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)

Cycl AMP concentrations were elevated and acrosome reactions were induced in intact sea urchin spermatozoa by Nigericin, A23187, and pH 9.0 seawater. To determine whether or not the metabolism of cyclic AMP was being altered in sperm heads, the heads were mechanically separated from the flagella, and the flagella-less heads were then isolated by differential centrifugation. The isolated heads contained 1 to 2 nmol of ATP and 1 to 2 pmol of cyclic AMP/mg wet weight and retained these concentrations for several hours if stored at 0 degrees C. The flagella-less heads also retained the mitochondria of the midpiece area. The heads retained their functional status and could be stimulated to undergo acrosome reactions (filament extension) in response to Nigericin, A23187, or pH 9.0 seawater. Furthermore, the isolated heads could activate sea urchin eggs after induction of an acrosome reaction by Nigericin or pH 9.0 seawater. The isolated heads contained appreciable adenylate cyclase, cyclic AMP phosphodiesterase, cyclic GMP phosphodiesterase, guanylate cyclase, cyclic AMP-dependent protein kinase, and calmodulin. Nigericin, pH 9.0 seawater, and A23187 caused not only the induction of an acrosome reaction but also elevations of cyclic AMP in the isolated heads, and extracellular Ca2+ was an absolute requirement for both responses. At 16 degrees C, Nigericin caused elevations of cyclic AMP within 5 s, but maximal elevations were not observed until 1 min; it induced a maximal percentage of acrosome reactions by 40 s. Incubation of cells at 0 degrees C resulted in a delay of maximal acrosome reactions until between 10 and 20 min after addition of Nigericin. Under these conditions, maximal elevations of cyclic AMP were observed by 5 min, demonstrating that cyclic AMP elevations precede the complete morphological change associated with an acrosome reaction. ATP concentrations within the sperm heads declined in response to Nigericin, pH 9.0 seawater, or A23187, and its decrease also required the presence of extracellular Ca2+. The decline in ATP concentrations was slightly more rapid in the presence of rotenone, suggestive of some ATP synthetic capabilities of the isolated head preparation. 45Ca2+ uptake was increased by Nigericin elevated pH, and A23187 but was not appreciably altered by monensin. Monensin also did not cause appreciable elevations of cyclic AMP concentrations, induction of an acrosome reaction, or decreases of ATP concentrations. Here, we describe for the first time that cyclic AMP concentrations can be increased in flagella-less heads of spermatozoa and show that these changes are associated with an acrosome reaction.
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PMID:The elevation of cyclic AMP concentrations in flagella-less sea urchin sperm heads. 625 63

Slow-twitch soleus and fast-twitch extensor digitorum longus muscles of the rat were denervated unilaterally by sciatic nerve section at mid-thigh level. Activities of adenylate cyclase, guanylate cyclase, low Km and high Km cyclic AMP phosphodiesterase, and cyclic GMP phosphodiesterase were compared on the same, freshly prepared homogenates of denervated and shamoperated contralateral muscles one, two, three, or five days after surgery. As an early consequence of denervation, cyclic AMP metabolism was differentially affected in these different types of skeletal muscle. The adenylate cyclase activity of soleus muscle increased significantly by the second day following denervation and continued to rise through the fifth day, while this enzyme did not increase in denervated extensor digitorum longus even by the fifth day. The high Km cyclic AMP phosphodiesterase was already increased by day one in the denervated soleus, but not until the fifth day in the denervated extensor digitorum longus. Parallel increases beginning the first day were observed for the low Km cyclic AMP phosphodiesterase in both muscles. Since the activity of cytosolic cyclic AMP-dependent protein kinase of soleus muscle was also increased two days following denervation, the changes in cyclic AMP synthetic and degradative enzymes apparently result in a rise in intracellular cyclic AMP concentration. Alterations of the cyclic GMP enzymes following denervation were similar in the soleus and extensor digitorum longus, but were delayed relative to the increases in activity in the cyclic AMP enzymes.
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PMID:Effect of denervation on cyclic nucleotide metabolism in different types of skeletal muscle of the rat. 627 85

1. Our previous study demonstrated that YC-1, a derivative of benzylindazole, is a novel activator of soluble guanylate cyclase (sGC) in rabbit platelets. This work investigated whether the antiplatelet effect of YC-1 was mediated by a nitric oxide (NO)/sGC/cyclic GMP pathway in human platelets. 2. In human washed platelets, YC-1 inhibited platelet aggregation and ATP released induced by U46619 (2 microM), collagen (10 micro ml(-1)) and thrombin (0.1 u ml(-1)) in a concentration-dependent manner with IC50 values of (microM) 2.1 +/- 0.03, 11.7 +/- 2.1 and 59.3 +/- 7.1, respectively. 3. In a 30,000 g supernatant fraction from human platelet homogenate, YC-1 (5-100 microM) increased sGC activity in a concentration-dependent manner. At the same concentration-range, YC-1 elevated cyclic GMP levels markedly, but only slightly elevated cyclic AMP levels in the intact platelets. 4. MY-5445, a selective inhibitor of cyclic GMP phosphodiesterase, potentiated the increases in cyclic GMP caused by YC-1, and shifted the concentration-anti-aggregation curve of YC-1 to the left. In contrast, HL-725, a selective inhibitor of cyclic AMP phosphodiesterase, did not affect either the increases in cyclic nucleotides or the anti-aggregatory effect caused by YC-1. 5. Methylene blue, an inhibitor of sGC, blocked the increases of cyclic GMP caused by YC-1, and attenuated markedly the anti-aggregatory effect of YC-1. The adenylate cyclase inhibitor, 2',5'-dideoxyadenosine (DDA) did not affect YC-1-induced inhibition of platelet aggregation. 6. Haemoglobin, which binds NO, prevented the activation of sGC and anti-aggregatory effect caused by sodium nitroprusside, but did not affect YC-1 response. 7. These results would suggest that YC-1 activates sGC of human platelets by a NO-dependent mechanism, and exerts its antiplatelet effects through the sGC/cyclic GMP pathway.
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PMID:YC-1 inhibited human platelet aggregation through NO-independent activation of soluble guanylate cyclase. 864 Mar 34

In isolated adipocytes, the nitrosothiols S-nitroso-N-acetyl-penicillamine (SNAP) and S-nitrosoglutathione stimulate basal lipolysis, whereas the nitric oxide (NO.) donor 1-propamine, 3-(2-hydroxy-2-nitroso-1-propylhydrazine) (PAPA-NONOate) or NO gas have no effect. The increase in basal lipolysis due to nitrosothiols was prevented by dithiothreitol but not by a guanylate cyclase inhibitor. In addition the cyclic GMP-inhibited low Km, cyclic AMP phosphodiesterase activity was inhibited by SNAP suggesting that SNAP acting as NO+ donor increases basal lipolysis through a S-nitrosylation mediated inhibition of phosphodiesterase. Contrasting with these findings, SNAP reduced both isoproterenol-stimulated lipolysis and cyclic AMP production, whereas it failed to modify forskolin-, dibutyryl cyclic AMP-, or isobutylmethylxanthine-stimulated lipolysis, suggesting that SNAP interferes with the beta-adrenergic signal transduction pathway upstream the adenylate cyclase. In contrast with SNAP, PAPA-NONOate or NO gas inhibited stimulated lipolysis whatever the stimulating agents used without altering cyclic AMP production. Moreover PAPA-NONOate slightly reduces (30%) the hormone-sensitive lipase (HSL) activity indicating that stimulated lipolysis inhibition by NO. is linked to both inhibition of the HSL activity and the cyclic AMP-dependent activation of HSL. These data suggest that NO. or related redox species like NO+/NO- are potential regulators of lipolysis through distinct mechanisms.
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PMID:Modulation of white adipose tissue lipolysis by nitric oxide. 959 81

Lack of endothelial nitric oxide synthase (eNOS) may affect the sensitivity of cyclic GMP signaling through soluble guanylyl cyclase (sGC). We hypothesized that in eNOS knockout (eNOS-/-) mice, stimulation of guanylyl cyclase would have enhanced effects inhibiting cardiac contraction. We measured cell shortening and calcium transients in isolated ventricular myocytes from adult eNOS-/- and wild-type (WT) mice after stimulating particulate guanylyl cyclase (pGC) with C-type natriuretic peptide (CNP, 10(-8) and 10(-7) M) or sGC with S-nitroso-N-acetyl-penicillamine (SNAP, NO donor, 10(-6) and 10(-5) M). Although sGC activity was increased by +71% in eNOS-/-, SNAP had similar effects in the two groups (%shortening -39% control vs. -37% eNOS-/-), suggesting that the cyclic GMP pathway was desensitized in eNOS-/- myocytes. CNP had significantly smaller effects on cell contraction (%shortening -34% control vs. -14% eNOS-/-) and pGC activity was not changed in eNOS-/- myocytes. Similar effects were also produced by guanylin and carbon monoxide, stimulators of pGC and sGC. CNP's effects on Ca(2+) transients were also attenuated in eNOS-/- myocytes. SNAP did not alter Ca(2+) transients in eNOS-/- or control cells. In the eNOS-/- mice, cyclic GMP-dependent protein kinase and cyclic AMP phosphodiesterase activity were reduced. This study demonstrated that the downstream cyclic GMP pathway was attenuated in eNOS-/- mice and this was partially compensated for by increased sGC, but not pGC activity in ventricular myocytes.
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PMID:Alterations in ventricular myocyte contraction caused by C-type natriuretic peptide and nitric oxide in eNOS-/- mice. 1623 10

Cyclic nucleotides (cAMP and cGMP) are the main second messengers linked to vasodilatation. They are synthesized by cyclases and degraded by different types of phosphodiesterases (PDE). The effect of PDE inhibition and cyclases stimulation on 5-hydroxytryptamine (5-HT; 1 microM) and histamine (10 microM) contracted arteries was analysed. Stimulation of guanylate cyclase or adenylate cyclase relaxed the histamine- and 5-HT-induced contractions indicating that intracellular increase of cyclic nucleotides leads to vasodilatation of the human umbilical artery. We investigated the role of different PDE families in the regulation of this effect. The presence of the different PDE types in human umbilical artery smooth muscle was analysed by RT-PCR and the expression of PDE1B, PDE3A, PDE3B, PDE4C, PDE4D and PDE5A was detected. The unspecific PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX; 50 microM) relaxed histamine-contracted human umbilical artery on 47.4+/-7.2%. This effect seems to be due to PDE4 and PDE5 inhibition because among the selective PDE inhibitors used only the PDE4 inhibitor (rolipram; 1 microM) and the PDE5 inhibitors (dipyridamole and T0156; 3 microM and 1 microM respectively) induced significant relaxation (39.0+/-8.7, 30.4+/-6.0 and 36.3+/-2.8 respectively). IBMX, dipyridamole and T0156 produced similar relaxation on 5-HT-induced contraction. After forskolin, the addition of IBMX or rolipram increased the effect of the adenylate cyclase stimulator and almost completely relaxed the human umbilical artery contracted by histamine (92.5+/-4.9 and 90.9+/-4.7 respectively), suggesting a main role of PDE4. The data obtained with 5-HT contracted arteries confirmed this, because only rolipram and IBMX significantly increased the forskolin vasodilator effect. The administration of dipyridamole and T0156 after sodium nitroprusside (SNP) induced a significant increase of the SNP relaxant effect on histamine-contracted arteries, but PDE1 and PDE3 inhibition did not increase the effect of the guanylate cyclase stimulator. Similar effects were obtained in 5-HT contracted arteries, the SNP induced relaxation was increased by the PDE5 inhibition, but not by PDE1 or PDE3 inhibition. In summary, our results demonstrate that: 1) the increase of cAMP and/or cGMP levels induces relaxation of the human umbilical vascular smooth muscle; 2) four families of PDE are expressed in this smooth muscle: PDE1, PDE3, PDE4 and PDE5; 3) between these families, PDE4 and PDE5 are the key enzymes involved in the regulation of the relaxation associated to cAMP and cGMP, respectively.
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PMID:PDE4 and PDE5 regulate cyclic nucleotides relaxing effects in human umbilical arteries. 1823 84


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