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 thick ascending limb of Henle's loop (TAL) is involved in the urinary dilution/concentration process by actively reabsorbing NaCl through a complex mechanism. Some years ago, compelling evidence was provided that cAMP stimulates NaCl reabsorption through the activation of adenylyl cyclase by several hormones other than antidiuretic hormone (ADH). Synthesis of cyclic AMP is inhibited by prostaglandin E2 (PGE2) and arachidonic acid per se, via the pertussis toxin-sensitive protein Gi activation. Cyclic GMP cascade down-regulates NaCl reabsorption, through activation of both guanylyl cyclase receptors (by ANF and urodilatin), and soluble guanylyl cyclase (by nitric oxide, NO). In TAL, NO is produced by the cytokine-inducible form of NO synthase, but not by the constitutive one. Agonists known to activate protein kinase C (PKC) in TAL elicit opposite effects on NaCl reabsorption. Five PKC isoforms belonging to the conventional, novel, and atypical enzyme subclasses have been recently defined in TAL and might differently regulate NaCl flux. Increments in intracellular calcium ([Ca2+]i) inhibit NaCl reabsorption via three pathways: (i) a possible direct effect on ion channels, (ii) a PLA2-mediated production of arachidonic acid derivatives (20-HETE), and (iii) inhibition of the ADH-induced cAMP accumulation. This last effect results from activation of phosphodiesterase (common to the agents that increase [Ca2+]i), and inhibition of adenylyl cyclase (only elicited by Ca2+c). Finally, the apical localization of some agonists effects is documented.
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PMID:Transducing pathways involved in the control of NaCl reabsorption in the thick ascending limb of Henle's loop. 955 29

Accumulating evidence indicates that protein kinase C (PKC)-dependent, Ca2+-independent smooth muscle contraction plays the central role in the occurrence of chronic vasospasm following aneurysmal subarachnoid hemorrhage. As far as we know, the nitric oxide/ cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG) system comprises the most efficacious inhibitory mechanism against the PKC-dependent contractile mechanism, and the myogenic tonus of normal cerebral arteries is thought to be maintained on the balance between these systems. Recent studies indicate that in spastic cerebral arteries, the rise in the intracellular diacylglycerol level causes PKC activation presumably owing to the overexpression of endothelin (ET)-1 as well as the generation of free radicals, whereas the cGMP level is inversely reduced owing to the inactivation of soluble guanylate cyclase through some as yet unknown mechanism. The resultant loss of balance between the two systems is considered to culminate in the occurrence of chronic vasospasm lasting for nearly 2 weeks. Based on the above concept, recent papers concerning the effects of reactive oxygen species on the arterial smooth muscle, alterations of various membrane ion channels, particularly of adenosine triphospate (ATP)-activated potassium channels in spastic arteries, the preventive effects of ET antagonists on vasospasm, and the causative role of ET-1 were reviewed in the present article. The roles of the above spasmogenic factors or mechanisms may be more clearly understood on the basis of the antagonistic interrelation between the PKC and the PKG systems, which exert diverse influences on the force-generating system as well as on its multifarious regulatory mechanisms in smooth muscle cells.
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PMID:Various pathogenetic factors revolving around the central role of protein kinase C activation in the occurrence of cerebral vasospasm 957 13

We examined some of the signalling events in the negative modulation of isoproterenol-induced stimulation of contractility in rat isolated atria. Isoproterenol-mediated positive inotropic response is accompanied by the stimulation of nitric oxide synthase (NOS) and an increase in the production of cyclic GMP (cGMP). Inhibition of NOS and guanylate cyclase increased the dose-response curve of isoproterenol on contractility. Inhibitors of calcium flux or calcium calmodulin, but not of protein kinase C, abrogated these mechanisms. The existence of a modulatory negative inotropic-cyclic GMP-mediated mechanism limiting the effect of beta-adrenergic stimulation in myocardium is discussed.
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PMID:Role of nitric oxide in cardiac beta-adrenoceptor-inotropic response. 961 82

Vasodilation by agents such as bradykinin and ATP is dependent on nitric oxide, the endothelium-dependent relaxing factor (EDRF). The release of EDRF results in elevation of cGMP in endothelial and smooth muscle cells (9). The signaling pathway that leads to increases in cGMP is not completely understood. The role of protein kinase C (PKC) in the elevation of cGMP induced by ATP and bradykinin was studied in cultured porcine aortic endothelial cells, by measuring PKC phosphorylation of a substrate and by measuring cGMP levels by radioimmunoassay. Extracellular ATP and bradykinin simultaneously elevated cGMP levels and PKC activity. The PKC inhibitors staurosporine, calphostin C, and Cremophor EL (T. Tamaoki and H. Nakano. Bio/Technology 8: 732-735, 1990; F. K. Zhao, L. F. Chuang, M. Israel, and R. Y. Chuang. Biochem. Biophys. Res. Commun. 159: 1359-1367, 1989) prevented the elevation of cGMP elicited by ATP and reduced that produced by bradykinin. Cremophor did not affect the elevation of cGMP by nitroprusside, an agent that directly increases guanylate cyclase activity (9). The PKC activator phorbol 12-myristate 13-acetate, but not a phorbol ester analog inactive on PKC, also elevated cGMP levels. These results suggest that EDRF agonists elevate cGMP in endothelial cells via PKC stimulation.
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PMID:Extracellular ATP and bradykinin increase cGMP in vascular endothelial cells via activation of PKC. 968 41

S100 beta is a calcium-binding protein, which regulates the activities of several enzymes and inhibits the phosphorylation of a variety of protein kinase C substrates in a calcium-dependent manner. The protein was recently found to activate a retinal membrane guanylate cyclase, and in this paper, we report that it inhibits the phosphorylation of an 80 kDa retinal protein (p80). Structurally, S100 beta consists of two EF-hands connected by a hinge region. In view of its small size, wide distribution in a variety of tissues, and regulation of many different proteins, it is of interest to identify the sites on the protein that interact with the effectors, and to determine if the same sites are responsible for interaction with different effectors. We addressed these questions with the use of synthetic peptides with sequences corresponding to different regions of S100 beta and testing their effects on the protein's activation of guanylate cyclase, and inhibition of p80 phosphorylation. Peptides with sequences corresponding to effector interaction sites were anticipated to either block or simulate the effects of S100 beta. The results show that two regions of S100 beta interact with effectors: the C-terminal region of Thr81-Glu91 and the hinge region of Leu32-Leu40. The synthetic peptide containing the latter sequence blocked the S100 beta activation of guanylate cyclase and inhibition of p80 phosphorylation, while the peptide containing the former sequence blocked cyclase activation and simulated S100 beta in inhibiting p80 phosphorylation. By determining the effects of including or excluding dithiothreitol in the assays, we observed that the cysteine residue in the C-terminal region of S100 beta (Cys84) participates in the regulation of guanylate cyclase but not of p80 phosphorylation. We conclude from these results that the C-terminal and hinge regions of S100 beta are important in the regulation of effector proteins and that Cys84 is essential for interaction with only specific effectors.
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PMID:Identification of effector binding sites on S100 beta: studies with guanylate cyclase and p80, a retinal phosphoprotein. 969 60

The purpose of this study was to explore the pharmacological and biochemical mechanisms involved in diabetic cardiomyopathy, with particular interest in the abnormal function of cholinergic neurotransmission at the onset of the pathology. The muscarinic acethylcholine agonist carbachol showed a negative inotropic response on both normal and diabetic isolated atria, but the latter showed a supersensitive response. No changes were found in muscarinic acethylcholine receptor (mAChR) expression. Measurements of mAChR-associated second messengers indicated no significant differences between normal and diabetic rat atria in the stimulatory effect of carbachol on protein kinase C activity and the production of inositol phosphates, or in the inhibitory effect induced by carbachol on cyclic AMP (cAMP) production. On the contrary, nitric oxide (NO) synthase activity and cyclic GMP production were higher in diabetic cardiac preparations than in normal ones. Moreover, in diabetic atria, nitric oxide synthase and guanylate cyclase inhibitors shifted the carbachol concentration-response curve on contractility to the right, reaching values similar to those of normal atria. These results suggest an early alteration in the mACh system during the diabetic state, associated with increased production of nitric oxide and cyclic GMP (cGMP). This, in turn, could increase the biological mechanical activity of the mAChR agonist, inducing in this way a higher pharmacological response, without changes in mAChR expression.
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PMID:Participation of nitric oxide and cyclic GMP in the supersensitivity of acute diabetic rat myocardium by cholinergic stimuli. 971 19

Nitric oxide has several signalling mechanisms that can potentially control force generation by vascular smooth muscle. Some of these mechanisms include the stimulation of cGMP production by the soluble heme-containing form of guanylate cyclase (sGC), inhibition of mitochondrial respiration, and the modulation of vasoactive mediator release by the endothelium. Reactive O2 species (ROS) can also regulate force generation by vascular smooth muscle through mechanisms including the stimulation of production of vasoactive prostaglandins, the stimulation of sGC by catalase-mediated metabolism of H2O2 and inhibition of sGC activation by superoxide, the activation of protein kinase C, and the modulation of mediator release from the endothelium. Interactions between NO and ROS signalling mechanisms result in additional processes which modulate vascular force generation. For example, NO-elicited stimulation of sGC can be attenuated by superoxide, and this results in the formation of peroxynitrite (ONOO-). However, high levels of NO result in a ONOO- and thiol dependent formation of a species which regenerates NO in a time-dependent manner. It appears that NO inhibits catalase through an O2 and superoxide dependent process which results in inhibition of relaxation mediated by H2O2-elicited stimulation of sGC. Furthermore, evidence exists suggesting additional signalling mechanisms resulting from interactions between regulatory systems involving NO and ROS which appear to be important in control of vascular force generation in pathophysiological states.
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PMID:Oxidant--nitric oxide signalling mechanisms in vascular tissue. 972 33

Mobilization of intracellular Ca2+ stores is coupled to Ca2+ influx across the plasma membrane, a process termed capacitative Ca2+ entry. Capacitative Ca2+ entry was examined in cultured guinea pig enteric glia exposed to 100 microM ATP, an inositol trisphosphate-mediated Ca2+-mobilizing agonist, and to 1 microM thapsigargin, an inhibitor of microsomal Ca2+ ATPase. Both agents caused mobilization of intracellular Ca2+ stores followed by influx of extracellular Ca2+. This capacitative Ca2+ influx was inhibited by Ni2+ (88 +/- 1%) and by La3+ (87 +/- 1%) but was not affected by L- or N-type Ca2+ channel blockers. Pretreatment of glia with 100 nM phorbol 12-myristate 13-acetate for 24 h decreased capacitative Ca2+ entry by 48 +/- 2%. Chelerythrine (0.1-10 microM), a specific antagonist of protein kinase C (PKC), dose dependently inhibited capacitative Ca2+ entry. The nitric oxide synthase inhibitor NG-nitro-L-arginine (1 mM) decreased Ca2+ influx by 42 +/- 1%. Capacitative Ca2+ entry was inhibited to a similar degree by the guanylate cyclase inhibitor (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one). Capacitative Ca2+ entry occurs in enteric glial cells via lanthanum-inhibitable channels through a process regulated by PKC and nitric oxide.
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PMID:Capacitative Ca2+ entry in enteric glia induced by thapsigargin and extracellular ATP. 972 68

1. Subarachnoid haemorrhage (SAH) is a unique disorder and a major clinical problem that most commonly occurs when an aneurysm in a cerebral artery ruptures, leading to bleeding and clot formation. Subarachnoid haemorrhage results in death or severe disability of 50-70% of victims and is the cause of up to 10% of all strokes. Delayed cerebral vasospasm, which is the most critical clinical complication that occurs after SAH, seems to be associated with both impaired dilator and increased constrictor mechanisms in cerebral arteries. Mechanisms contributing to development of vasospasm and abnormal reactivity of cerebral arteries after SAH have been intensively investigated in recent years. In the present review we focus on recent advances in our knowledge of the roles of nitric oxide (NO) and cGMP, endothelin (ET), protein kinase C (PKC) and potassium channels as they relate to SAH. 2. Nitric oxide is produced by the endothelium and is an important regulator of cerebral vascular tone by tonically maintaining the vasculature in a dilated state. Endothelial injury after SAH may interfere with NO production and lead to vasoconstriction and impaired responses to endothelium-dependent vasodilators. Inactivation of NO by oxyhaemoglobin or superoxide from erythrocytes may also occur in the subarachnoid space after SAH. 3. Nitric oxide stimulates activity of soluble guanylate cyclase in vascular muscle, leading to intracellular generation of cGMP and relaxation. Subarachnoid haemorrhage appears to cause impaired activity of soluble guanylate cyclase, resulting in reduced basal levels of cGMP in cerebral vessels and often decreased responsiveness of cerebral arteries to NO. 4. Endothelin is a potent, long-lasting vasoconstrictor that may contribute to the spasm of cerebral arteries after SAH. Endothelin is present in increased levels in the cerebrospinal fluid of SAH patients. Pharmacological inhibition of ET synthesis or of ET receptors has been reported to attenuate cerebral vasospasm. Production of and vasoconstriction by ET may be due, in part, to the decreased activity of NO and formation of cGMP. 5. Protein kinase C is an important enzyme involved in the contraction of vascular muscle in response to several agonists, including ET. Activity of PKC appears to be increased in cerebral arteries after SAH, indicating that PKC may be critical in the development of cerebral vasospasm. Recent evidence suggests that PKC activation may occur in cerebral arteries after SAH as a result of decreased negative feedback influence of NO/cGMP. 6. Cerebral arteries are depolarized after SAH, possibly due to decreased activity of potassium channels in vascular muscle. Decreased basal activation of potassium channels may be due to several mechanisms, including impaired activity of NO (and/or cGMP) or increased activity of PKC. Vasodilator drugs that produce hyperpolarization, such as potassium channel openers, appear to be unusually effective in cerebral arteries after SAH. 7. Thus, endothelial damage and reduced activity of NO may contribute to cerebral vascular dysfunction after SAH. Potassium channels may represent an important therapeutic target for the treatment of cerebral vasospasm after SAH.
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PMID:Subarachnoid haemorrhage: what happens to the cerebral arteries? 980 57

Tumor necrosis factor (TNF)-alpha, a pluripotent cytokine implicated in the pathogenesis of airway inflammation, has been shown to provoke hypersecretion of mucin by airway epithelial cells in vitro. In this study, we investigated potential signaling pathways mediating TNF-alpha-induced mucin secretion using guinea pig tracheal epithelial (GPTE) cells in air-liquid interface culture. Exogenously applied TNF-alpha (human recombinant) stimulated mucin secretion in a concentration-dependent manner, with maximal effects at 10 to 15 ng/ml (286 to 429 U/ml). The pathway of stimulated secretion appeared to involve generation of intracellular nitric oxide (NO), activation of soluble guanylate cyclase (GC-S), production of cyclic guanosine monophosphate (cGMP), and activation of cGMP-dependent protein kinase (PKG). TNF-alpha increased production of nitrite and nitrate by GPTE cells; both mucin secretion and cGMP production were attenuated by NG-monomethyl-L-arginine (1 mM), a competitive inhibitor of nitric oxide synthase (NOS), or by the GC-S inhibitor LY83583 (50 microM); and mucin secretion in response to TNF-alpha or to the cGMP analogue dibutyryl cGMP (100 and 500 microM) was attenuated by the specific PKG inhibitor KT5823 (1 microM). Increased mucin secretion and increased cGMP production in response to TNF-alpha both appeared to be mediated by a phospholipase C that hydrolyzes phosphatidylcholine (PC-PLC), and by protein kinase C (PKC), since both responses were attenuated by either D609 (10 and 20 microg/ml), a specific PC-PLC inhibitor, or by each of three PKC inhibitors: Calphostin C (0.3 and 0.5 microM), bisindoylmaleimide (GF 109203X, Go 6850; 20 nM), or Ro31-8220 (10 microM). Collectively, the results suggest that TNF-alpha stimulates secretion of mucin by GPTE cells via a mechanism(s) dependent on PC-PLC and PKC, and involving activation of NOS, generation of NO, production of cGMP, and activation of PKG.
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PMID:Tumor necrosis factor-alpha stimulates mucin secretion and cyclic GMP production by guinea pig tracheal epithelial cells in vitro. 1003 Aug 39


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