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 response of isolated rat pulmonary arteries to acute hypoxia has previously been reported to be biphasic, consisting of an initial rapid contraction of short duration, followed by partial relaxation (phase 1) and then a second slowly developed but sustained contraction (phase 2). The purpose of this study was to determine the following: 1) whether products from the endothelium might be required, 2) whether extra- and/or intracellular calcium or protein kinase C might be second messengers in mediating the pulmonary arterial hypoxic contraction, and 3) whether or not guanosine 3',5'-cyclic monophosphate (cGMP), endothelium-derived relaxing factor (EDRF), prostaglandin I2 (PGI2) or A2 adenosine receptor activation is involved in phase 1 relaxation. Neither Ca(2+)-free media nor verapamil (a Ca2+ channel blocker) altered the phase 1 contraction, but the phase 2 contraction was abolished by either of these treatments. Ryanodine (a sarcoplasmic reticulum Ca2+ depleter) had no effect on phase 1 contraction. H-7 (a PKC inhibitor) inhibited the phase 2 contraction, whereas it had no effect on phase 1 contraction. Removal of the endothelium abolished phase 1 contraction in either Ca(2+)-free media or normal Ca2+ media but did not alter phase 2 contraction or phase 1 relaxation. Neither methylene blue (guanylate cyclase inhibitor), N omega-nitro-L-arginine, (EDRF blocker), acetylsalicylic acid (cyclooxygenase inhibitor), xanthine amino congener (adenosine receptor blocker), nor glybenclamide blocked the phase 1 relaxation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pulmonary arterial hypoxic contraction: signal transduction. 135 5

Protein kinase C catalyzes phosphorylation of purified rat brain guanylate cyclase. The phosphorylation is marked by concomitant increase in guanylate cyclase activity. TPA further enhances both phosphorylation and activity of guanylate cyclase. Data seem to provide clues to the molecular mechanism of one of the transformation-like responses mimicked by 12-O-tetradecanoylphorbol-13-acetate, i.e. the elevation of cyclic GMP. It is envisaged that protein kinase C may have a central role in the understanding of molecular events triggering carcinogenesis.
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PMID:Protein kinase C catalyzes phosphorylation of guanylate cyclase in vitro. 285 74

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

Na+/Ca2+ exchange contributes to the control of cytosolic free Ca2+ levels ([Ca2+]i) in resting and activated cultured human mesangial cells. We have previously shown that activation of phospholipase C by vasoconstrictors enhances Ca2+ influx upon extracellular Na+ withdrawal. This effect is not mediated by concurrent activation of protein kinase (PK) C, since it occurs even after PKC inhibition, and phorbol esters actually blunt both basal and stimulated Na+/Ca2+ exchange. We now studied the effects of PKA and PKG activation by adenylate/guanylate cyclase stimuli or by permeant analogues of cyclic nucleotides in monolayer cultures loaded with the fluorescent Ca(2+)-sensitive probe, fura-2. The exchanger was inhibited by the stable prostaglandin I2 analogue, iloprost, which is transduced by cAMP (peak [Ca2+]i inhibition by 1 microM iloprost 35 +/- 3%). Similarly, non-receptor activation of adenylate cyclase by 10 microM forskolin inhibited basal and agonist-stimulated Na+/Ca2+ exchange by 52 +/- 4 and 66 +/- 4%, respectively. Dibutyryl-cAMP (0.1 mM) also inhibited stimulated Na(+)-dependent Ca2+ influx by 72 +/- 2%. The particulate guanylate cyclase agonist, atriopeptin III, and the soluble guanylate cyclase activator, glyceryltrinitrate, also inhibited both basal and angiotensin II-stimulated Na+Ca2+ exchange (to a maximum of 53 +/- 5 and 62 +/- 3%, respectively). Dibutyryl-cGMP (1 mM) mimicked the effects of cGMP stimuli, reducing stimulated Na+/Ca2+ exchange by 79 +/- 2%. Therefore, similar to PKC, cyclic nucleotide activation of PKA and PKG regulates Na+/Ca2+ exchange, providing a functional link between transmembrane signalling systems for vasoactive agents in cultured human mesangial cells.
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PMID:Cyclic nucleotides inhibit Na+/Ca2+ exchange in cultured human mesangial cells. 752 69

cGMP and Ca2+ are intracellular messengers in vertebrate rod photoreceptors. cGMP is the excitatory messenger, while intracellular free Ca2+ has been implied to be (one of) the messenger(s) in the process of light adaptation in vertebrate rod photoreceptors. The enzyme guanylyl cyclase (GC, EC 4.6.1.2.) catalyzes the reaction GTP-->cGMP + PPi. Bovine retinal rod outer segments (ROS) contain a particulate GC which is inhibited by an increase in free Ca2+ in the submicromolar range, although the precise molecular mechanism underlying this inhibition is unclear. We have developed an optical enzyme-coupled assay to study regulation of the particulate GC endogenous to bovine ROS. The particulate GC exhibited a Ca(2+)-inhibited (IC50 83-144 nM) activity of 13-23 nmol of PPi/(min-(mg of rhodopsin)). ATP increased the maximal velocity of GC by about 2-fold, and this increase was inhibited by the specific PKC inhibitors chelerythrine and the pseudosubstrate-based peptide inhibitor PKC R10-31N. When the factor that mediated the ATP-dependent increase in GC rate was removed by washing, the ATP-dependent increase in GC rate could be reestablished by addition of purified, constitutively active PKC.
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PMID:Activation by PKC of the Ca(2+)-sensitive guanylyl cyclase in bovine retinal rod outer segments measured with an optical assay. 771 73

To characterize Ser1029 in STaR at a consensus sequence of phosphorylation site by PKC, two mutants of mS1029A with replacement of Ser1029 to Ala1029 and C delta 1029 lacking 22 amino acids including Ser1029 were prepared. Preincubation of the wild type-STaR (wt-STaR) transfectant with 1 microM PMA caused additional STa-mediated guanylyl cyclase (GC) activation compared to control, whereas the mS1029A- and C delta 1029-transfected cells did not show a similar enhanced GC activation by PMA. After metabolic labeling with [32P]phosphate, transfected cells with wt-STaR and mutants were incubated with 1 microM PMA. Subsequent 32P-radiolabeled proteins were immunoprecipitated using anti-STaR antibody, and analyzed by autoradiography after separation on SDS-PAGE. The immunoprecipitated wt-STaR but not mS1029A and C delta 1029 had a significant radioactivity. These results suggest that the effect of PMA on wt-STaR transfectants may be caused by phosphorylation of Ser1029. The C delta 1012 mutant, with further truncation (Gln1012-Phe1050) of the carboxy terminus, did not show STa-mediated GC activation. Based on these data, these 17 amino acids (Gln1012-Ala1028), essential for signaling of GC activation by STa, have an abundance of basic amino acids which might be functionally influenced by phosphorylation of Ser1029.
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PMID:The significance of Ser1029 of the heat-stable enterotoxin receptor (STaR): relation of STa-mediated guanylyl cyclase activation and signaling by phorbol myristate acetate. 879 7

1. In rat aortic rings precontracted by phenylephrine, H7 (10(-5)M) and staurosporine (10(-7)M), which inhibit PKA, PKG and PKC, and H-89 (10(-6)M), which inhibits PKA and PKG, potentiated relaxations induced by nitroglycerin. Forskolin-induced relaxations were not affected by H7 (10(-5)M). 2. Nitroglycerin-induced relaxations were not affected by calphostin-C (10(-7)M), which inhibits PKC, H-89 (10(-7)M), which inhibits PKA, and staurosporine (2 x 10(-9)M), which inhibits PKC. 3. Iberiotoxin (3 x 10(-8)M), an inhibitor of large conductance Kca channels, partly inhibited the relaxation induced by nitroglycerin and completely inhibited the potentiating effect of H7 on nitroglycerin-induced relaxations. 4. The potentiating effect of zaprinast (10(-5)M), an inhibitor of cGMP-phosphodiesterase, on nitroglycerin-induced relaxation was not affected by iberiotoxin. In the presence of methylene blue (10(-5)M), an inhibitor of guanylate cyclase, the residual relaxing response to nitroglycerin was not affected by H7, but it was inhibited by iberiotoxin. 5. These results suggest that the potentiation of nitroglycerin-induced relaxation by H7, staurosporine and H-89 may be due to inhibition of PKG.
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PMID:The potentiation of nitroglycerin-induced relaxation by PKG inhibition in rat aortic rings. 885 8

Central sensitization of spinothalamic tract (STT) neurons in anesthetized monkeys after intradermal injection of capsaicin depends in part on disinhibition. Protein kinase C is suggested to participate in this process. The present study shows that the nitric oxide-cGMP (NO-cGMP) signal transduction system also contributes to sensitization of wide dynamic range (WDR) STT neurons located in the deep dorsal horn. The NO-cGMP system was activated by microdialysis administration into the dorsal horn of 8-bromo-cGMP, an analog of cGMP. Sensitization of STT cells by 8-bromo-cGMP increased the responses of deep WDR STT cells to both weak and strong mechanical stimulation of the skin and simultaneously attenuated the inhibition of the same neurons produced by stimulation in the periaqueductal gray (PAG). In contrast, WDR STT cells in the superficial dorsal horn and high-threshold (HT) STT cells in superficial or deep layers showed reduced responses to mechanical stimulation of the skin after infusion of 8-bromo-cGMP, and PAG inhibition of these neurons was unaffected. Sensitization of STT cells and the attenuation of PAG inhibition induced by intradermal injection of capsaicin were prevented by preteatment of the dorsal horn with a guanylate cyclase inhibitor, 1 H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. The results support the hypothesis that activation of the NO-cGMP signal transduction system contributes to the sensitization of WDR STT neurons in the deep dorsal horn and helps explain why intradermal capsaicin injections often fail to sensitize superficial and HT STT cells. The results also support the idea that sensitization of STT cells is produced in part by disinhibition.
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PMID:Involvement of cGMP in nociceptive processing by and sensitization of spinothalamic neurons in primates. 909 62

The chemoattractant cAMP induces directed cell locomotion in Dictyostelium cells. Several second messenger pathways are activated upon binding of cAMP to G-protein-coupled receptors, including adenylyl cyclase, guanylyl cyclase, phospholipase C, and the opening of plasma membrane Ca2+ channels. These second messenger responses are unaltered in many chemotactic mutants, except for the cGMP response. Activation of guanylyl cyclase depends on G-proteins and is regulated by a cGMP-binding protein in a complex manner. This cGMP-binding protein also mediates intracellular functions of cGMP to activate a PKC-related kinase that phosphorylates myosin II heavy chain, thereby allowing myosin filaments to rearrange during cell movement.
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PMID:cGMP as second messenger during Dictyostelium chemotaxis. 924 16

Biochemical experiments by others have indicated that protein kinase C activity is present in the rod outer segment, with potential or demonstrated targets including rhodopsin, transducin, cGMP-phosphodiesterase (PDE), guanylate cyclase, and arrestin, all of which are components of the phototransduction cascade. In particular, PKC phosphorylations of rhodopsin and the inhibitory subunit of PDE (PDE ) have been studied in some detail, and suggested to have roles in downregulating the sensitivity of rod photoreceptors to light during illumination. We have examined this question under physiological conditions by recording from a single, dissociated salamander rod with a suction pipette while exposing its outer segment to the PKC activators phorbol-12-myristate,13-acetate (PMA) or phorbol-12,13-dibutyrate (PDBu), or to the PKC-inhibitor GF109203X. No significant effect of any of these agents on rod sensitivity was detected, whether in the absence or presence of a background light, or after a low bleach. These results suggest that PKC probably does not produce any acute downregulation of rod sensitivity as a mechanism of light adaptation, at least for isolated amphibian rods.
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PMID:Protein kinase C activity and light sensitivity of single amphibian rods. 937 74


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