J. Weidmann, J. Hodler, A. Zimmermann & A. Paternostro (1987) J. Clin. Invest. 80, 1232-1237). Since atrial natriuretic peptide has been shown to be a potent vasodilator, this beneficial effect may be due entirely to improved haemodynamics. To determine whether atrial natriuretic peptide also has a protective effect at the cellular level, rat hepatocyte cell cultures were treated with atrial natriuretic peptide prior to or after induction of cell damage by hypoxia (0.5% O2 for 4 h) or reactive oxygen (hypochlorous acid). Bleb formation, degradation of radiolabeled trichloroacetic acid-precipitable peptides, release of lactate dehydrogenase and trypan blue exclusion were used as indicators of cell damage. Atrial natriuretic peptide treatment distinctly protected the cell cultures against damage in both cases. This beneficial effect of atrial natriuretic peptide was partly mimicked by sodium nitroprusside, which, like atrial natriuretic peptide, largely increased the cellular cGMP content. 6-Anilino-5,8-quinolinedione (Ly 83583), an inhibitor of particulate guanylate cyclase, blocked the protective effect of atrial natriuretic peptide. Therefore a cGMP-mediated mechanism seems to be involved in the cytoprotective action of atrial natriuretic peptide. Fluorometric measurements using the Ca2+-sensitive dye Quin-2 showed that the elevation of intracellular Ca2+ after cellular insult by hypochlorous acid is prevented by atrial natriuretic peptide. These results suggest that atrial natriuretic peptide may attenuate hypoxic and toxic cell damage by increasing cGMP and reducing intracellular Ca2+.
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PMID:Atrial natriuretic peptide protects hepatocytes against damage induced by hypoxia and reactive oxygen. Possible role of intracellular free ionized calcium. 255 49

The novel neuropeptide, brain natriuretic peptide (BNP), causes concentration-dependent relaxations in rat isolated arterial rings. The pD2 value of BNP in rat thoracic aorta is 8.05 +/- 0.06, almost identical to the pD2 value of atrial natriuretic peptide (the 28 amino acid peptide, rat sequence, AP-28, 8.11 +/- 0.08), indicating that BNP and ANP have the same potency in relaxing thoracic aorta. In addition, BNP is equally potent at causing relaxation in abdominal aorta and mesenteric and renal arteries. However, BNP is less potent in causing vasorelaxation in the common iliac and femoral arteries and shows no relaxant effects in caudal arteries. This pharmacological profile of BNP in different rat arteries is very similar to that of ANP. Like ANP, BNP induces a vasorelaxation that is independent of endothelium and is associated with very sustained increases in cyclic GMP, but not cyclic AMP, levels in rat thoracic aorta. The BNP-induced cyclic GMP elevation, like the vasorelaxation, is also independent of endothelium and is not blocked by methylene blue (10 microM), a soluble guanylate cyclase inhibitor. Furthermore, BNP-induced cyclic GMP elevation is independent of extracellular calcium and potentiated by the cyclic GMP-phosphodiesterase inhibitor M & B 22948. Therefore, the pharmacological characteristics of BNP in rat blood vessels are very similar to those of ANP, suggesting that BNP and ANP may act through a common receptor and post-receptor mechanism to cause vasodilation.
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PMID:Brain natriuretic peptide (BNP) causes endothelium-independent relaxation and elevation of cyclic GMP in rat thoracic aorta. 255 55

Using an antiserum raised against the purified atrial natriuretic peptide (ANP) receptor that has a disulfide-linked homodimeric structure and represents one subtype of the multiple ANP receptors, we showed that the receptor is coupled to the guanylate cyclase activation; formerly, this type of ANP receptor is not considered to be coupled to the cyclase. The specificity of the antiserum was determined by immunoblot analysis and immunoprecipitation. The anti-receptor antiserum did not compete with 125I-ANP for binding to the receptor but it lowered the affinity of the receptor. When added to bovine endothelial cell cultures, the antiserum blocked the cyclic GMP response of the cells triggered by ANP. These results indicate that the subtype of the ANP receptor recognized by the antiserum is responsible for the activation of particulate guanylate cyclase as well as the double function type receptor that has been assumed to contain both the receptor domain and the catalytic domain for cGMP synthesis on the same molecule. The presence of dissociative complexes of ANP receptor and particulate guanylate cyclase was also demonstrated by radiation inactivation analysis.
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PMID:Inhibition of atrial natriuretic peptide-induced cyclic GMP accumulation in the bovine endothelial cells with anti-atrial natriuretic peptide receptor antiserum. 256 41

The interaction between the receptor (Rc) for atrial natriuretic peptide (ANP) and the effector enzyme particulate guanylate cyclase (GC) has been studied by radiation inactivation. Irradiation of bovine lung membranes produced an increase in GC activity at low radiation doses followed by a dose-dependent reduction at higher doses. This deviation from linearity in the inactivation curve disappeared when lung membranes were pretreated with ANP. Essentially identical results were also obtained with adrenal membranes. Based on these radiation inactivation data, the following dissociative mechanism of activation of particulate guanylate cyclase by ANP has been proposed: Rc.GC(inactive) + ANP----Rc.ANP + GC(active).
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PMID:Mechanism of activation of particulate guanylate cyclase by atrial natriuretic peptide as deduced from radiation inactivation analysis. 256 50

The structure-activity relationships for affinity and selective binding of atrial natriuretic peptide (ANP) and analogues to guanylate cyclase coupled (CC) and non-cyclase coupled (NC) receptors in rabbit lung membranes are described. We have designed a series of peptides to try to identify the minimal sequence involved in specific recognition of each receptor subtype. The affinity of the peptides was determined from competitive binding experiments. Several peptides derived from the rat ANP sequence, e.g., des-[Phe106, Gly107, Ala115, Gln116]ANP-(103-125)NH2 (4), des-[Cys105,121]ANP-(104-126) (5), and [Acm-Cys105]ANP-(105-114)NH2 (9) have high affinity and selectivity for the noncoupled site. Peptide 4 was the most selective ligand with an affinity superior to that of ANP-(103-126). This compound does not displace the radiolabeled ligand from the guanylate cyclase coupled receptor at the highest concentration tested (100 nM). The structure-activity relationship for affinity and selectivity is discussed. Comparison of the peptide sequences suggests that the structural feature responsible for recognition of the NC site resides in a single sequence of seven contiguous amino acids from the cyclic core of the hormone. The corresponding heptapeptide retains affinity to the guanylate cyclase uncoupled binding site and is proposed to encompass the minimal sequence for specific recognition of the non-guanylate cyclase coupled ANP receptor.
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PMID:Identification of structural requirements for analogues of atrial natriuretic peptide (ANP) to discriminate between ANP receptor subtypes. 256 95

Our previous characterization of equilibrium binding kinetics of atrial natriuretic peptide (ANP) to the surface of inner medullary collecting duct (IMCD) cells suggested the existence of a single class of high-affinity receptors, functionally coupled to increases in cellular guanosine 3',5'-cyclic monophosphate (cGMP). We have now sought to understand the mode of regulation of this signal transduction system by studying the particulate guanylate cyclase (PGC) enzyme from these cells. PGC activity with and without ANP in membranes, made by homogenization and high-speed centrifugation of suspensions of IMCD cells, was linear up to 5 min and was stimulated by ANP [143 +/- 21 (ANP) vs. 38 +/- 7 (control) pmol/mg protein, n = 3, P less than 0.02]. Vmax increased more than threefold with ANP [130 +/- 19 (ANP) vs. 35 +/- 4 (control) pmol.mg protein-1.min-1, n = 4, P less than 0.005] without significant change in the Km [0.68 +/- 0.17 (ANP) vs. 0.55 +/- 0.08 (control) mM] of the enzyme. Half-maximal stimulation of guanylate cyclase activity occurred at 5 x 10(-10) M ANP, a concentration consistent with our binding data, and with physiological effect. PGC required divalent cations for basal activity and for ANP-stimulated activity; Mg2+ and Mn2+ were most potent in this respect, and Ca2+ was without effect. Both basal and stimulated PGC activities were inhibited in response to changes in the NaCl, but not urea concentration of the assay system. We conclude that binding to the single 120-130 kDa ANP receptor in IMCD cells results in stimulation of PGC by increasing its Vmax and thereby elevating intracellular cGMP, the likely mediator of ANP action in these cells.
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PMID:Characteristics of ANP-sensitive guanylate cyclase in inner medullary collecting duct cells. 256 78

1. The effect of steroid hormones on atrial natriuretic peptide (ANP)-stimulated cyclic guanosine monophosphate (cyclic GMP) formation was studied in cultured rat renal cells. 2. ANP increased cyclic GMP formation in a dose-dependent manner, while cyclic AMP was not changed by ANP. 3. Steroid hormones did not affect basal cyclic GMP levels in cultured rat renal cells. 4. Dexamethasone at 10(-8) M increased ANP (human and rat ANP)-stimulated cyclic GMP dose-dependently in cultured rat renal cells. Cortisol, corticosterone and aldosterone at a concentration of 10(-7) M also potentiated ANP-stimulated cyclic GMP formation, although triiodothyronine, oestradiol and testosterone were ineffective. Potentiation of ANP action by these steroids seems to parallel glucocorticoid activity. 5. Dexamethasone did not affect cyclic GMP formation stimulated by sodium nitroprusside which stimulates soluble guanylate cyclase in the cytosol. Therefore, the potentiating action of dexamethasone may be mediated through the action on particulate guanylate cyclase at the plasma membrane. 6. It is suggested that the diuretic action of glucocorticoids may, at least in part, be mediated through the potentiating effect of glucocorticoids on cyclic GMP response to ANP.
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PMID:Potentiation of atrial natriuretic peptide-stimulated cyclic guanosine monophosphate formation by glucocorticoids in cultured rat renal cells. 256 41

Particulate guanylate cyclase is stimulated by several hormones through receptor-dependent and by nitrosovasodilators through receptor-independent mechanisms. A subtype of atrial natriuretic peptide (ANP) receptors is coupled to guanylate cyclase. It has been shown that there is a down-regulation of the affinity of ANP receptors to alpha-hANP in placental plasma membranes obtained from severely toxemic patients. We have asked the question whether these changes are associated with a down-regulation of ANP-dependent guanylate cyclase activity. Guanylate cyclase was determined by in vitro experiments using a placental plasma membrane fraction obtained from normal and from severely toxemic patients. The presence of ANP-dependent placental guanylate cyclase activity was demonstrated both in normal and toxemic placentas. Although basal guanylate cyclase activity was not influenced by toxemia of pregnancy, there was a significant decrease in the maximum stimulation of this enzyme by alpha-hANP (104.81 +/- 12.02% (n = 4) vs 49.41 +/- 8.73% (n = 7) for normal and toxemics, respectively). Finally, stimulation by a nitrosovasodilator, sodium azide (NaN3), was also lower in toxemic placentas than in normal controls. These observations extend our previously reported results on placental ANP receptor function but also suggest the presence of a possibly receptor-independent decrease in guanylate cyclase activity in toxemic placentas.
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PMID:Atrial natriuretic peptide and sodium azide dependent guanylate cyclase activities in placentas from normal and severely toxemic patients. 256 14


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