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)

Folic acid and cAMP are chemoattractants in Dictyostelium discoideum, which bind to different surface receptors. The signal is transduced from the receptors via different G proteins into a common pathway which includes guanylyl cyclase and acto-myosin. To investigate this common pathway, ten mutants which do not react chemotactically to both cAMP and folic acid were isolated with a simple new chemotactic assay. Genetic analysis shows that one of these mutants (KI-10) was dominant; the other nine mutants were recessive, and comprise nine complementation groups. In wild-type cells, the chemoattractants activate adenylyl cyclase, phospholipase C, and guanylyl cyclase in a transient manner. In mutant cells the formation of cAMP and IP3 were generally normal, whereas the cGMP response was altered in most of the ten mutants. Particularly, mutant KI-8 has strongly reduced basal guanylyl cyclase activity; the enzyme is present in mutant KI-10, but can not be activated by cAMP or folic acid. The cGMP response of five other mutants is altered in either magnitude, dose dependency, or kinetics. These observations suggest that the second messenger cGMP plays a key role in chemotaxis in Dictyostelium.
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PMID:Non-chemotactic Dictyostelium discoideum mutants with altered cGMP signal transduction. 790 39

We have recently found the calcium dependent glycogenolytic effect of a pancreastatin on rat hepatocytes and the mobilization of intracellular calcium. To further investigate the mechanism of action of pancreastatin on liver we have studied its effect on guanylate cyclase, adenylate cyclase, and phospholipase C, and we have explored the possible involvement of GTP binding proteins by measuring GTPase activity as well as the effect of pertussis toxin treatment of plasma liver membranes on the pancreastatin stimulated GTPase activity and the production of cyclic GMP and myo-inositol 1,4,5-triphosphate. Pancreastatin stimulated GTPase activity of rat liver membranes about 25% over basal. The concentration dependency curve showed that maximal stimulation was achieved at 10(-7)M pancreastatin (EC50 = 3 nM). This stimulation was partially inhibited by treatment of the membranes with pertussis toxin. The effect of pancreastatin on guanylate cyclase and phospholipase C were examined by measuring the production of cyclic GMP and myo-inositol 1,4,5-triphosphate respectively. Pancreastatin increased the basal activity of guanylate cyclase to a maximum of 2.5-fold the unstimulated activity at 30 degrees C, in a time- and dose-dependent manner, reaching the maximal stimulation above control with 10(-7) M pancreastatin at 10 min (EC50 = 0.6 nM). This effect was completely abolished when rat liver membranes had been ADP-ribosylated with pertussis toxin. On the other hand, adenylate cyclase activity was not affected by pancreastatin. Phospholipase C activity of rat liver membranes was rapidly stimulated (within 2-5 min) at 30 degrees C by 10(-7) M pancreastatin, reaching a maximum at 15 min.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pancreastatin activates pertussis toxin-sensitive guanylate cyclase and pertussis toxin-insensitive phospholipase C in rat liver membranes. 791 48

In Dictyostelium discoideum extracellular cyclic AMP (cAMP), as shown by previous studies, induces a transient accumulation of intracellular cyclic guanosine-5'-monophosphate (cGMP), which peaks at 10 s and recovers basal levels at 30 s after stimulation, even with persistent cAMP stimulation. Additional investigations have shown that the cAMP-mediated cGMP response is built up from surface cAMP receptor-mediated activation of guanylyl cyclase and hydrolysis of cGMP by phosphodiesterase. The regulation of these activities was measured in detail on a seconds time-scale, demonstrating complex adaptation of the receptor, allosteric activation of cGMP-phosphodiesterase by cGMP, and potent inhibition of guanylyl cyclase by Ca2+. In this paper we present a computer model that combines all experimental data on the cGMP response. The model is used to investigate the contribution of each structural and regulatory component in the final cGMP response. Four models for the activation and adaptation of the receptor are compared with experimental observations. Only one model describes the magnitude and kinetics of the response accurately. The effect of Ca2+ on the cGMP response is simulated by changing the Ca2+ concentrations outside the cell (Ca2+ influx) and in stores (IP3-mediated release) and changing phospholipase C activity. The simulations show that Ca2+ mainly determines the magnitude of the cGMP accumulation; simulations are in good agreement with experiments on the effect of Ca2+ in electropermeabilized cells. Finally, when cGMP-phosphodiesterase activity is deleted from the model, the simulated cGMP response is elevated and prolonged, which is in close agreement with the experimental observations in mutant stmF that lacks this enzyme activity. We conclude that the computer model provides a good description of the observed response, suggesting that the main structural and regulatory components have been identified.
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PMID:A model for cAMP-mediated cGMP response in Dictyostelium discoideum. 791 38

Calcium can influence the cGMP/guanylate cyclase system in many tissues, including rat colon. The mechanisms involved in this phenomenon, however, are unclear. To further elucidate the mechanisms involved in the Ca(2+)-induced activation of rat colonic particulate guanylate cyclase, isolated colonocytes were incubated with Ca2+ or other agents, and crude membrane prepared and analyzed for particulate guanylate cyclase activity. Alternatively, the test agents were directly added to the guanylate cyclase reaction mixture containing isolated membranes. The results of these studies demonstrated: (i) extracellular Ca2+ (1 and 2 mM) increased basal particulate guanylate cyclase activity; (ii) increases in intracellular Ca2+ induced by 10 microM thapsigargin activated this enzyme; (iii) preincubation of the cells with 50 nM staurosporine, a broad-spectrum inhibitor of protein kinases, including protein kinase C (PKC), or 5 microM U73122, a specific inhibitor of phosphoinositide-phospholipase C-dependent processes, blocked the Ca(2+)-induced increase in particulate guanylate cyclase activity; (iv) incubation of cells with 1 microM 12-O-tetradecanoyl phorbol 13-acetate (TPA), an activator of PKC, stimulated guanylate cyclase; (v) no additivity in stimulation of this enzyme was observed when cells were concomitantly incubated with 1 microM TPA and 2 mM extracellular Ca2+; (vi) incubation of membranes with 250 nM TPA, in the presence of 0.2 mM Ca2+, 6 mM Mg2+, and 1 mM ATP, activated guanylate cyclase; and (vii) incubation of membranes with purified rat brain PKC further augmented this stimulation. These results indicate that Ca2+ activates rat colonic particulate guanylate cyclase, at least in part, via a PKC-dependent mechanism.
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PMID:Protein kinase C mediates the calcium-induced activation of rat colonic particulate guanylate cyclase. 794 95

The role of intracellular signal transduction mechanisms in regulating the motility and metabolism of rat spermatozoa in undiluted caudal epididymal fluid (CEF) was examined. Samples of CEF containing immotile spermatozoa were exposed to drugs and other agents that either stimulate signal transduction pathways or mimic the action of their second messengers. Under these conditions, sperm motility in 25-30 nl of CEF was stimulated by calcium ions (Ca2+), N2,2'-O-dibutyrylguanosine 3':5'-cyclic monophosphate (dibutyryl cGMP), cyclic adenosine 3':5'-monophosphate (cAMP), N6,2'-O-dibutyryladenosine 3':5'-cyclic monophosphate (dibutyryl cAMP), 8-bromoadenosine 3':5'-cyclic monophosphate (8-bromo cAMP), caffeine, theophylline and bicarbonate ions (HCO3-). Other agents such as magnesium ions (Mg2+), veratridine, phospholipase C (PLC), ionophore A23187, 1,2-dioctenoyl-sn-glycerol (DAG), phorbol 12-myristate 13-acetate, phospholipase A2 (PLA2), arachidonic acid, and melittin did not significantly influence motility. In the presence of radiolabelled energy substrates, untreated (immotile) spermatozoa in samples of CEF utilised D-[U-14C]glucose and [1-14C]acetate as exogenous energy sources for oxidative metabolism. No detectable 14C-lactate was produced, and none of the drugs altered the rate of glycolytic or oxidative metabolism. The findings suggest that the motility of rat caudal epididymal spermatozoa is regulated by Ca2+ and the guanylate cyclase and adenylate cyclase pathways, but not through the PLC and PLA2 pathways. Also, their metabolism of exogenous substrate was uncoupled from the induction of motility, and their oxidative capacity exceeded the rate of flux of glucose-carbon through the glycolytic pathway.
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PMID:Intracellular signal transduction mechanisms of rat epididymal spermatozoa and their relationship to motility and metabolism. 804 68

1. Kinins exert a contractile effect on rabbit aortic rings via the stimulation of B1 receptors. Des-Arg9-bradykinin (BK) is more potent than BK on this receptor type. The mode of action of des-Arg9-BK on rabbit aortic tissue has been studied by both the aortic ring contractility assay and a cellular model using cultured aortic smooth muscle cells (SMCs). 2. The des-Arg9-BK-induced contractions in rabbit aortic rings were unaffected by pretreatments with nifedipine, indomethacin, REV-5901 (a 5-lipoxygenase blocker) and LY-83583 (a guanylyl cyclase inhibitor); however, the protein kinase inhibitors H-7 and H-9 significantly reduced the maximal effect of des-Arg9-BK. 3. The contractile responses to des-Arg9-BK in calcium-free Krebs solution were slightly but not significantly attenuated in amplitude, as compared to paired control tissues bathed in Krebs solution, and sustained plateaus of contraction were observed in the absence of Ca2+. However, Ca2+ replenishment further increased the kinin-induced contraction measured in Ca(2+)-free bathing fluid. 4. Despite the lack of evidence of a mediating role for prostaglandin in the mechanical response to des-Arg9-BK, the kinin stimulated the release of prostacyclin from rabbit aorta rings measured as immunoreactive 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha). 5. Smooth muscle cells (SMCs) derived from the rabbit aorta exhibit functional responses to des-Arg9-BK in acute release of 6-keto-PGF1alpha and of inositol phosphate turnover which were inhibited by pretreatment with the B1 receptor antagonist, Lys[Leu8]des-Arg9-BK, but not by the B2 receptor antagonist, Hoe-140. Preincubation of the cells with interleukin- 1 (IL-1) 20 h before stimulation with the kinin had no effect on basal inositol phosphate turnover, but potentiated the acute effect of des-Arg9-BK.6. These results suggest that second mesengers derived from the action of phospholipase C are produced by SMCs when B1 receptors are activated in rabbit aortic tissue. Intracellular calcium stores are primarily mobilized by des-Arg9-BK, although receptor-controlled calcium influx has not been ruled out, and may contribute to initiate the contractile responses. The maintenance of the contractile state involves protein kinase C activity and is consistent with a current model of SMC function. The cell model retains some of the cardinal properties of B1 receptor-mediated vascular responses: endothelium independent PGI2 release and up-regulation by the cytokine IL-1. PGI2 is not involved in the mechanical response, possible because the rabbit aorta is refractory to this prostaglandin.
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PMID:Vascular mode of action of kinin B1 receptors and development of a cellular model for the investigation of these receptors. 810 48

The present studies were performed to determine whether the major biologically active metabolite of vitamin D3, 1,25-dihydroxycholecalciferol [1,25(OH)2D3], could influence the activities of rat colonic particulate guanylate cyclase and adenylate cyclase. To address these issues, colonocytes were harvested from Sprague-Dawley rats and suspended in Krebs-Ringer bicarbonate buffer. The cells were then treated with 1,25(OH)2D3 or other agents (see below) and crude membranes were prepared and analyzed for particulate guanylate cyclase and adenylate cyclase activities. The results of these studies demonstrated that: 1) 1,25(OH)2D3, in a concentration-dependent manner, rapidly (within minutes) stimulated guanylate, but not adenylate cyclase activity; 2) preincubation of the cells with staurosporine, a protein kinase inhibitor, or U73122, an inhibitor of phosphoinositide-phospholipase C-dependent processes, blocked the increase in guanylate cyclase activity induced by 1,25(OH)2D3; and 3) 12-O-tetradecanoyl phorbol 13-acetate and 1,2-dioctanoyl-sn-glycerol, known activators of protein kinase C, also rapidly stimulated rat colonic particulate guanylate cyclase activity. Taken together, these results demonstrate that 1,25(OH)2D3 rapidly stimulates together, these results demonstrate that 1,25(OH)2D3 rapidly stimulates rat colonic particulate guanylate cyclase, at least in part, via a protein kinase C-dependent mechanism.
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PMID:1,25-Dihydroxycholecalciferol rapidly activates rat colonic particulate guanylate cyclase via a protein kinase C-dependent mechanism. 810 80

Olfactory transduction in invertebrates seems to be similar to that in vertebrates. Three signalling systems involving activation of adenylate cyclase, phospholipase C and guanylate cyclase are present. A variety of second messengers, including cAMP, inositol 1,4,5-trisphosphate, diacylglycerol, nitric oxide and Ca2+, have been identified but their target sites and mode of action are not yet fully understood. The central projections of olfactory signals in invertebrates are relatively simple and perhaps more hard-wired than in vertebrates. Information about circuitry and functional mapping in the olfactory pathway is lacking. This is essential for understanding the sensory code and higher olfactory functions. Neurogenetic analysis has provided useful insights into olfaction and olfactory learning.
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PMID:Olfaction in invertebrates. 821 21

L-Amino acids are potent olfactory stimuli for Atlantic salmon. A plasma membrane fraction, previously shown to be rich in amino acid binding sites, was prepared from olfactory rosettes of Atlantic salmon (Salmo salar) and utilized to investigate the role of phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis in olfactory signal transduction. A cocktail of L-amino acids (Ser, Glu, Lys, and Gly) stimulated PIP2 hydrolysis by phospholipase C (PLC) in a dose-dependent manner with half-maximal stimulation when all amino acids were present at approximately 1 microM. Stimulation of PIP2 hydrolysis by amino acids required GTP gamma S, which alone had no effect on PLC activity. Unlike GTP gamma S, AlF4- and Ca2+ stimulated PIP2 breakdown. Preincubation with 1 mM GDP beta S eliminated the effect of amino acids and AlF4- on PIP2 hydrolysis, suggesting the involvement of G protein regulation. The lack of stimulation by GTP gamma S alone suggested that there was negligible exchange of GTP gamma S for GDP in the absence of odorant. There were no significant effects of amino acids on either adenylate cyclase or guanylate cyclase activities in the membrane preparation under these conditions. The effect of the amino acid cocktail was maximal at 1-10 nM free Ca2+. At or above 100 nM free Ca2+, no effect of amino acids on PIP2 hydrolysis was found. However, between 100 nM and 100 microM, Ca2+ directly stimulated PLC activity in a dose-dependent manner. This stimulation by Ca2+ appeared to be G protein independent because it did not require GTP gamma S and was not inhibited by GDP beta S.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Stimulation of Ca(2+)-regulated olfactory phospholipase C by amino acids. 824 Nov 23

In Dictyostelium discoideum extracellular cAMP induces chemotaxis via a transmembrane signal transduction cascade consisting of surface cAMP receptors, G-proteins and effector enzymes including adenylyl cyclase, guanylyl cyclase and phospholipase C. Previously it was demonstrated that some cAMP derivatives such as 3'-deoxy-3'-aminoadenosine 3':5'-monophosphate (3'NH-cAMP) bind to the receptor and induce normal activation of adenylyl cyclase and guanylyl cyclase. However these analogues do not induce chemotaxis, probably because the signal is transduced in an inappropriate manner. We have now studied the regulation of phospholipase C by cAMP and these chemotactic antagonists. cAMP induced the two-fold activation of phospholipase C leading to a transient increase of Ins(1,4,5)P3 levels. In contrast, the analogues induced a rapid decrease of intracellular Ins(1,4,5)P3 levels, due to the inhibition of phospholipase C activity. In a transformed cell-line lacking the G-protein that mediates phospholipase C inhibition, 3'NH-cAMP did not decrease phospholipase C activity and was no longer an antagonist of chemotaxis. These results suggest that inhibition of phospholipase C leads to aberrant chemotaxis.
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PMID:Chemotactic antagonists of cAMP inhibit Dictyostelium phospholipase C. 838 94


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