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:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We attempted to identify and establish the role of cyclic nucleotide phosphodiesterase (PDE) isozymes in human basophils by using standard biochemical techniques as well as describing the effects of isozyme-selective and nonselective inhibitors of PDE. The nonselective PDE inhibitors, theophylline and 3-isobutyl-1-methylxanthine, inhibited anti-IgE-induced release of histamine and leukotriene C4 (LTC4) from basophils. This inhibition was accompanied by elevations in cAMP levels. Rolipram, an inhibitor of the low Km cAMP-specific PDE (PDE IV), inhibited the release of both histamine and LTC4 from activated basophils and increased cAMP levels in these cells. In contrast, mediator release from basophils was not inhibited by either siguazodan or SK&F 95654, inhibitors of the cGMP-inhibited PDE (PDE III) or zaprinast, an inhibitor of the cGMP-specific PDE (PDE V). SK&F 95654 failed to elevate basophil cAMP in these experiments whereas zaprinast induced significant increases in cAMP content. The inhibitory effect of rolipram on mediator release was potentiated by siguazodan or SK&F 95654, but not by zaprinast. SK&F 95654 also enhanced the ability of rolipram to increase cAMP content. Forskolin, a direct activator of adenylate cyclase, inhibited IgE-dependent release of mediators from basophils and increased cAMP levels in these cells. These effects were enhanced by rolipram, but not by SK&F 95654 or zaprinast. The cell permeant analog of cAMP, dibutyryl cAMP, inhibited mediator release from these cells, a property not shared by either dibutyryl-cGMP or sodium nitroprusside, an activator of soluble guanylate cyclase. The presence of both PDE III and PDE IV was confirmed by partially purifying and characterizing PDE activity in broken cell preparations. Overall, these data lend support to the hypothesis that cAMP inhibits mediator release from basophils and suggest that the major PDE isozyme responsible for regulating cyclic AMP content in these cells is PDE IV, with a minor contribution from PDE III. However, the finding that zaprinast caused increases in cAMP without inhibiting mediator release indicates that cAMP accumulation is not invariably linked to an inhibition of basophil activation.
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PMID:Preliminary identification and role of phosphodiesterase isozymes in human basophils. 137 72

The formation of new blood capillaries (angiogenesis) occurs in response to angiogenic factors released by either normal or tumoral cells. In the present study, we cultured human umbilical vein endothelial cells (HUVEC) on collagen gels and aimed to clarify the effects of cyclic nucleotides on angiogenesis induced by endothelial cell growth factor (ECGF). HUVEC invaded the underlying collagen matrix and formed tube-like structures when ECGF was added. ECGF (9.4 to 75 micrograms/ml) induced angiogenesis in a concentration-dependent manner; the effect reached a plateau at 75 micrograms/ml. Cyclic AMP (10(-3) M), dibutyryl cyclic AMP (10(-3) M), 8-bromo cyclic AMP (10(-5) M) and Sp-cAMPS (10(-3) M), a stimulator of cyclic AMP-dependent protein kinase, each significantly inhibited ECGF-induced angiogenesis by 64.2, 86.1, 46.5, 74.7%, respectively. Forskolin and cholera toxin, which are activators of adenylate cyclase, did not inhibit ECGF-induced angiogenesis. Dibutyryl cyclic GMP (10(-4), 10(-3) M) also did not affect the formation of capillary-like tubes induced by ECGF. In conclusion, cyclic AMP, but not cyclic GMP, inhibits angiogenesis in vitro. This antiangiogenic activity may be applicable to the treatment of such conditions as solid tumors, diabetic retinopathy and rheumatoid arthritis in which the suppression of angiogenesis is important.
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PMID:Adenosine 3':5'-cyclic monophosphate inhibits in vitro angiogenesis induced by endothelial cell growth factor. 138 60

Forskolin and milrinone both increase cyclic AMP concentrations to enhance cardiac contractility and cause vascular dilation in vitro and in vivo. However, forskolin acts via direct stimulation of adenylate cyclase while milrinone inhibits phosphodiesterase (PDE-III) activity. The forskolin analog, 7-desacetyl-7-(O-propionyl)-hydroxyl-aminocarbonyl-forskolin (P87-7692) has also been shown to directly stimulate adenylate cylase and increase cyclic AMP production in isolated cardiac tissue; however, the in vivo activity of this compound has not been described. Thus, the purpose of this study was to compare the cardiovascular effects of equivalent doses of these compounds and to further characterize the cardiotonic activity of P87-7692 in the anesthetized dog. It was found that both i.v. (3-30 micrograms/kg) and intracoronary (0.1-30 micrograms) administration of milrinone, forskolin, and P87-7692 caused dose-related positive inotropic, coronary, and peripheral vasodilator effects in anesthetized dogs; however, P87-7692 produced significantly greater and more sustained cardiotonic activity following a single 30-micrograms/kg, i.v., bolus injection when compared to the same dose of milrinone and forskolin. Analysis of the dose-response relationship between the changes in contractile force and heart rate for these compounds revealed that a 50% augmentation in contractile force was associated with increases in heart rate of 2.1% for milrinone, 6.4% for P87-7692, and 13.7% for forskolin. These data indicate an improved separation between the chronotropic and inotropic effects for P87-7692 as compared to forskolin. All three compounds also produced coronary vasodilation in vivo and in vitro; however, P87-7692 consistently showed greater activity relative to the same doses of milrinone and forskolin. Moreover, P87-7692 was significantly (p less than 0.05) more potent at relaxing KC1-precontracted canine coronary rings, with an EC50 of 2.1 x 10(-7) M as compared to 1.1 x 10(-6) M for forskolin and 3.2 x 10(-6) M for milrinone. The results of these studies indicate that structural modification of the forskolin molecule can increase the separation between positive inotropic and chronotropic effects, improve the overall hemodynamic profile, and prolong the duration of cardiotonic activity for this class of compounds.
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PMID:Cardiotonic and coronary vasodilator responses to milrinone, forskolin, and analog P87-7692 in the anesthetized dog. 138 77

In A-431 cells, platelet-activating factor (PAF) induces the expression of c-fos and TIS-1 genes in both the absence and the presence of cycloheximide in a structurally specific and receptor-coupled manner. We have now investigated the molecular mechanisms of this response, particularly in relation to the role of protein kinases. Pretreatment of cells with genistein or methyl-2,5-dihydroxycinnamate (tyrosine kinase inhibitors) or staurosporine (a protein kinase C inhibitor) for 20 min abolished the c-fos expression induced by PAF. Interestingly, when genistein was added 90 s after addition of PAF, no inhibition was observed. Similarly, staurosporine did not inhibit c-fos expression when added 8 min after PAF addition to the cells. These inhibitions were dose-dependent (IC50 for staurosporine was 180 nM, and for genistein 50 microM). Simultaneous addition of PAF and phorbol 12-myristate 13-acetate (PMA) did not give a synergistic effect on c-fos expression. Pretreatment of cells with PMA had no effect on [3H]PAF binding, but abolished the PAF-induced gene expression. PAF-stimulated gene expression was desensitized if cells were pretreated with PAF. Interestingly, epidermal growth factor was able to stimulate c-fos expression in PAF-desensitized cells, and thus indicated involvement of distinct mechanisms for the two stimuli. Forskolin, an activator of adenylate cyclase, did not induce c-fos expression and had no effect on the PAF response. Exposure of cells to PAF for as little as 1 min, followed by its removal, was sufficient to activate the gene expression and demonstrated the rapidity and the exquisite nature of the signalling involved in this process. It is concluded that activation of PAF receptor (a proposed G-protein-coupled receptor) causes rapid production of signals which induce the expression of c-fos gene and that this is mediated via tyrosine kinase and protein kinase C.
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PMID:Involvement of tyrosine kinase and protein kinase C in platelet-activating-factor-induced c-fos gene expression in A-431 cells. 138 9

Odors activate at least two distinct transduction pathways in lobster olfactory receptor cells that, respectively, excite and inhibit the cell. Data presented suggest that odors selectively activate the inhibitory conductance through the second messenger cAMP. Not all cells support both odor-evoked excitatory and inhibitory conductances; in the current investigation, about 50% of the cells tested were inhibited by odors. In the majority of cells that, as a group, support an inhibitory response to odor stimulation, activation of adenylate cyclase with forskolin or inhibition of phosphodiesterase activity with 3-isobutyl-1-methylxanthine (IBMX) elicits an outward current with a time course similar to that of odor-evoked outward currents. The membrane-permeant cyclic nucleotide analogs 8-Br-cAMP and 8-Br-cGMP have a similar effect. Forskolin and IBMX enhance the magnitude of odor-evoked outward currents when the drug and the odor are copresented to the cell. In contrast, these same drugs have little or no effect on cells that, as a group, fail to support an inhibitory response to odor stimulation. This study provides the first direct evidence implicating cAMP in olfactory transduction in an invertebrate and contrasts with similar studies in vertebrates that have implicated cAMP as a second messenger mediating excitation.
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PMID:Cyclic nucleotides mediate an odor-evoked potassium conductance in lobster olfactory receptor cells. 138 77

The alterations of second-messenger ligand binding and cerebral blood flow (CBF) were evaluated in the gerbil brain after 2-h unilateral common carotid artery occlusion. [3H]Forskolin (FK) and [3H]phorbol-12,13-dibutyrate (PDBu) were used as specific ligands for adenylate cyclase (AC) and protein kinase C (PKC) activity estimation, respectively. CBF was determined at the end of the experiment by the [14C]iodoantipyrine method. A quantitative autoradiographic method permitted simultaneous measurement of the three parameters in the same brain. The levels in the caudate-putamen, globus pallidus, and hippocampus were analyzed. The animals were divided into three groups: Group 1 with severe ischemia (CBF in the lateral nuclei of the thalamus (CBFt) less than 50 ml/100 g/min), Group 2 with mild ischemia (CBFt greater than or equal to 50 ml/100 g/min), and the Sham Group. The PDBu binding revealed a statistically significant increase in the caudate-putamen, lateral nuclei of the thalamus and hippocampus (CA1 and CA3 regions and dentate gyrus) on the ischemic side in Group 1 as compared to that in Group 2 and the Sham Group. In contrast, the FK binding did not show any significant changes in any of the regions. These data and our previous findings for 6-h ischemia suggest that (1) PKC translocation to the cell membrane may occur at the early ischemic phase in particular regions including the caudate-putamen, lateral nuclei of the thalamus and hippocampus, with the translocated PKC gradually diminishing during the subsequent ischemic period; and (2) the suppression of the AC system observed in 6-h ischemia may not appear in the early ischemic phase.
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PMID:Alteration of second-messenger ligand binding following 2-hr hemispheric ischemia in the gerbil brain. 139 61

In GH3 cells and other clonal rat pituitary tumor cells, TRH has been shown to mediate its effects on prolactin release via a rise of cytosolic Ca2+ and activation of protein kinase C. In this study, we examined the role of protein kinase C in TRH-stimulated prolactin release from female rat primary pituitary cell culture. Both TRH and PMA stimulated prolactin release in a dose-dependent manner. When present together at maximal concentrations, TRH and PMA produced an effect which was slightly less than additive. Pretreatment of rat pituitary cells with 10(-6) M PMA for 24 hrs completely down-regulated protein kinase C, since such PMA-pretreated cells did not release prolactin in response to a second dose of PMA. Interestingly, protein kinase C down-regulation had no effect on TRH-induced prolactin release from rat pituitary cells. In contrast, PMA-pretreated GH3 cells did not respond to a subsequent stimulation by either PMA or TRH. Pretreatment of rat pituitary cells with TRH (10(-7) M, 24 hrs) inhibited the subsequent response to TRH, but not PMA. Forskolin, an adenylate cyclase activator, stimulated prolactin release by itself and in a synergistic manner when incubated together with TRH or PMA. The synergistic effects of forskolin on prolactin release was greater in the presence of PMA than TRH. Down-regulation of protein kinase C by PMA pretreatment abolished the synergistic effect produced by PMA and forskolin but had no effect on those generated by TRH and forskolin. sn-1,2-Dioctanylglycerol (DOG) pretreatment attenuated the subsequent response to DOG and PMA but not TRH. The effect of TRH, but not PMA, on prolactin release required the presence of extracellular Ca2+. In conclusion, the mechanism by which TRH causes prolactin release from rat primary pituitary cells is different from that of GH3 cells; the former is a protein kinase C-independent process whereas the latter is at least partially dependent upon the activation of protein kinase C.
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PMID:PMA-sensitive protein kinase C is not necessary in TRH-stimulated prolactin release from female rat primary pituitary cells. 145 79

Electrical stimulation patterned after the hippocampal theta rhythm produces a robust and stable long-term potentiation (LTP) effect. Pharmacological manipulations were used in the present studies in an effort to relate characteristics of the responses occurring during theta stimulation to the magnitude of potentiation which follows it. Comparisons were made using five or ten bursts of stimulation which respectively induce sub-maximal or near maximal degrees of LTP. DPCPX, a drug that increases release by blocking adenosine A1 receptors, was used to enhance the depolarization produced by individual theta bursts. This resulted in a marked increase in the amount of stable LTP induced by five theta bursts but did not affect that resulting from ten bursts. This finding suggested that depolarization occurring during a burst response influences per burst potentiation but not the ceiling on maximum LTP. Aniracetam, a nootropic drug that enhances responses via an action on glutamate (AMPA) receptors, was used to test this conclusion. Like DPCPX, aniracetam increased the size of the burst response and enhanced the degree of LTP caused by five but not ten theta bursts. Forskolin, an activator of adenylate cyclase, was used to test the effects of blocking the hyperpolarization normally present between theta bursts on the induction of LTP. The drug augmented the degree of LTP resulting from five theta bursts and, in contrast to DPCPX and aniracetam, nearly doubled that obtained with ten bursts. Thus the drug affected both per burst potentiation and the ceiling on LTP. These results are discussed in terms of an hypothesis in which the magnitude of NMDA receptor mediated currents affects the degree of potentiation produced by individual theta bursts while the duration of the currents is related to the limit on the maximum LTP induced by a series of bursts. The possible implications of the findings for learning are also considered.
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PMID:Factors regulating the magnitude of long-term potentiation induced by theta pattern stimulation. 148 79

1. Cultured epithelia derived from whole human sweat glands, isolated secretory coils, isolated reabsorptive ducts and whole glands from cystic fibrosis (CF) subjects have been used to examine drug sensitivity by use of short circuit current recording. 2. Short circuit current increases were observed with lysylbradykinin, carbachol and histamine in epithelia of different origins. All responses were due to stimulation of electrogenic sodium absorption, evidenced by the inhibition of these responses by amiloride. The latter also abolished the basal current. The terpenes, thapsigargin and forskolin had no effect on transport. 3. The stimulation of a sodium current by agonists was dependent upon calcium, responses being inhibited by lanthanum ions and EGTA. Further A23187 induced a sodium current. 4. Pronounced oscillations in the sodium currents were a feature of the responses, implying synchronous, regulated cell activity. 5. Forskolin produced a ten fold increase in adenylate cyclase activity. All agonists listed in 2 except forskolin caused an increase in intracellular calcium [Ca]i, [Ca]i responses in CF cells were not different from those of normal cells, except with thapsigargin where the responses were smaller. 6. It is concluded that in culture, cells develop ductal characteristics, whether derived from normal or CF glands, coils or ducts. An increase in [Ca]i followed by activation of calcium-sensitive potassium channels and apical membrane hyperpolarization may be the major mechanism for increasing sodium influx.
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PMID:Ion transport in cultured epithelia from human sweat glands: comparison of normal and cystic fibrosis tissues. 164 63

The present study identified physiological factors which influence the generation (and degradation) of cyclic AMP (cAMP) in the arterial chemoreceptor tissue of the mammalian carotid body. Experiments established a 3-way correlation between cAMP generation, neurotransmitter release from chemoreceptor cells, and carotid sinus nerve (CSN) activity. Incubation of carotid bodies in vitro for 10 min in media equilibrated with different low O2 ('hypoxic') gas mixtures (5% O2 or 10% O2, balance N2) elevated basal cAMP levels (100% O2 media) in proportion to the stimulus intensity. Similar experiments using nodose sensory ganglia showed that low O2 stimulation did not alter cAMP levels in this non-chemosensory tissue. However, the adenylate cyclase (AC) activator, forskolin (10 microM), evoked large increases in the cyclic nucleotide content in both carotid bodies and nodose ganglia. After chronic (10 days) CSN denervation or sympathectomy, the basal levels of cAMP in the carotid body were elevated; the cAMP response to low O2 media (stimulus minus control) was increased after CSN denervation but remained unaltered after sympathectomy. The effects of zero Ca2+ media on cAMP generation was examined in order to assess whether feedback from released neurotransmitters acting on known (presynaptic) type I cell receptors could have contributed to the observed changes in cAMP. Basal levels of cAMP were increased 2.8-fold, and the response to hypoxic stimulation was elevated 5-fold, in the absence of extracellular Ca2+. Forskolin (10 microM) did not alter basal release of [3H]-catecholamines ([3H]CA; synthesized from [3H]tyrosine), or resting CSN discharge; however, stimulus-evoked [3H]CA release and CSN discharge were potentiated in the presence of forskolin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The role of cyclic AMP in chemoreception in the rabbit carotid body. 164 48


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