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)

Three classes of vasodilators mediate their effects through the activation of guanylate cyclase and the increased synthesis of cyclic GMP. Nitrovasodilators such as nitroglycerin, nitroprusside, hydroxylamine, azide, etc. result in the generation of the nitric oxide free radical that activates the cytosolic (soluble) isoenzyme form of guanylate cyclase. These agents have been useful in increasing cyclic GMP synthesis in numerous model systems and these effects are independent of extracellular calcium. The increased synthesis of cyclic GMP and the activation of cyclic GMP-dependent protein kinase result in the altered phosphorylation of many smooth muscle proteins including the dephosphorylation of myosin light chain, which is associated with vascular and tracheal smooth muscle relaxation. These latter effects may result from cyclic GMP decreasing cytosolic free calcium concentrations and the activity of myosin light chain kinase. Another class of vasodilators, designated endothelium-dependent vasodilators, includes a long list of agents such acetylcholine, histamine, A23187, ATP, thrombin, etc. that relax vessels only when the endothelium is intact. These agents result in the increased endothelial synthesis and/or release of a factor(s) designated endothelial-derived relaxant factor (EDRF), the structure of which is unknown. This labile factor also activates the soluble isoenzyme form of guanylate cyclase in the smooth muscle resulting in cyclic GMP accumulation and the same cascade of events as above. There is evidence that even under basal, non-stimulated conditions there is EDRF release that influences vascular tone due to the increased synthesis of cyclic GMP. A third class of vasodilators, atrial natriuretic factor (ANF) or atriopeptins, includes a family of peptides that are produced in cardiac atria and other tissues and influence cardiovascular volume and dynamics by causing natriuresis, diuresis, vasodilation and decreased renin, aldosterone and vasopressin secretion. These peptide hormones also increase cyclic GMP synthesis in vascular, renal, adrenal and other tissues. These effects are mediated through specific ANF receptors that couple to and activate the membrane (particulate) isoenzyme form of guanylate cyclase and increase cyclic GMP-dependent protein kinase activity. There are two ANF receptor subtypes in most cells and tissues that are 130,000 and 66,000 daltons. The ANF receptor of about 130,000 daltons, designated receptor ANF-R1 copurifies with particulate guanylate cyclase through numerous procedures and may be part of the membrane-associated guanylate cyclase complex.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regulation and role of guanylate cyclase-cyclic GMP in vascular relaxation. 289 Jan 72

Guanylate cyclase has been strongly implicated as a cell-surface receptor on spermatozoa for a chemotactic peptide, and on various other cells as a receptor for atrial natriuretic peptides. Resact (Cys-Val-Thr-Gly-Ala-Pro-Gly-Cys-Val-Gly-Gly-Gly-Arg-Leu-NH2), the chemotactic peptide released by sea urchin Arbacia punctulata eggs, is specifically crosslinked to A. punctulata spermatozoan guanylate cyclase. After the binding of the peptide the state of guanylate cyclase phosphorylation modulates enzyme activity. We report here that the deduced amino-acid sequence of the spermatozoan membrane form of guanylate cyclase predicts an intrinsic membrane protein of 986 amino acids with an amino-terminal signal sequence. A single transmembrane domain separates the protein into putative extracellular and cytoplasmic-catalytic domains. The cytoplasmic carboxyl-terminal 95 amino acids contain 20% serine, the likely regulatory sites for phosphorylation. Unexpectedly, the enzyme is homologous to the protein kinase family.
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PMID:Membrane guanylate cyclase is a cell-surface receptor with homology to protein kinases. 290 Oct 39

Protein kinase activities are regulated by endogenous thermostable protein inhibitors. Type I inhibitor is a protein of MW 22,000-24,000 which inhibits specifically cyclic AMP-(cAMP) dependent protein kinase (APK) as a competitive inhibitor of catalytic subunits of the enzyme. Type I inhibitor activity changes inversely according to the activation of adenylate cyclase and the changes in cAMP content in tissues. It seems that type I inhibitor serves as a factor preventing spontaneous cAMP-dependent phosphorylation in unstimulated cell. The other thermostable protein which inhibits APK activity has been found in Sertoli cell-enriched testis (testis inhibitor). Physiological role of the testis inhibitor is unknown. Type II inhibitor is a protein of MW 15,000 which blocks phosphorylation mediated by cAMP and cyclic GMP (cGMP) dependent (APK and GPK) and cyclic nucleotide independent protein kinases as a competitive inhibitor of substrate proteins. Activity of this inhibitor specifically changes in reciprocal manner to the changes in cGMP content. It seems that type II inhibitor serves as a factor preventing the phosphorylation catalyzed by GPK when cGMP content is low. Stimulation of guanylate cyclase and activation of GPK is followed by a decrease of type II inhibitor activity. This change in relationship between activities of GPK and type II inhibitor allows for effective phosphorylation catalyzed by this enzyme when cGMP content is increased.
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PMID:Regulation of the activity of protein kinases by endogenous heat stable protein inhibitors. 299 38

Recent studies on endothelium-dependent vasorelaxation have been briefly reviewed and analyzed. The following processes appear to subserve this mechanism: In the endothelial cell: receptor activation, activation of phospholipases, mobilization of intracellular Ca2+, synthesis and release of 'endothelium-derived relaxing factor(s) (EDRF); In the smooth muscle cell: activation of guanyl cyclase and protein kinase, protein phosphorylation/dephosphorylation, relaxation. Alterations of this mechanism could be involved in certain cardiovascular disorders.
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PMID:Endothelium-derived relaxing factor (EDRF). 300 57

Several observations suggest that cyclic GMP might regulate some aspect of neuromuscular physiology or metabolism in the lobster. Homarus americanus: lobster muscle is one of the richest known sources of cyclic GMP-dependent protein kinase, the preparation contains several phosphoproteins whose state of phosphorylation is affected by cyclic GMP more effectively than by cyclic AMP, and guanylate cyclase and phosphodiesterase are active in this tissue. However, no factor has yet been identified that alters lobster muscle cyclic GMP levels. We have screened extracts of neural and neurosecretory structures for the capacity to promote cyclic GMP accumulation in isolated exoskeletal muscles. Extracts of the sinus gland (a neurohemal organ found in the eyestalk) contain a factor that induces up to 100-fold increases in muscle cyclic GMP content, whereas extracts of other tissues are ineffective. This factor can also act on targets other than muscle, with hepatopancreas, testis, and neuronal tissue showing the largest responses. The sinus gland factor does not appear to affect cyclic GMP metabolism by depolarizing the preparation or by mobilizing extracellular Ca2+. The effect on cyclic GMP levels is dose-dependent and linear with time. Biological activity is destroyed by boiling and by 90% ethanol. It is also destroyed by trypsin, chymotrypsin, or pronase, which suggests that the factor is a protein or peptide. Both gel filtration chromatography and experiments using dialysis tubing with different molecular weight exclusion limits indicate that the factor has an apparent molecular weight of 5,000-12,000 daltons. A preliminary fractionation scheme, based on gel filtration, ion-exchange, and reverse-phase chromatography, gives greater than 1,300-fold purification. Our long-range goal is to purify this factor to homogeneity, compare it to other peptide hormones, and use it as a probe to evaluate the role of cyclic GMP at the neuromuscular junction.
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PMID:Identification and characterization of a polypeptide from a lobster neurosecretory gland that induces cyclic GMP accumulation in lobster neuromuscular preparations. 302 64

The biochemical events initiated by mitogen in T lymphocytes are the subject of this paper. Following interaction of the mitogen with its receptors, a transmembrane 'trigger-type' signal is propagated which has both positive and negative correlates. The negative signal occurs with high mitogen concentrations and is associated with membrane freezing, microtubular aggregation, receptor capping, adenylate cyclase activation, and cellular cyclic AMP increases. The positive signal occurs with optimal mitogen concentrations and is associated with changes in membrane permeability and transport with influx of calcium and potassium ion and efflux of sodium, in transport processes for glucose, amino acids, and nucleosides, and in a collected series of early membrane lipid changes which can be considered essential for the positive signal. These lipid changes include the uptake of arachidonic acid and other fatty acids, choline, phosphate and other molecules, their incorporation into membrane phospholipids, particularly phosphatidylinositol (PI), and a turnover of PI with the production of inositol triphosphate, which can be related to calcium mobilization and diacylglycerol which activates a cytoplasmic protein kinase C. A key event associated with mitogen action is arachidonic acid release. Arachidonic acid may give rise to prostaglandins and thromboxanes as part of negative components of the signal through effects on the adenylate cyclase/cyclic AMP system. Arachidonic acid gives rise to eicosanoids like 5-, 11-, possibly 12- and 15-hydroxyperoxy and hydroxy eicosatetraenoic acids and leukotrienes B4 and C4. The activation of the 5-lipoxygenase, a critical calcium-dependent step, leads via the production of 5-HPETE and 5-HETE to the activation of membrane and soluble guanylate cyclase and the production of cyclic GMP. Cyclic GMP appears to be essential for mitogen activation and is associated with cyclic GMP-dependent protein kinase activation and the phosphorylation of a number of substrates. Calcium ion influx is clearly central to mitogen action. Calcium through its influx and mobilization from cellular stores is thought to contribute directly and indirectly through the action of calmodulin and protein kinase C to the activation of a number of enzymatic processes involved in the positive signal including phospholipase C, diglyceride kinase and lipase, 5-lipoxygenase, and guanylate cyclase. Cyclic GMP and calcium ion both participate in nuclear processes leading to RNA and protein synthesis. Interleukin 2 is associated with midcycle increases in cyclic GMP and entry into DNA synthesis.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Transduction of signals in the activation of T lymphocytes: relation to leukemia. 304 Mar 20

Estrogen-induced protein was purified from rat uteri and assayed for several enzymatic activities involved in the metabolism and action of cyclic nucleotides. No adenylate and guanylate cyclase (EC 4.6.1.1 and 4.6.1.2, respectively), protein kinase (EC 2.7.1.33), and cyclic nucleotide binding activities could be demonstrated in three independent preparations of the protein. However, all three preparations exhibited significant phosphoprotein phosphatase activity (EC 3.1.3.16) on phosphorylated protamine and histones F1. This activity is optimal at neutral pH, inhibited by Zn(++), and unaffected by cyclic AMP or cyclic GMP.
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PMID:Phosphoprotein phosphatase activity associated with estrogen-induced protein in rat uterus. 415 69

Several aspects of the mode of action of direct vasodilators are discussed. Nitro-compounds probably act via an intracellular formation of S-nitrosothiols, which stimulate cellular guanylate cyclase. Doubts, however, arise with regard to a generalization of this concept, e.g., methylene blue, an inhibitor of guanylate cyclase, interferes potently with the vasorelaxant action of nitroglycerin, but not with that of nitroprusside and sodium nitrite in KCl-stimulated rabbit aorta. Nitro-compounds do not interfere with transmembrane calcium movements. Hyperpolarization of the vascular smooth-muscle membrane, although reported to occur with nitroprusside, does not seem to be a common feature of the nitro-compounds. On the other hand, all nitro-compounds tested interfered with the noradrenaline-induced increase in 36-Cl steady-state exchange in rabbit aorta, and this effect could be mimicked by 8-Br-cGMP. Chemically skinned vascular smooth muscle was relaxed by pure cGMP-dependent protein kinase, but this effect requires confirmation. The action of hydralazine is augmented in chemically sympathectomized arteries and blocked by purines, such as adenosine, pointing to modulating role of purine-like compounds released from sympathetic nerve endings. The direct vasodilator action of hydralazine consists of a predominantly inhibitory effect on pharmacomechanical coupling. Membrane hyperpolarization with hydralazine has been reported. In addition to having direct effects on vascular smooth muscle, hydralazine can interfere with transmitter release by a prejunctional mechanism, and part of its vasorelaxant action seems to depend on the integrity of the endothelium in vascular smooth muscle.
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PMID:Direct vasodilators with unknown modes of action: the nitro-compounds and hydralazine. 608 7

The immunohistochemical localization of guanylate cyclase [GTP pyrophosphate-lyase (cyclizing), EC 4.6.1.2] has been examined in rat neocortex, caudate-putamen, and cerebellum by using specific monoclonal antibodies. Immunofluorescence could be seen within somata and proximal dendrites of neurons in the these regions. A nuclear immunofluorescence reaction to guanylate cyclase was characteristically absent. The staining pattern for guanylate cyclase was coincident with previously described localizations of cyclic GMP immunofluorescence within medium spiny neurons of the caudate-putamen and pyramidal cells of the neocortex. Cerebellar guanylate cyclase immunoreactivity was primarily confined to Purkinje cells and their primary dendrites, similar to the pattern reported for cyclic GMP-dependent protein kinase localization. Guanylate cyclase immunofluorescence was abolished when the monoclonal antibodies were exposed to purified enzyme prior to incubation of the tissue slices or when control antibody was substituted for the primary antibody. Immunohistochemical localization of cyclic AMP in these same tissues was readily distinguished from that of guanylate cyclase or cyclic GMP, showing uniform fluorescence throughout the cell bodies of neurons and glial elements.
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PMID:Immunohistochemical localization of guanylate cyclase within neurons of rat brain. 612 12

The existence of Ca2+-activated, phospholipid-dependent protein kinase (protein kinase C), the effect of gastrin on phospholipid metabolism and guanylate cyclase activity were investigated to elucidate the cellular mechanism of action of gastrin on the corporal mucosa of the canine stomach. Protein kinase activity was determined by measuring the incorporation of [32P] into calf thymus H1-histone from [32P]-ATP. One unit of protein kinase was defined as the amount of enzyme which incorporated 1 pmol of phosphate from ATP into H1-histone. Protein kinase C was found in 100,000xg supernatant of homogenate fractionated by a DEAE-cellulose column chromatography. Characteristics of further purified protein kinase C, such as dependency on divalent cations and phospholipids, were in agreement with those of previously reported protein kinase C in other tissues. Furthermore, the gastric corporal mucosa was found to contain protein kinase C in large quantities. The specific activity of protein kinase C was 26,000 units/mg protein. The phospholipid metabolism was evaluated by the incorporation of [14C]-glycerol-3-phosphate and the change of the radioactivity of [32P] in individual phospholipids. Each phospholipid was extracted from the gastric corporal mucosa and isolated by thin layer chromatography. Guanylate cyclase activity was determined by measuring the cGMP produced, using radioimmunoassay. Gastrin significantly increased the incorporation of [14C]-glycerol-3-phosphate into phosphatidylethanolamine in the presence of acetylcholine (Ach). Ach increased the uptake of the tracer into phosphatidylinositol significantly, and the increase was enhanced by the simultaneous addition of gastrin. In the experiments with [32P]-labeled phospholipids, gastrin increased the incorporation of [32P] into phosphatidylethanolamine significantly. The significant increase of the radioactivity in phosphatidylinositol by Ach failed to be enhanced by gastrin, but that of phosphatidylethanolamine by Ach was enhanced by gastrin. No stimulation of guanylate cyclase activity by gastrin was detected in the dispersed gastric corporal mucosal cells. These results indicate that gastric corporal mucosa was one of the most abundant tissues in which protein kinase C was contained, when compared with various mammalian tissues previously reported by Minakuchi, Nishizuka, et al. Nishizuka et al, recently proposed the novel hypothesis that phosphatidylinositol turnover activated by cAMP-independent agonists will be essentially required to activate protein kinase C. Our results suggest that gastrin can provoke phospholipids turnover including phosphatidylinositol turnover in gastric corporal mucosa. Therefore, our data indicate the possibility that the protein kinase C system plays an important role in the cellular mechanism of action of gastrin on gastric corporal mucosa.
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PMID:[The cellular mechanism of action of gastrin on the corporal mucosa of the canine stomach. (2) Ca2+-activated, phospholipid-dependent protein kinase and phospholipid turnover--possible mediator of gastrin action]. 613 23


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