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)

Extracts prepared from rat atria, which cause natriuresis and diuresis when injected into bioassay rats, relax aortic smooth muscle preparations. A family of atrial peptides has been isolated, purified and synthesized which elicit similar biological responses as the atrial extracts. The in vitro vasodilator profile of synthetic atrial natriuretic factor (sANF) exhibits many similarities to sodium nitroprusside including inhibition of agonist-induced but not high-K+-induced contractions, relaxation independent of the vascular endothelium and elevation of cyclic GMP in aortic smooth muscle coincident with relaxation. Aortic rings remain relaxed in the presence of sANF but can be recontracted following a sufficient washout period. sANF causes a significant activation of the particulate (but not soluble) form of guanylate cyclase which is seemingly consistent with the presence of high affinity receptors for sANF in plasma membranes prepared from aortic tissue. Both species and regional vascular differences exist for the vasodilator activity of the synthetic atrial peptides.
Life Sci 1985 Sep 23
PMID:The relaxant effects of atrial natriuretic factor on vascular smooth muscle. 286 31

cAMP induces a transient increase of cAMP and cGMP levels in Dictyostelium discoideum cells. Fast binding experiments reveal three types of cAMP-binding site (S, H and L), which have different off-rates (t0.5, 0.7-15 s) and different affinities (Kd, 15-450 nM). A time- and cAMP-concentration-dependent transition of H- to L-sites occurs during the binding reaction (Van Haastert, P.J.M. and De Wit, R.J.W. (1984) J. Biol. Chem. 13321-13328). Extracellular Ca2+ had multiple effects on cAMP-binding sites. (i) The number of H + L-sites increased 2.5-fold, while the number of S-sites was not strongly affected. (ii) The Kd of the S-sites was reduced from 16 nM to 5 nM (iii) The conversion of H-sites to L-sites was inhibited up to 80%. The kinetics of the cAMP-induced cAMP accumulation was not strongly altered by Ca2+, but the amount of cAMP produced was inhibited up to 80%. The kinetics of the cAMP-induced cGMP accumulation was strongly altered; maximal levels were obtained sooner, and the Ka was reduced from 15 to 3.5 nM cAMP. Ca2+, Mg2+ and Mn2+ increased the number of binding sites, all with EC50 = 0.5 mM. The S-sites and the cGMP response were modified by equal Ca2+ concentrations and by higher concentrations of Mg2+ and Mn2+ (EC50 are respectively 0.4 mM, 2.5 mM and about 25 mM). The conversion of H- to L-sites and the cAMP response were specifically inhibited by Ca2+ with EC50 = 20 microM. It is concluded that cAMP activates guanylate cyclase through the S-sites; adenylate cyclase is activated by the H + L-sites, in which the appearance of the L-sites during the binding reaction represents the coupling of occupied surface cAMP receptors to adenylate cyclase.
Biochim Biophys Acta 1985 Sep 30
PMID:cAMP activates adenylate and guanylate cyclase of Dictyostelium discoideum cells by binding to different classes of cell-surface receptors. A study with extracellular Ca2+. 286 84

17 beta-estradiol enhances guanylate cyclase activity when incubated in vitro with tissue slices from all areas of the neonatal rat forebrain. This action is not mimicked by other steroids. In vivo exposure of neonatal and adult rat brains to estradiol (either secreted directly or formed by metabolic conversion of testosterone) also increases guanylate cyclase activity in estrogen target areas of the brain.
Brain Res 1985 Sep 02
PMID:Effects of gonadal steroids on guanylate cyclase activity in the developing and adult brain. 286 3

According to our present understanding organic nitrates like glycerine trinitrate mediate their pharmacological effect by an intracellular stimulation of the enzyme guanylate cyclase (E.C. 4.6.1.2.) [1, 10]. The exact molecular mechanism underlying the process of enzyme activation is still a matter of controversial discussion. But there is general agreement in literature about the fact that organic nitrate compounds are able to activate the enzyme guanylate cyclase only in the presence or by the interaction of the amino acid cysteine [3, 5]. The stimulatory activity of nitric oxide-containing compounds may be due, at least in part, to the formation of active, unstable intermediate S-nitrosothiols, i.e. S-nitrosocysteine in case of the organic nitrates [7]. According to Craven and DeRubertis [2], the active intermediates of guanylate cyclase stimulation are represented by nitric oxide-heme complexes. There is, however, substantial evidence that the organic nitrates have to be cleaved before they become biologically active. During the transformation which takes place in the presence of cysteine or by means of enzymatic catalysis, nitric oxide radicals are reductively split off the molecule from which (via the intermediate formation of salpetric acid) the nitric oxide is liberated as the essential stimulatory agent. In this study we examined the transformation of glycerine trinitrate and other organic nitrates under the influence of different thiols and a purified soluble rat liver guanylate cyclase preparation. At the same time the stimulation of guanylate cyclase in the presence of the thiols mentioned was quantitatively estimated. Only in case of cysteine did we find a strict correlation between the liberation of nitric oxide from different organic nitrates and the degree of enzyme activation. Several other thiols were also able to liberate nitric oxide, but surprisingly enough, there was no equivalent stimulation of guanylate cyclase.(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Cell Cardiol 1985 Sep
PMID:Evidence for a correlation between nitric oxide formation by cleavage of organic nitrates and activation of guanylate cyclase. 286 57

Isolated adrenocortical carcinoma cells of rat contain alpha 2- and beta-adrenergic receptors. When these cells are incubated with alpha 2-adrenergic agonists, there is a concentration-dependent increase of cyclic GMP that is blocked by the alpha 2-adrenergic antagonist yohimbine but not by the beta-antagonist propranolol. Concomitantly, both p-aminoclonidine (20 microM) and clonidine (100 microM), the alpha 2-adrenergic agonists, stimulate membrane guanylate cyclase activity. In calcium free medium there is no alpha 2-agonist-dependent increase in cyclic GMP. Isoproterenol, a beta-agonist, and forskolin cause an increase in cyclic AMP but not cyclic GMP. The cyclic AMP increase induced by isoproterenol is blocked by propranolol but not by yohimbine. Isoproterenol- and forskolin-dependent increases in cyclic AMP are inhibited by p-aminoclonidine and the inhibition is relieved by yohimbine. These results indicate a dual regulation of guanylate cyclase and adenylate cyclase by the alpha 2-receptor signal: guanylate cyclase is coupled to the receptor in a positive fashion, whereas adenylate cyclase is coupled in a negative fashion. Calcium is obligatory in the cyclic GMP-mediated response.
Arch Biochem Biophys 1986 Sep
PMID:Dual regulation of adenylate cyclase and guanylate cyclase: alpha 2-adrenergic signal transduction in adrenocortical carcinoma cells. 287 90

Atrial natriuretic factor (ANF) specifically stimulated the endogenous phosphorylation of a protein band in an isolated membrane fraction of human placenta. The apparent molecular weight of the substrate protein as determined by SDS-polyacrylamide gel electrophoresis is 160-170,000. In the same membrane fraction, ANF also stimulated guanylate cyclase activity in a dose-dependent manner. Guanosine 3':5'-cyclic monophosphate (cyclic GMP), added to the membrane fraction in lieu of ANF, also stimulated the phosphorylation of several protein bands, one of which have the same apparent molecular weight as the one stimulated by ANF. In contrast, adenosine 3':5'-cyclic monophosphate (cyclic AMP) at a similar concentration and hormones such as angiotensin II, insulin and vasopressin had no effect on the phosphorylation state of this protein band. The finding that ANF alters the phosphorylation state of a certain membrane protein and that this effect is mimicked by cyclic-GMP suggests that at least some of the biological action of ANF may be mediated by the phosphorylation of membrane protein involving a cyclic GMP-dependent protein kinase.
Biochem Biophys Res Commun 1986 Sep 14
PMID:Atrial natriuretic factor induced phosphorylation of human placental membrane protein: an effect mimicked by guanosine 3':5'-cyclic monophosphate. 287 3

In the ciliated protozoan Paramecium, Ca2+ and cyclic nucleotides are believed to act as second messengers in the regulation of the ciliary beat. Ciliary adenylate cyclase was activated 20-30-fold (half-maximal at 0.8 microM) and inhibited by higher concentrations (10-20 microM) of free Ca2+ ion. Ca2+ activation was the result of an increase in Vmax., not a change in Km for ATP. The activation by Ca2+ was seen only with Mg2+ATP as substrate; with Mn2+ATP the basal adenylate cyclase activity was 10-20-fold above that with Mg2+ATP, and there was no further activation by Ca2+. The stimulation by Ca2+ of the enzyme in cilia and ciliary membranes was blocked by the calmodulin antagonists calmidazolium (half-inhibition at 5 microM), trifluoperazine (70 microM) and W-7 (50-100 microM). When ciliary membranes (which contained most of the ciliary adenylate cyclase) were prepared in the presence of Ca2+, their adenylate cyclase was insensitive to Ca2+ in the assay. However, the inclusion of EGTA in buffers used for fractionation of cilia resulted in full retention of Ca2+-sensitivity by the ciliary membrane adenylate cyclase. The membrane-active agent saponin specifically suppressed the Ca2+-dependent adenylate cyclase without inhibiting basal activity with Mg2+ATP or Mn2+ATP. The ciliary adenylate cyclase was shown to be distinct from the Ca2+-dependent guanylate cyclase; the two activities had different kinetic parameters and different responses to added calmodulin and calmodulin antagonists. Our results suggest that Ca2+ influx through the voltage-sensitive Ca2+ channels in the ciliary membrane may influence intraciliary cyclic AMP concentrations by regulating adenylate cyclase.
Biochem J 1987 Sep 01
PMID:Regulation of ciliary adenylate cyclase by Ca2+ in Paramecium. 289 52

The role of guanosine 3',5'-cyclic monophosphate (cGMP) as an inhibitory mediator of tissue renin release was examined in two different in vitro preparations. In rat superficial cortical slices, renin release stimulated by isoproterenol (10(-5) M) was ablated by atriopeptin III (ANP, 2.1 x 10(-8) M), nitroprusside (NP, 10(-3) M), and 8-bromoguanosine 3',5'-cyclic monophosphate (8-BrcGMP, 10(-3) and 10(-6) M). Arachidonic acid (10(-3) M)-stimulated renin release was also inhibited by ANP and 8-BrcGMP (10(-3) and 10(-6) M). Both ANP and NP increased tissue cGMP concentrations significantly (P less than 0.05), but neither had an effect on adenosine 3',5'-cyclic monophosphate (cAMP) concentrations. When methylene blue (10(-5) M), an inhibitor of guanylate cyclase, was added to slices incubated with isoproterenol and ANP, the inhibition of renin release by ANP was abolished. These results were confirmed in a preparation of isolated cultured rat juxtaglomerular cells. In these cells, isoproterenol induced a significant increase (58%, P less than 0.01) in renin release, which was inhibited by the addition of 8-BrcGMP (10(-6) M). These data demonstrate a direct inhibitory effect of ANP on isoproterenol- and arachidonic acid-induced renin release. The results with NP, 8-BrcGMP, and methylene blue suggest that cGMP is an intracellular mediator of this inhibition.
Am J Physiol 1988 Sep
PMID:Guanosine 3',5'-cyclic monophosphate as a mediator of inhibition of renin release. 290 Dec 30

An association between guanosine 3',5'-monophosphate (cyclic GMP) and the nonadrenergic noncholinergic inhibitory system (NANCIS) has been demonstrated in the isolated bovine tissue (Bowman and Drummond, 1984). In order to investigate this association in the guinea pig trachea, we used cyclic GMP derivatives, guanylate cyclase activators (N-methylhydroxylamine (NMH) and nitroglycerin (NG)] and inhibitors [oxyhemoglobin (HbO2) and methylene blue (MB)]. Under general anesthesia paralysis, the animals were ventilated and hourly injected with atropine (0.2 mg/kg) and propranolol (1 mg/kg). Cervical segment of the trachea was converted to a closed tracheal pouch and then filled with Kreb's solution augmented with atropine (1 microM) and propranolol (3.5 microM). A decrease in the pouch pressure (Pp) reflected NANCIS nerve transmural stimulation (TS)--or drug-induced relaxation. Pharmacological agents were applied intravenously. At 2-11 min after injection, NMH and NG decreased baseline Pp and reduced TS-induced relaxation. NMH, which is more potent than NG in activating particulate guanylate cyclase activity, potentiated the TS-induced relaxation at high frequencies, but NG did not. HBO2 inhibited the TS-induced relaxation at high but not at low frequencies. In contrast, MB inhibited the relaxation at low but not high frequencies. The results suggest that activation of particulate or membrane bound guanylate cyclase potentiates NANCIS-induced decrease in Pp. Therefore, there is a possible association between cyclic GMP and the NANCIS in the guinea pig trachea.
Respir Physiol 1988 Sep
PMID:Cyclic GMP affecting the tracheal nonadrenergic noncholinergic inhibitory system. 290 72

The present investigation was designed to determine if atrial natriuretic factor relaxes non-vascular smooth muscle. Rather than cause a relaxation, atrial natriuretic factor induced a two-to-four fold enhancement in the amplitude of the spontaneous phasic contractions of duodenal longitudinal muscle. Dose-response curves revealed that ANF enhanced these contractions over a concentration range of 10 picomoles to 100 nanomoles with the ED50 at 1 nanomolar. The increased amplitude of contraction began within 30 seconds and was calcium-dependent. The increased force of contraction was associated with a three-fold increase in cyclic GMP levels and activation of particulate guanylate cyclase [E.C.4.5.1.2.]. Atrial natriuretic factor had its half-maximal [ED50] activation of guanylate cyclase at its 1 nM concentration while maximal enhancement was at its 100 nM concentration in duodenum, jejunum, and ileum. Atrial natriuretic factor did not stimulate adenylate cyclase [E.C.4.6.1.1.]. Thus, atrial natriuretic factor increases the force of the spontaneous phasic contractions of the small intestine which are calcium-dependent and associated with activation of the guanylate cyclase-cyclic GMP system.
Biochem Biophys Res Commun 1988 Sep 30
PMID:Atrial natriuretic factor increases the magnitude of duodenal spontaneous phasic contractions. 290 55


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