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:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of calmodulin on the integral cGMP-activated conductance of ROS plasma membrane has been investigated by using the "patch-clamp" techniques (inside-out configuration). Calmodulin increased the apparent Michaelis constant (Km) from 19 +/- 1.5 (in the absence of calmodulin) to 33.7 +/- 5.5 mM. However, it did not influence the Hill coefficient and the maximum conductance of cGMP-channels. Ca2+ ions were required for the calmodulin effect (EC(50)= 452 +/- 47 nM). The results of our experiments with the use of 8-Br-cGMP and IBMX suggest that the modulating action of calmodulin was not mediated by the ROS phosphodiesterase activation. The action of some calmodulin inhibitors has been tested. On the basis of our study calmodulin is suggested to be very significant for the recovery and light adaptation processes by changing the affinity of the cGMP-channel for agonist.
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PMID:Modulation of the cGMP-activated conductance of the plasma membrane of photoreceptor cells by calmodulin. 913 56

Transient elevations of intracellular Ca2+ play an important role in regulating the sensitivity of olfactory transduction, but such elevations have not been demonstrated in the olfactory cilia, which are the site of primary odor transduction. To begin to understand Ca2+ signaling in olfactory cilia, we used high-resolution imaging techniques to study the Ca2+ transients that occur in salamander olfactory receptor neurons (ORNs) as a result of cyclic nucleotide-gated (CNG) channel activation. To visualize ciliary Ca2+ signals, we loaded ORNs with the Ca2+ indicator dye Fluo-3 AM and measured fluorescence with a laser scanning confocal microscope. Application of the phosphodiesterase inhibitor IBMX increased fluorescence in the cilia and other neuronal compartments; the ciliary signal occurred first and was more transient. This signal could be abolished by lowering external Ca2+ or by applying LY83583, a potent blocker of CNG channels, indicating that Ca2+ entry through CNG channels was the primary source of fluorescence increases. Direct activation of CNG channels with low levels of 8-Br-cGMP (1 microM) led to tonic Ca2+ signals that were restricted locally to the cilia and the dendritic knob. Elevated external K+, which depolarizes cell membranes, increased fluorescence signals in the cell body and dendrite but failed to increase ciliary Ca2+ fluorescence. The results demonstrate the existence and spatiotemporal properties of Ca2+ transients in individual olfactory cilia and implicate CNG channels as a major pathway for Ca2+ entry into ORN cilia during odor transduction.
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PMID:Calcium entry through cyclic nucleotide-gated channels in individual cilia of olfactory receptor cells: spatiotemporal dynamics. 915 31

In the retina of newborn rats there is evidence for two mechanisms of programmed cell death. Apoptosis of ganglion cells (RGCs) following axotomy depends on protein synthesis. In contrast, inhibition of protein synthesis leads to apoptosis in the neuroblastic layer (NBL). The induction of apoptosis following translational arrest suggests that post-translational modifications of apoptosis-associated proteins may be crucial to the cell death programs in the developing retina. We investigated the possible role of protein kinases upon apoptosis in retinal explants in vitro. An increase in the intracellular concentration of cAMP produced either by the adenylyl-cyclase activator forskolin (10 microM) or by 8-Br-cAMP (1 mM), prevented apoptosis induced in the NBL by inhibition of protein synthesis, but had no statistically significant effect upon RGC death. In contrast, neither 8-Br-cGMP (1 mM) nor the specific cGMP-phosphodiesterase inhibitor zaprinast (10-100 microM) had significant effects on apoptosis in the retina. The cAMP-phosphodiesterase inhibitors isobutylmethylxantine (IBMX, 0.1-1 mM) and Ro-201724 (50-200 microM) also prevented apoptosis in the NBL. The isoquinolinesulfonamide H89 (20 microM), a specific cAMP-dependent protein kinase inhibitor, partially reverted the protective effect of either forskolin or IBMX within the NBL. Neither 12-O-tetradecanoyl phorbol-13-acetate (TPA, 10 nM) nor bisindolylmaleimide (0.2-0.5 microM), respectively an activator and an inhibitor of protein kinase C had significant effects upon the retinal explants. The protein kinase inhibitor 2-aminopurine (2-AP, 10 mM) prevented apoptosis of axotomized ganglion cells and induced apoptosis in the NBL. Forskolin prevented the apoptosis induced by 2-AP in the NBL, whereas TPA had no effect. The effects of 2-AP were, however, not dependent on inhibition of protein synthesis. The data indicate that modulation of the activity of both cAMP-dependent protein kinase and several protein kinases sensitive to 2-aminopurine selectively affect apoptosis in distinct cell layers of the developing retina.
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PMID:Protein kinases selectively modulate apoptosis in the developing retina in vitro. 922 Apr 54

Quantitative autoradiography was used to characterize and localize [3H]cGMP binding sites in the rat brain. [3H]cGMP binding was found to be pH-sensitive (with two optima at 7.4 and 5.0) and Mg2+-dependent. At pH 7.4, the binding was dependent on inclusion of the phosphodiesterase inhibitor IBMX. In contrast, at pH 5.0, IBMX had little effect on binding. The binding of [3H]cGMP was reversible and saturable with a Kd of 22 nM at pH 7.4 and 36 nM at pH 5.0. Bmax values were 172 fmol/mg at pH 7.4 and 462 fmol/mg at pH 5.0. [3H]cGMP binding was inhibited by cGMP and its analogues, with cGMP and cAMP being the most potent at pH 7.4 and cGMP and 8-Br-cGMP being the most potent at pH 5.0. Using an extracellular pH 7.4 buffer, the selective cGMP-dependent protein kinase (PKG) inhibitor Rp-8pCPT-cGMPS had very little effect on [3H]cGMP binding. In contrast, with a cytosolic pH 5.0 buffer, Rp-8pCPT-cGMPS displaced binding in the cerebellum. This indicates that PKG is localized in the cerebellum, and that the binding to PKG is favored under cytosolic conditions. Autoradiographic localization of [3H]cGMP binding sites revealed a heterogeneous distribution with the highest densities in the substantia nigra and interpeduncular nucleus. High densities were also observed in the basal ganglia, the medial habenular nucleus, the frontoparietal cortex, the lateral amygdaloid nucleus and the subiculum. It is concluded that the nature of [3H]cGMP binding is complex, with one site probably being related to cytosolic PKG mainly found in the cerebellum, and one site probably representing cGMP-stimulated phosphodiesterase mainly located in the forebrain.
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PMID:Autoradiographic characterization of [3H]cGMP binding sites in the rat brain. 927 22

The stimulation of NMDA receptor increased [3H]GABA release from preloaded cultured retina cells. This effect appears to be mediated by NO production, since addition of L-NA reduces NMDA-evoked [3H]GABA release. Spermine/NO complex, an NO donor, mimics the effect produced by NMDA. The addition of zaprinast, a phosphodiesterase inhibitor, as well as 8-Br-cGMP enhances the NMDA-evoked [3H]GABA release. These results agree with the existence in chick retina cells of NO/cGMP pathways and support a role for NO in NMDA-evoked events. The activation of this receptor complex through maturative stages of the retina together with the NO-mediated increase in GABA release may account for NMDA differentiative effect in culturing retina cells.
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PMID:Nitric oxide mediates NMDA-evoked [3H]GABA release from chick retina cells. 940 48

Wild type and calmodulin mutants (cam) of Paramecium tetraurelia were examined for cold-sensitive responses. Among mutants tested, cam12 and cam13 mutants, which have substitutions in N-terminal lobe of calmodulin molecule, reduced both responses in the swimming and the membrane potential. Under voltage clamp conditions, the cooling stimulus to the wild type cell induced a transient inward current whose amplitude increased with the rate of temperature drop. The cam12 cell did not induce inward currents in response to cooling with a rate slower than -0.4 degree C/s. The reduced current response of cam12 mutant was restored by an external application of a phosphodiesterase inhibitor, theophylline. Also, an intracellular injection of hydrolysis-resistant cyclic nucleotides, either 8-bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP) or 8-bromoguanosine 3,5'-cyclic monophosphate (8-Br-cGMP), restored the current response. Such restoration was accompanied by shifts of the resting potential to hyperpolarized levels and by an increase in the membrane conductance. The results suggest the possibility that calmodulin and cyclic nucleotide regulate K+ channels responsive to the cooling stimulus.
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PMID:Defect of cold-sensitive response in calmodulin mutants of Paramecium and the restoration by cyclic nucleotide. 943 53

Soluble guanylyl cyclase (GC) is a heme-containing protein that is a predominant target of nitric oxide (NO). This study examined whether the reductant, ascorbate (ASC), the oxidant, dehydroascorbate (DHAA), or other redox agents modulated the sensitivity of isolated rat coronary arteries to NO-induced vasodilations. Based on NO measurements with a NO-sensitive electrode, NO dilated the arteries with a pEC50 of 8.24 +/- 0.05. The potency of NO was significantly enhanced in the presence of ASC (pEC50 = 8.70 +/- 0.02) but was diminished in the presence of DHAA (pEC50 = 7.91 +/- 0.15). The potency of NO was not affected by other redox agents including dithiothreitol, beta-mercaptoethanol, diamide, 1-chloro-2,4-dinitrobenzene, ferricyanide, or ferrocyanide. Experiments involving the cyclic guanosine monophosphate (cGMP) analog, 8-Br-cGMP, and the phosphodiesterase inhibitor, isobutyl-methylxanthine, indicated that neither ASC nor DHAA has an effect on the degradation or potency of cGMP. ASC and DHAA also failed to affect vasodilations induced by diltiazem or forskolin. However, ASC and DHAA affected the potency of NO in human mesenteric arteries. The results are consistent with other evidence that ASC and DHAA affect the redox state of GC, and through this modulate arterial sensitivity to NO. This suggests that the regulation of the redox state of GC may be an additional site of modulation of the NO/cGMP pathway.
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PMID:Ascorbate and dehydroascorbate modulate nitric oxide-induced vasodilations of rat coronary arteries. 1044 82

Phototransduction in Drosophila is mediated by a G-protein-coupled phospholipase C transduction cascade in which each absorbed photon generates a discrete electrical event, the quantum bump. In whole-cell voltage-clamp recordings, cAMP, as well as its nonhydrolyzable and membrane-permeant analogs 8-bromo-cAMP (8-Br-cAMP) and dibutyryl-cAMP, slowed down the macroscopic light response by increasing quantum bump latency, without changes in bump amplitude or duration. In contrast, cGMP or 8-Br-cGMP had no effect on light response amplitude or kinetics. None of the cyclic nucleotides activated any channels in the plasma membrane. The effects of cAMP were mimicked by application of the non-specific phosphodiesterase inhibitor IBMX and the adenylyl cyclase activator forskolin; zaprinast, a specific cGMP-phosphodiesterase inhibitor, was ineffective. Bump latency was also increased by targeted expression of either an activated G(s) alpha subunit, which increased endogenous adenylyl cyclase activity, or an activated catalytic protein kinase A (PKA) subunit. The action of IBMX was blocked by pretreatment with the PKA inhibitor H-89. The effects of cAMP were abolished in mutants of the ninaC gene, suggesting this nonconventional myosin as a possible target for PKA-mediated phosphorylation. Dopamine (10 microM) and octopamine (100 microM) mimicked the effects of cAMP. These results indicate the existence of a G-protein-coupled adenylyl cyclase pathway in Drosophila photoreceptors, which modulates the phospholipase C-based phototransduction cascade.
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PMID:Modulation of the light response by cAMP in Drosophila photoreceptors. 1051 99

1. The sensitivity of the soluble guanylate cyclase (sGC)-cyclic guanosine-3',5'-monophosphate (cyclic GMP) system to nitric oxide (NO) was investigated in mouse aorta from wild type (WT) and NO synthase (NOS) knockout (KO) animals. 2. The NO donor, spermine-NONOate (SPER-NO) was more potent in aortas from eNOS KO mice compared to WT (pEC50 7.30+/-0.06 and 6.56+/-0.04, respectively; n=6; P<0.05). In contrast, the non-NO based sGC activator, YC-1 was equipotent in vessels from eNOS WT and KO mice. The sensitivity of aortas from nNOS and iNOS KO animals to SPER-NO was unchanged. Forskolin (an adenylate cyclase activator), was equipotent in vessels from eNOS WT and KO animals. 3. The cyclic GMP analogue, 8-Br-cGMP was equipotent in eNOS WT and KO mice (pEC50 4. 38+/-0.04 and 4.40+/-0.05, respectively; n=5; P>0.05). Zaprinast (10-5 M) a phosphodiesterase type V (PDE V) inhibitor, had no effect on the response to SPER-NO in vessels from eNOS WT or KO mice. 4. The NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 3x10-4 M) increased the potency of SPER-NO in aortas from WT mice (pEC50 6. 64+/-0.02 and 7.37+/-0.02 in the absence and presence of L-NAME, respectively; n=4; P<0.05). 5. In summary, there is increased sensitivity of vessels from eNOS KO animals to NO. Cyclic AMP-mediated dilatation is unchanged, consistent with a specific up-regulation of sGC - cyclic GMP signalling. The functional activity of cyclic GMP-dependent protein kinase (G-kinase) and PDE V was also unchanged, suggesting that sGC is the site of up-regulation. These alterations in the sensitivity of the sGC - cyclic GMP pathway might represent a mechanism for the dynamic regulation of NO bioactivity.
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PMID:Autoregulation of nitric oxide-soluble guanylate cyclase-cyclic GMP signalling in mouse thoracic aorta. 1055 46

Earlier studies have demonstrated that nitric oxide (NO) exerts a fast-acting inhibitory influence on endothelial NO synthase (eNOS) enzymatic activity in isolated vascular tissue preparations. The present study was designed to examine the possible effect of NO on eNOS protein expression in cultured endothelial cells and intact animals. Human coronary endothelial cells were incubated with S-nitroso-N-acetyl-penicillamine (SNAP, an NO donor), oxyhemoglobin (HGB, an NO trapping agent), SNAP plus HGB, or inactive vehicle (control). In other experiments, cells were treated with 3-isobutyl-1-methylxanthine (a phosphodiesterase inhibitor), 1H-[1,2, 4]oxadiazolo-[4,3-2]quinoxalin-1-one (ODQ, a guanylate cyclase inhibitor), SNAP plus ODQ, 8-bromo-cGMP (8-Br-cGMP, a cell-permeable cGMP compound), 8-Br-cGMP plus HGB, or inactive vehicle in order to discern the effect of cGMP. The incubations were conducted for 24 hours, and total nitrate plus nitrite production and eNOS protein abundance (Western analysis) were measured. To determine the effect of NO on eNOS expression in vivo, rats were treated with either the NO donor isosorbide dinitrate or placebo by gastric gavage for 48 hours, and aortic eNOS protein expression was examined. The NO donor SNAP markedly depressed, whereas the NO scavenger HGB significantly raised, eNOS protein expression. The downregulatory action of SNAP was completely abrogated by HGB. Phosphodiesterase inhibitor and 8-Br-cGMP downregulated, whereas the guanylate cyclase inhibitor ODQ upregulated eNOS protein expression. The downregulatory action of SNAP was completely overcome by the guanylate cyclase inhibitor ODQ, and the upregulatory action of the NO scavenger HGB was abrogated by 8-Br-cGMP. Administration of NO donor resulted in a marked downregulation of aortic eNOS protein expression in intact animals, thus confirming the in vitro findings. NO serves as a negative-feedback regulator of eNOS expression via a cGMP-mediated process.
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PMID:cGMP-mediated negative-feedback regulation of endothelial nitric oxide synthase expression by nitric oxide. 1060 Nov 24


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