Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.11 (AMPK)
 12,425 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

When myofibrils from rat hearts were dissolved in concentrated salt solutions and reprecipitated by dilution, they contained both protein kinase (partly cyclic 3':5'-AMP-dependent) and protein phosphatase activities. Troponin-I was the major protein to be phosphorylated by the endogenous myofibril-associated kinase and by added protein kinase. Approximately 1 mole of phosphate per mole of troponin-I was incorporated from radioactive ATP, but the extent of troponin-I phosphorylation could be varied experimentally. An inverse correlation was found between protein phosphorylation and the maximum Ca2+-stimulated myofibrillar Mg2+-ATPase activity, while the amout of calcium required for half-maximum activation was proportional to the extent of protein phosphorylation. The changes in Mg2+-ATPase activity produced in vitro by protein phosphorylation were reproduced in isolated perfused rat hearts treated for short periods with L-noradrenaline (10(-6)M). The changes in myofibrillar function brought about as the result of the phosphorlyation by cAMP-dependent protein kinase suggest that the contractile response is desensitized in order to cope with the rise in intracellular Ca2+ which results from the action of catecholamines on cardiac ventricular cells.
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PMID:Cardiac myofibrillar phosphorylation and adenosine triphosphatase activity. 22 75

Isoprenaline and adrenaline produced an increase of cAMP content and a decrease of the activity of the endogenous inhibitor of cAMP-dependent protein kinase (type I inhibitor) in human lymphocytes and in rat heart. The maximal effect was seen at a concentration of 10(-6) M. Noradrenaline and dopamine required much higher concentration to elicite the same effect. The decrease of type I inhibitor activity was mediated through beta-adrenergic receptors because propranolol, but not phentolamine, blocked the effects produced by isoprenaline. Stimulation of beta-adrenergic receptors did not influence the activity of type II inhibitor.
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PMID:The effect of beta-receptor stimulation on the activity of the inhibitor of cAMP-dependent protein kinase. 612 59

The effect of acidosis and alkalosis on lipolysis, cAMP production and cAMP-dependent protein kinase activity in isolated rat fat cells incubated in the presence of norepinephrine and norepinephrine plus theophylline has been investigated. The pH of the incubation medium was adjusted to 6.8, 7.4 and 7.8 respectively. Acidosis inhibited both norepinephrine- and norepinephrine plus theophylline-induced release of glycerol whereas alkalosis led to slight stimulation. Norepinephrine produced an increase in cAMP and cAMP-dependent protein kinase activity. However, comparison of both parameters in acidosis and alkalosis with those at pH 7.4 indicates that they were higher at pH 7.8 and lower at pH 6.8. Addition of theophylline in combination with norepinephrine increases cAMP production within 5 min, under acidosis to values similar to those obtained at pH 7.4 with norepinephrine. The same effect on protein kinase activity was obtained. In spite of this increment in cAMP and protein kinase activity produced by addition of norepinephrine plus theophylline, lipolysis remains inhibited by acidosis. Addition of theophylline at pH 7.4 and 7.8 induced a much higher cAMP production and cAMP-dependent protein kinase activity although at pH 7.8 there was a statistically significant increase in protein kinase activity at 10 min it did not induce a significant increase in lipolysis. This is discussed and possible mechanisms are suggested to explain the effect of acidosis and alkalosis on the lipolysis induced by norepinephrine in rat fat cells.
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PMID:Effect of pH on lipolysis, cAMP and cAMP-dependent protein kinase activity in isolated rat fat cells. 616 23

We examined [3H]-noradrenaline ([3H]-NA) release from rat brain cortical synaptosomes permeated with streptolysin-O (SLO) under a variety of conditions. Three temperatures (20 degrees C, 25 degrees C, and 30 degrees C) were tested at different times of permeation. Lowering the incubation temperature to 20 degrees C decreased basal release, but Ca(2+)-induced [3H]-NA release increased slightly. Also, the incubation time to achieve the maximal ratio of Ca(2+)-induced release to basal release shifted to longer times with decreasing incubation temperature. If the synaptosomes were permeated with SLO before release was triggered, similar results were observed. Permeation at 20 degrees C allowed [gamma-32P] ATP and cAMP-dependent protein kinase (PKA) catalytic subunit to rapidly enter the synaptosomes to phosphorylate synapsins. Lactate dehydrogenase (LDH) efflux was time- and SLO-concentration dependent. The fact that 0.1 mM Cd2+ did not inhibit [3H]-NA release from permeabilized synaptosomes indicated that permeabilization by SLO was complete under these conditions. This also suggests that the release machinery involved after Ca2+ entry is not sensitive to Cd2+.
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PMID:[3H]-noradrenaline release from streptolysin-O permeated rat cortical synaptosomes: enhancement of the Ca(2+)-induced signal. 758 44

Enhancement of cAMP degradation by increased cGMP-inhibited cAMP phosphodiesterase (cGI-PDE) activity is thought to be an important component of the mechanism whereby insulin counteracts catecholamine-induced lipolysis in adipocytes. In this study the selective cGI-PDE inhibitor OPC3911 was used to evaluate this role of cGI-PDE activation in intact rat adipocytes with special reference to changes in cAMP levels measured as cAMP-dependent protein kinase (cAMP-PK) activity ratios. OPC3911 completely blocked (IC50 = 0.3 microM) the maximal inhibitory effect of insulin on noradrenaline-induced lipolysis and the net dephosphorylation of hormone-sensitive lipase and other intracellular target proteins for insulin action, whereas insulin-induced lipogenesis was not changed. The effect of OPC3911 on cAMP-PK activity ratios at different levels of lipolysis achieved by noradrenaline stimulation revealed that the reduction of cAMP-PK caused by 1 nM insulin was completely blocked by 3 microM OPC3911. The effect of OPC3911 was not due to an excessive increase in cellular cAMP resulting in 'supramaximal' lipolysis unresponsive to insulin. These data demonstrate that reduction in cAMP levels by the activation of cGI-PDE may be sufficient to account for the antilipolytic action of insulin.
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PMID:Evidence for the key role of the adipocyte cGMP-inhibited cAMP phosphodiesterase in the antilipolytic action of insulin. 771 14

In canine myocardium, the beta-subunit of the L-type Ca2+ channel is phosphorylated by cAMP dependent protein kinase in vitro as well as in vivo (Haase et al. FEBS Lett 335: 217-222, 1993). We have assessed the identity of the beta-subunit as well as its in vivo phosphorylation in representative experimental groups of catecholamine-challenged canine hearts. Adrenergic stimulation by high doses of both noradrenaline and isoprenaline induced rapid (within 20 sec) and nearly complete phosphorylation of the Ca2+ channel beta-subunit. Phosphorylation in vivo was about 4-fold higher as compared to untreated controls. When related to catecholamine-depleted (reserpine-treated) hearts noradrenaline and isoprenaline increased the in vivo phosphorylation of the beta-subunit even 8-fold. This phosphorylation correlated positively with tissue levels of cAMP, endogenous particulated cAMP-dependent protein kinase (PKA) and the rate of contractile force development dP/dtmax. The results imply the involvement of a PKA-mediated phosphorylation of the Ca2+ channel beta-subunit in the adrenergic stimulation of intact canine myocardium.
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PMID:In-vivo phosphorylation of the cardiac L-type calcium channel beta-subunit in response to catecholamines. 897 44

1. Cellular mechanisms underlying the enhancement by noradrenaline (NA) of inhibitory postsynaptic currents (IPSCs) were studied at inhibitory synapses in the molecular layer of the cerebellum. IPSCs were obtained from stellate cells in rat cerebellar slices using tight-seal whole-cell recording. 2. Miniature IPSCs (mIPSCs) were recorded in the presence of tetrodotoxin (TTX; 100 nM). NA (10 microM) markedly increased the frequency of mIPSCs, but did not alter their mean amplitude. Bath application of the inhibitor of adenylyl cyclase 9-(tetrahydro-2'-furyl) adenine (SQ 22,536; 300 microM), of the wide spectrum protein kinase inhibitor staurosporine (1 microM), and of the Rp-diastereomer of adenosine-3',5'-cyclic monophosphothioate (Rp-cAMPS; 500 microM), a specific inhibitor of cAMP-dependent protein kinase (PKA), inhibited the mIPSC frequency increase induced by NA. 3. The increase in mIPSC frequency was not attenuated by Cd2+ (100 microM), a blocker of voltage dependent calcium channels. However, after a 12-15 min pre-incubation in Ca(2+)-free saline, the effect of NA on mIPSCs was markedly inhibited. If Ca2+ ions were readmitted in the presence of NA, enhancement of the mIPSC frequency was largely restored. 4. Application of the membrane permeant analogue of cAMP, 8-Br-cAMP (1 mM), together with the inhibitor of cAMP phosphodiesterase, 3-isobutyl-1-methylxanthine (IBMX; 100 microM), caused a frequency increase of mIPSCs. Forskolin also mimicked the stimulatory effect of NA on mIPSC frequency. The effects of both 8-Br-cAMP and forskolin persisted in Ca(2+)-free saline, suggesting that the modulation of transmitter release does not require Ca2+ influx. 5. On the whole, the results indicate that the potentiation of mIPSC frequency by NA is mediated through the sequential activation of adenylyl cyclase and protein kinase A (PKA), and that PKA modulates the vesicle release mechanism rather than Ca2+ influx. The lack of effect of NA after prolonged incubation in Ca(2+)-free solution may be due to an inhibition of adenylyl cyclase by a gradual lowering of the cytosolic presynaptic Ca2+ concentration.
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PMID:Protein kinase A-mediated enhancement of miniature IPSC frequency by noradrenaline in rat cerebellar stellate cells. 902 76

1. Evidence for a 'putative beta 4-adrenoceptor' originated over 20 years ago when cardiostimulant effects were observed to non-conventional partial agonists. These agonists were originally described as beta 1- and beta 2-adrenoceptor antagonists; however, they cause cardiostimulant effects at much higher concentrations than those required to block beta 1- and beta 2-adrenoceptors. Cardiostimulant effects of non-conventional partial agonists have been observed in mouse, rat, guinea-pig, cat, ferret and human heart tissues. 2. The receptor is expressed in several heart regions, including the sinoatrial node, atrium and ventricle. 3. The receptor is resistant to blockade by most antagonists that possess high affinity for beta 1- and beta 2-adrenoceptors, but is blocked with moderate affinity by (-)-bupranolol and CGP 20712A. 4. The receptor is pharmacologically distinct from the beta 3-adrenoceptor. Micromolar concentrations of beta 3-adrenoceptor agonists have no agonist or blocking activity. The receptor is also resistant to blockade by a beta 3-adrenoceptor-selective antagonist. 5. The receptor mediates increases in cAMP levels and cAMP-dependent protein kinase (PK) A activity in cardiac tissues. Phosphodiesterase inhibition potentiates the positive chronotropic and inotropic effects of non-conventional partial agonists. 6. The receptor mediates hastening of atrial and ventricular relaxation, which is consistent with involvement of a cAMP-dependent pathway. 7. The non-conventional partial agonist (-)-[3H]-CGP 12177A labels the cardiac putative beta 4-adrenoceptor. Non-conventional partial agonists compete for binding with affinities that are closely similar to their agonist potencies. Catecholamines compete for binding in a stereoselective manner with a rank order of affinity of (-)-RO363 > (-)-isoprenaline > (-)-noradrenaline > or = (-)-adrenaline >> (+)-isoprenaline, suggesting that catecholamines can interact with the receptor. 8. The putative beta 4-adrenoceptor appears to be coupled to the Gs-adenylyl cyclase system, which could serve as a guide to its future cloning. Activation of the receptor may plausibly improve diastolic function but could also mediate arrhythmias.
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PMID:Proposal for the interaction of non-conventional partial agonists and catecholamines with the 'putative beta 4-adrenoceptor' in mammalian heart. 931 64

1. We examined the effects of noradrenaline on steady-state intracellular pH (pHi) and the recovery of pHi from internal acid loads imposed by the NH4+ prepulse technique in hippocampal CA1 neurones acutely dissociated from adult rats. 2. Under nominally HCO3--free conditions, acid extrusion was accomplished by a Na+-dependent mechanism, probably the amiloride-insensitive variant of the Na+-H+ exchanger previously characterized in both fetal and adult rat hippocampal neurones. In the presence of external HCO3-, acid extrusion appeared to be supplemented by a Na+-dependent HCO3--Cl- exchanger, the activity of which was dependent upon the absolute level of pHi. 3. Noradrenaline evoked a concentration-dependent and sustained rise in steady-state pHi and increased rates of pHi recovery from imposed intracellular acid loads. The effects of noradrenaline were not dependent upon the presence of external HCO3- but were blocked by substituting external Na+ with N-methyl-D-glucamine, suggesting that noradrenaline acts to increase steady-state pHi by increasing the activity of the Na+-H+ exchanger. 4. The effects of noradrenaline on steady-state pHi and on rates of pHi recovery from imposed acid loads were mimicked by beta1- and beta2-, but not alpha-, adrenoceptor agonists. The beta-adrenoceptor antagonist propranolol blocked the ability of noradrenaline to increase both steady-state pHi and rates of pHi recovery from acid loads. 5. The effects of noradrenaline on steady-state pHi and on pHi recovery rates following acid loads were not dependent on changes in [Ca2+]i. However, the effects of noradrenaline were blocked by pre-treatment with the adenylate cyclase inhibitor 2',5'-dideoxyadenosine and the cAMP-dependent protein kinase inhibitors Rp-adenosine-3',5'-cyclic monophosphorothioate (sodium salt; Rp-cAMPS) and N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulphonamide (H-89). 6. Forskolin, an activator of endogenous adenylate cyclase, and 3-isobutyl-1-methylxanthine, a phosphodiesterase inhibitor, mimicked the ability of noradrenaline to increase both steady-state pHi and rates of pHi recovery from imposed acid loads, as did Sp-cAMPS, a selective activator of cAMP-dependent protein kinase. The effect of forskolin on steady-state pHi was blocked by pre-treatment with Rp-cAMPS whereas the effect of Sp-cAMPS was enhanced by pre-treatment with the protein phosphatase inhibitor, okadaic acid. 7. Noradrenaline also increased steady-state pHi and rates of pHi recovery from imposed acid loads in cultured postnatal rat hippocampal neurones. In this preparation, the effects of noradrenaline were occluded by 18-24 h pre-treatment with cholera toxin. 8. We conclude that noradrenaline increases the activity of the Na+-H+ exchanger in rat hippocampal neurones, probably by inducing an alkaline shift in the pHi dependence of the antiport, thereby raising steady-state pHi. The effects of noradrenaline are mediated by beta-adrenoceptors via a pathway which involves the alpha-subunit of the stimulatory G-protein Gs (Gsalpha), adenylate cyclase, cAMP and the subsequent activation of cAMP-dependent protein kinase which, in turn, may phosphorylate the exchange mechanism.
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PMID:Effects of noradrenaline on intracellular pH in acutely dissociated adult rat hippocampal CA1 neurones. 976 38

Effects of YT-146 [2-(1-octynyl) adenosine], an adenosine A2 receptor agonist, on cAMP production and noradrenaline (NA) release were investigated in PC12 cells. YT-146 caused a concentration-dependent cAMP accumulation (EC50: 1.2+/-0.9 nM). In [3H]NA-prelabeled cells, YT-146 increased the basal NA release and enhanced ATP-evoked NA release in a concentration-dependent manner (EC50: 0.23+/-0.15 nM). YT-146 augmented the maximal response to ATP without affecting the EC50 value of ATP. These effects of YT-146 were inhibited by several adenosine receptor antagonists with a characteristic of adenosine A2A receptor subtype. The effects of YT-146 were mimicked by forskolin, dibutylyl cAMP and Sp-cAMPS, and inhibited by H-89, a cAMP-dependent protein kinase inhibitor. YT-146 had little effect on ATP-induced increase in intracellular Ca2+ concentration. YT-146 enhanced the NA release induced by several different stimuli including Ca2+ ionophore A23187. The present results suggest that YT-146 is a potent agonist on adenosine A2A receptors in PC12 cells and causes a cAMP-dependent enhancement of NA release by affecting the exocytosis process at a point downstream of the intracellular Ca2+ increase.
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PMID:Effects of YT-146 [2-(1-octynyl) adenosine], an adenosine A2A receptor agonist, on cAMP production and noradrenaline release in PC12 cells. 986 60


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