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)

Heat-stable enterotoxins activate guanylate cyclase, whereas heat-labile enterotoxins stimulate adenylate cyclase. Both classes of toxins cause secretory diarrhea at least in part by stimulating Cl- secretion in the intestine. The mechanism for regulation of Cl- secretion by guanosine 3',5'-cyclic monophosphate (cGMP) was investigated using cultured T84 intestinal cells as a model for intestinal crypt cells. Escherichia coli heat-stable enterotoxin (ST) markedly stimulated cGMP production in T84 cells. Cl- secretion across T84 cell monolayers cultured on permeable filters was stimulated by E. coli ST, cholera toxin, or 8-BrcAMP, but 8-BrcGMP was ineffective. cGMP analogues that are known to be potent and specific activators of cGMP-dependent protein kinase (cG-kinase) also had little effect on 36Cl- uptake by T84 cells cultured in plastic dishes. E. coli ST, forskolin, cholera toxin, or membrane-permeant cAMP analogues markedly increased 36Cl- uptake into T84 cells. The general protein kinase inhibitor, staurosporine, inhibited the stimulation of Cl- permeability elicited by E. coli ST, vasoactive intestinal peptide (VIP), or 8-BrcAMP. DEAE-Sephacel chromatography revealed a predominant type II isoform of cAMP-dependent protein kinase (cA-kinase) in T84 cells, whereas little or no cytosolic cG-kinase activity was found. Treatment of T84 cells with E. coli ST or VIP resulted in an increase in the cA-kinase activity ratio (-cAMP/+cAMP) if the cytosolic enzyme was assayed at reduced temperature (on ice).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Stimulation of intestinal Cl- transport by heat-stable enterotoxin: activation of cAMP-dependent protein kinase by cGMP. 132 20

Cyclic GMP (cGMP) mediates the relaxing action of a variety of vasodilator drugs and endogenous vasodilator substances. Cyclic AMP (cAMP) mediates relaxation by beta-adrenergic agonists as well as other activators of adenylate cyclase. Both second messengers appear to reduce the concentration of intracellular Ca2+ in vascular smooth muscle cells, thus affecting relaxation. The presence of cGMP-dependent protein kinase in vascular smooth muscle cells is required for the reduction of Ca2+ by cAMP and cGMP, suggesting that this enzyme mediates the relaxing effects of both cyclic nucleotides. Although the specific substrate proteins for cGMP-dependent protein kinase are not well characterized in vascular smooth muscle, new evidence indicates that Ca2(+)-ATPase activation by phosphorylation of phospholamban by the kinase may underlie the mechanism of action of cyclic-nucleotide-dependent relaxation.
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PMID:Towards an understanding of the mechanism of action of cyclic AMP and cyclic GMP in smooth muscle relaxation. 184 22

The major action of forskolin, the diterpine activator of adenylate cyclase, in primary (unpassaged) rat aortic smooth muscle cells is to reduce vasopressin-stimulated Ca2+ concentrations. In repetitively passaged cells, however, forskolin by itself increased Ca2+ levels by apparently stimulating Ca2+ uptake into the cell and had much smaller effects on inhibiting vasopressin-stimulated Ca2+ elevations. Both primary and passaged smooth muscle cells contained adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase. Guanosine 3',5'-cyclic monophosphate (cGMP)-dependent protein kinase was greatly reduced or absent in passaged smooth muscle cells. The introduction of purified cGMP-dependent protein kinase into the cytoplasm of passaged cells prevented forskolin from elevating intracellular Ca2+ and restored the capacity of forskolin to reduce vasopressin-stimulated Ca2+ mobilization. Similar effects were observed for isoproterenol in passaged smooth muscle cells. When introduced into cells, the active catalytic subunit of the cAMP-dependent protein kinase did not lead to reductions in Ca2+ levels. These results suggest that cAMP elevations lead to profound changes in Ca2+ metabolism through activation of both cAMP- and cGMP-dependent protein kinases. Activation of cGMP-dependent protein kinase by cAMP leads to the reduction in intracellular Ca2+, whereas activation of cAMP-dependent protein kinase may only mediate the uptake of Ca2+ from extracellular sources.
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PMID:cGMP-dependent protein kinase mediates the reduction of Ca2+ by cAMP in vascular smooth muscle cells. 215 36

The slow inward Ca2+ current, ICa, is fundamental in the initiation of cardiac contraction and neurohormonal regulation of cardiac function. It is increased by beta-adrenergic agonists, which stimulate synthesis of cyclic AMP (cAMP) and cAMP-dependent phosphorylation. The neurotransmitter acetylcholine reduces ICa by an unknown mechanism. There is strong evidence that acetylcholine reduces ICa by decreasing adenylate cyclase activity, but cGMP has also been implicated as ACh stimulates cGMP accumulation and activates cGMP-dependent protein kinase. Application of cGMP decreases contractile force, decreases Ca flux, shortens the duration of action potentials and inhibits Ca-dependent action potentials. Other studies, however, have concluded that cGMP levels do not correlate with contractile force and that cGMP has no effect on ICa. We have therefore examined the effects of intracellular perfusion of cGMP on ICa using isolated, voltage-clamped cells from frog ventricle. We find that cGMP has negligible effects on basal ICa, but greatly decreases the ICa that had been elevated by beta-adrenergic agonists or by intracellular perfusion with cAMP. The decrease of ICa is mediated by cAMP hydrolysis via a cGMP-stimulated cyclic nucleotide phosphodiesterase.
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PMID:Opposite effects of cyclic GMP and cyclic AMP on Ca2+ current in single heart cells. 242 89

Modifications in characteristics and activities of beta-adrenergic receptors and certain parameters of the cyclic nucleotide systems were observed in the hypertrophied heart of the rat chronically treated with T4. These include: 1) an increased number of beta-adrenergic receptors without a change in their affinity, as determined by binding of (-)-[3H]dihydroalprenolol to the membrane; 2) increased sensitivity and magnitude of stimulation of adenylate cyclase in homogenates by isoproterenol, without a change in the basal or NaF-stimulated (total) enzyme activity; 3) decreased formation of cAMP and decreased activation of cAMP-dependent protein kinase in the minced heart stimulated by isoproterenol, probably due to decreased myocardial ATP concentration; 4) decreased activity of cAMP phosphodiesterase in the particulate fraction; 5) decreased activity of cGMP-dependent protein kinase in both the soluble and particulate fractions, accompanied by decreased activity of cAMP-dependent protein kinase in the particulate fraction; 6) decreased activity of the stimulatory modulator of cGMP-dependent protein kinase and, conversely, increased activity of the inhibitory modulator of cAMP-dependent protein kinase; and 7) increased sensitivity accompanied by decreased maximum tension development of the ventricular strip to contract in response to isoproterenol. These alterations largely disappeared upon regression of the hyperthyroid state. It is suggested that the above changes, many of which were the opposite of those reported earlier for the desensitized and hypertrophied rat heart caused by isoproterenol, may in part consitute the molecular basis for the reputed catecholamine supersensitivity of the heart in the hyperthyroid state.
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PMID:Thyroxine-induced changes in characteristics and activities of beta-adrenergic receptors and adenosine 3',5'-monophosphate and guanosine 3',5'-monophosphate systems in the heart may be related to reputed catecholamine supersensitivity in hyperthyroidism. 624 45

Na+/H+ exchanger (NHE) activity is regulated by several types of receptors directly coupled to distinct classes (i.e. Gs, Gi, Gq, and G12) of heterotrimeric (alpha beta gamma) GTP-binding proteins (G proteins), which, upon activation, modulate production of various second messengers (e.g. cAMP, cGMP, diacylglycerol, inositol trisphosphate, and Ca2+). Recently, four isoforms of the rat Na+/H+ exchanger were identified by molecular cloning. To examine their intrinsic responsiveness to G protein and second messenger stimulation, three of these isoforms, NHE-1, -2, and -3, were stably expressed in mutant Chinese hamster ovary cells devoid of endogenous NHE activity (AP-1 cells). Incubation of cells with either AIF4-, a general agonist of G proteins, or cholera toxin, a selective activator of G alpha s that stimulates adenylate cyclase, accelerated the rates of amiloride-inhibitable 22Na+ influx mediated by NHE-1 and -2, whereas they inhibited that by NHE-3. Similarly, short term treatment with phorbol 12-myristate 13-acetate, which mimics diacylglycerol activation of protein kinase C (PKC), or with agents (i.e. forskolin, 8-(4-chlorophenylthio)-cAMP, and isobutylmethylxanthine) that lead to activation of cAMP-dependent protein kinase (PKA) also stimulated transport by NHE-1 and NHE-2 but depressed that by NHE-3. The effects of phorbol 12-myristate 13-acetate were blocked by depleting cells of PKC or by inhibiting PKC using chelerythrine chloride, confirming a role for PKC in modulating NHE isoform activities. Likewise, the PKA antagonist, H-89, attenuated the effects of elevated cAMPi on NHE-1, -2, and -3, further demonstrating the regulation by PKA. Unlike cAMPi, elevation of cGMPi by treatment with dibutyryl-cGMP or 8-bromo-cGMP had no influence on NHE isoform activities, thereby excluding the possibility of a role for cGMP-dependent protein kinase in these cells. These data support the concept that the NHE isoforms are differentially responsive to agonists of the PKA and PKC pathways.
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PMID:Plasma membrane Na+/H+ exchanger isoforms (NHE-1, -2, and -3) are differentially responsive to second messenger agonists of the protein kinase A and C pathways. 749 49

Na+/Ca2+ exchange contributes to the control of cytosolic free Ca2+ levels ([Ca2+]i) in resting and activated cultured human mesangial cells. We have previously shown that activation of phospholipase C by vasoconstrictors enhances Ca2+ influx upon extracellular Na+ withdrawal. This effect is not mediated by concurrent activation of protein kinase (PK) C, since it occurs even after PKC inhibition, and phorbol esters actually blunt both basal and stimulated Na+/Ca2+ exchange. We now studied the effects of PKA and PKG activation by adenylate/guanylate cyclase stimuli or by permeant analogues of cyclic nucleotides in monolayer cultures loaded with the fluorescent Ca(2+)-sensitive probe, fura-2. The exchanger was inhibited by the stable prostaglandin I2 analogue, iloprost, which is transduced by cAMP (peak [Ca2+]i inhibition by 1 microM iloprost 35 +/- 3%). Similarly, non-receptor activation of adenylate cyclase by 10 microM forskolin inhibited basal and agonist-stimulated Na+/Ca2+ exchange by 52 +/- 4 and 66 +/- 4%, respectively. Dibutyryl-cAMP (0.1 mM) also inhibited stimulated Na(+)-dependent Ca2+ influx by 72 +/- 2%. The particulate guanylate cyclase agonist, atriopeptin III, and the soluble guanylate cyclase activator, glyceryltrinitrate, also inhibited both basal and angiotensin II-stimulated Na+Ca2+ exchange (to a maximum of 53 +/- 5 and 62 +/- 3%, respectively). Dibutyryl-cGMP (1 mM) mimicked the effects of cGMP stimuli, reducing stimulated Na+/Ca2+ exchange by 79 +/- 2%. Therefore, similar to PKC, cyclic nucleotide activation of PKA and PKG regulates Na+/Ca2+ exchange, providing a functional link between transmembrane signalling systems for vasoactive agents in cultured human mesangial cells.
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PMID:Cyclic nucleotides inhibit Na+/Ca2+ exchange in cultured human mesangial cells. 752 69

Nitric oxide (NO) and angiotensin II (AII) can effect vascular smooth muscle cell (SMC) proliferation. However, the effects of such agents on SMC migration, an equally important phenomenon with regard to vascular pathophysiology, have received little attention. The objectives of the present study were: (a) to determine whether NO inhibits AII-induced migration of vascular SMCs; (b) to investigate the mechanism of the interaction of NO and AII on SMC migration; and (c) to evaluate the AII receptor subtype that mediates AII-induced SMC migration. Migration of rat SMCs was evaluated using a modified Boydens Chamber (transwell inserts with gelatin-coated polycarbonate membranes, 8 microns pore size). AII stimulated SMC migration in a concentration-dependent manner, and this effect was inhibited by sodium nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine (SNAP). In the presence of L-arginine, but not D-arginine, IL-1 beta, an inducer of inducible NO synthase, also inhibited AII-induced SMC migration, and this effect was prevented by the NO-synthase inhibitor, N-nitro-L-arginine methyl ester. The effects of NO donors on AII-induced SMC migration were mimicked by 8-bromo-cGMP. Also, the antimigratory effects of SNAP were partially inhibited by LY83583 (an inhibitor of soluble guanylyl cyclase) and by KT5823 (an inhibitor of cGMP-dependent protein kinase). Although 8-bromo-cAMP (cAMP) also mimicked the antimigratory effects of NO donors, the antimigratory effects of SNAP were not altered by 2',5'-dideoxyadenosine (an inhibitor of adenyl cyclase) or by (R)-p-adenosine-3',5'-cyclic phosphorothioate (an inhibitor of the cAMP-dependent protein kinase). Low concentrations of the subtype AT1-receptor antagonist CGP 48933, but not the subtype AT2-receptor antagonist CGP 42112, blocked AII-induced SMC migration. These findings indicate that (a) NO inhibits AII-induced migration of vascular SMCs; (b) the antimigratory effect of NO is mediated in part via a cGMP-dependent mechanism; and (c) AII stimulates SMC migration via an AT1 receptor.
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PMID:Nitric oxide inhibits angiotensin II-induced migration of rat aortic smooth muscle cell. Role of cyclic-nucleotides and angiotensin1 receptors. 761 84

In a previous study, we demonstrated that a high concentration (> or = 1 microM) of isoproterenol (ISO) produced a dual effect on L-type Ca2+ current (ICa(L)) in vascular smooth muscle (VSM) cells from the portal vein: an initial stimulatory action followed by a sustained inhibition. The first stimulatory phase was fast (presumably more direct) and may reflect G-protein gating of the Ca2+ channels. The second inhibitory phase was slower (presumably more indirect) and may be mediated by the adenylate cyclase/cAMP pathway. In order to define further the mechanism for the ISO inhibition of ICa(L), the effects of cyclic nucleotides and their related protein kinases were examined in freshly isolated single smooth muscle cells from the rabbit portal vein using the whole-cell voltage clamp technique. To isolate ICa(L), the pipette solution contained high Cs+ (to block K+ outward current), and the bath contained physiological salt solution. Upon extracellular application of membrane-permeable cAMP and cGMP analogs (8-Br-cAMP and 8-Br-cGMP, 3 mM), ICa(L) was significantly inhibited by 27.9 +/- 5.0 and 33.5 +/- 4.8%, respectively. Forskolin (100 microM) also depressed ICa(L). The protein kinase inhibitor, H-7, prevented the inhibitory effects of both cyclic nucleotides and forskolin. In addition, intracellular application (via the patch pipettes) of cAMP-dependent protein kinase (PK-A, catalytic subunit; 1.76 microM) and cGMP-dependent protein kinase (PK-G, 50 nM, pre-activated by 10 microM cGMP) significantly inhibited the peak amplitude of ICa(L) by 45.5 +/- 10 and 43.2 +/- 6.2%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of L-type calcium channels by cyclic nucleotides and phosphorylation in smooth muscle cells from rabbit portal vein. 791 17

Embryonic quail neural crest cells migrate towards the negative pole of an imposed dc electric field as small as 7 mV/mm (0.4 mV per average cell length). The involvement of protein kinases in the mechanism utilized by these cells to detect and respond to such imposed fields was tested through the use of several kinase inhibitors. Evidence for the involvement of protein kinase C (PKC) included: (1) inhibition of the directed motility by 1 microM sphingosine that was reversed by the addition of the phorbol ester, PMA; (2) stimulation of a faster response to the imposed field by PMA; and (3) inhibition of the directed translocation by 5 microM H-7. However, another PKC inhibitor, staurosporine, did not inhibit the directed translocation (1 nM-1 microM). We also found evidence for the involvement of either cAMP- or cGMP-dependent protein kinase. The galvanotactic response was partially inhibited by the addition of 10 microM H-9 and the response was enhanced in the presence of the phosphodiesterase inhibitor, IBMX. However, the adenylate cyclase stimulant, forskolin, had no significant influence on the directed motility, although it reduced the average cell velocity. While these experiments suggest that cAMP- or cGMP-dependent protein kinase or PKC may be involved in the galvanotaxis response, two other protein kinases appeared not to be required. The myosin light chain kinase inhibitor, ML-7, had no effect on the directed motility in an imposed field, so myosin light chain kinase may not be required for galvanotaxis. Similarly, 5 microM W-7 had no significant effect on the directed translocation, suggesting that calmodulin-dependent protein kinase is not involved. Interestingly, the continuous activity of a protein kinase is apparently not required for the directed translocation response. The addition of the PKC and cAMP-dependent protein kinase inhibitor, H-7, after the cells had been exposed to the field for 1 hour, had no effect on the subsequent directed translocation. Thus, for these inhibitors to block the directed translocation, they must be present at the same time as the initial field application. This implies that an integral step in the cellular response mechanism for galvanotaxis involves the stimulation of a protein kinase whose effect is long lasting.
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PMID:Protein kinases are required for embryonic neural crest cell galvanotaxis. 831 67


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