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)

The purpose of the present study was to examine whether cAMP-dependent mechanisms regulated excitatory synaptic transmission in the neostriatum. A brain slice preparation was utilized for intracellular recordings of the excitatory postsynaptic potentials (EPSPs) evoked by electrical stimulation. Bath application of forskolin, an activator of adenylate cyclase, enhanced the EPSP amplitude and duration. This potentiation was dose dependent and did not occur with the inactive analog 1,9-dideoxyforskolin. Forskolin potentiation was unaltered by treatment with the GABAA receptor antagonist bicuculline. Furthermore, two inhibitors of cAMP-dependent protein kinase (PKA), Rp-cAMPS and IP20-amide, attenuated forskolin's enhancement of the EPSP. In addition, the PKA activator Sp-cAMPS enhanced excitatory synaptic transmission. Interestingly, treatment with PKA inhibitors alone depressed while the phosphatase inhibitor okadaic acid enhanced the synaptic response. These results suggest a role for tonic kinase and phosphatase activity in regulating excitatory synaptic transmission in the neostriatum. Finally, forskolin was found to enhance the responses of neostriatal neurons to glutamate receptor agonists. This potentiation, which occurred in the presence of tetrodotoxin, provides at leas part of the explanation for the cAMP/PKA-dependent regulation of the EPSP. Overall, these results suggest a role for the adenylate cyclase cascade in the regulation of excitatory synaptic transmission in the neostriatum.
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PMID:Excitatory synaptic transmission in neostriatal neurons: regulation by cyclic AMP-dependent mechanisms. 789 Nov 29

The intracellular mechanisms underlying the facilitatory action of isoproterenol (Iso) on the NMDA receptor-mediated synaptic potential (EPSPNMDA) was investigated in an in vitro slice preparation of rat amygdala. Intracellular recordings were made from basolateral amygdala neurons in the presence of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM) and picrotoxin (50 microM) which block non-NMDA and GABAA receptors, respectively. Superfusion of Iso (15 microM) produced a sustained increase in EPSPNMDA. Rp-adenosine-3',5'-cyclic monophosphotioate (Rp-cAMPS), a potent inhibitor of protein kinase A (PKA) alone decreased the amplitude of EPSPNMDA below baseline values and prevented the subsequent potentiation by Iso. Forskolin, a direct activator of adenylate cyclase, mimics the effect of Iso, and Rp-cAMPS also reversed forskolin-induced enhancement of EPSNMDA. These results suggest that cAMP-dependent protein kinase mediates the enhancement of EPSPNMDA by Iso in the amygdala.
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PMID:Enhancement of NMDA receptor-mediated synaptic potential by isoproterenol is blocked by Rp-adenosine 3',5'-cyclic monophosphothioate. 790 1

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

When PC-12 cells were treated with 10 microM forskolin, the expression of two members of the granin family, secretogranin II (SgII) and chromogranin B (CgB), were differentially regulated. SgII mRNA levels declined progressively after forskolin treatment to reach a level of 22 +/- 1% of control after 48 hr, whereas CgB mRNA levels increased more rapidly, reaching a maximum of 3-fold above control after 24 hr. The dependence of these changes on an increase in cellular cAMP levels, activation of cAMP-dependent protein kinase (PKA), protein synthesis, and changes in the rate of transcription was investigated. The effects of forskolin on SgII and CgB mRNAs were reproduced by 1 mM 8-bromo-cAMP but not by 10 microM 1,9-dideoxyforskolin, an inactive analog of forskolin. The actions of forskolin on SgII and CgB mRNAs were blocked by treatment with 60 microM H-89, a selective PKA inhibitor, and were blunted in PKA-deficient PC-12 cell clones. To examine whether forskolin action was dependent on ongoing protein synthesis, PC-12 cells were treated with 1 microgram/ml cycloheximide before the addition of forskolin. The reduction in SgII mRNA levels by forskolin was not evident in PC-12 cells treated with cycloheximide. Rather, in the presence of cycloheximide, forskolin stimulated SgII mRNA levels 3.6 +/- 0.7-fold above control. The induction of CgB mRNA by forskolin was not affected by cycloheximide treatment. The superinduction of SgII mRNA by cycloheximide and forskolin was related to the extent of protein synthesis inhibition, was observed in cells treated with forskolin and other protein synthesis inhibitors, and was blunted in PKA-deficient PC-12 cells, suggesting that this effect was dependent on inhibition of protein synthesis and activation of PKA. To determine whether changes in SgII and CgB mRNA levels resulted from changes in the rate of transcription, nuclear run-on assays were performed in nuclei isolated from PC-12 cells that had been treated for 2 hr with cycloheximide, forskolin, or the two combined. Transcription of the SgII gene was not significantly affected by treatment with either forskolin or cycloheximide alone but was increased 12.9 +/- 1.0-fold above control in nuclei from cells treated with cycloheximide and forskolin together. Forskolin caused a 3.8 +/- 0.8-fold induction of CgB transcription.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Transcriptional regulation of secretogranin II and chromogranin B by cyclic AMP in a rat pheochromocytoma cell line. 796 75

The effects of pertussis toxin, forskolin, and cAMP analogues on the antinociceptive action of nicotine were examined to investigate the possible involvement of adenylate cyclase and G-proteins in nicotine's antinociceptive effect. Intrathecal injection of pertussis toxin (0.25 and 0.50 micrograms) in mice inhibited nicotine-induced antinociception in the tail-flick test. The effect of the toxin was dose and time dependent. Forskolin, a potent adenylate cyclase activator, and 8-(-4-chlorophenylthio) adenosine-3':5' monophosphate, cyclic (8-CPT-cAMP), a cAMP analogue, inhibited the antinociceptive effects of nicotine in a dose-dependent manner. EGTA reversal of 8-CPT-cAMP's inhibitory effects suggests that calcium may to be involved. These data implicate the possible involvement of a G-protein and a second messenger system (activation of a cAMP-dependent protein kinase and increase in cyclic AMP levels) in nicotine-induced analgesia in mice.
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PMID:Nicotine-induced antinociception in mice: role of G-proteins and adenylate cyclase. 802 3

Effects of cAMP on insulin-stimulated mitogen-activated protein (MAP) kinase pathway were examined using rat hepatoma H4EII cells. MAP kinase was rapidly activated and reached a peak 3 min after the stimulation by insulin. Forskolin (1 microM) and 8(4-chlorophenylthio)cAMP (8-CPT-cAMP) (0.1 mM) inhibited the insulin-stimulated MAP kinase activity. Pretreatment of the cells with H-8 (50 microM), a cAMP-dependent protein kinase inhibitor, enhanced the insulin-stimulated MAP kinase activity and partially restored the inhibitory effect of cAMP. Furthermore, insulin-induced phosphorylation of MAP kinase was inhibited by 8-CPT-cAMP, and the inhibition was restored by H-8. 8-CPT-cAMP did not inhibit the autophosphorylation of insulin receptor. These data indicate that elevation of intracellular cAMP blocks the insulin-stimulated MAP kinase pathway downstream of insulin receptor.
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PMID:cAMP inhibits the insulin-stimulated mitogen-activated protein kinase pathway in rat hepatoma H4EII cells. 804 24

We investigated the effects of age and nafidrofuryl oxalate (Naftidrofuryl), a 5-HT2 antagonist, on neurotransmission and transduction systems in the gerbil hippocampus using quantitative autoradiography. [3H]Quinuclidinyl benzilate (QNB), [3H]cyclohexyl-adenosine (CHA), [3H]MK-801, and [3H]muscimol were used to label muscarinic acetylcholine, adenosine A1, N-methyl-D-aspartate (NMDA), and gamma-aminobutyric acid-A (GABAA) receptors, respectively. [3H]PN200-110 labeled L-type Ca2+ channels. [3H]Forskolin, [3H]cyclic adenosine monophosphate (cAMP), [3H]phorbol 12,13-dibutyrate (PDBu), and [3H]inositol 1,4,5-triphosphate (IP3) were used to label adenylate cyclase, cAMP-dependent protein kinase, protein kinase C (PKC), and IP3 receptors, respectively. Approximately 20% reductions in [3H]QNB, [3H]forskolin, and [3H]PDBu binding were observed in the hippocampus of 9-month-old gerbils in comparison with 5-week-old gerbils. Treatment with Naftidrofuryl (10 mg/kg, i.p., once a day for 7 days) ameliorated these reductions. No changes were found in [3H]CHA, [3H]MK-801, [3H]muscimol, [3H]PN200-110, [3H]cAMP, and [3H]IP3 binding. The results suggest that Naftidrofuryl may have beneficial effects on the age-related alterations in signal transmission and transduction systems in the brain. Because the acetylcholine system, adenylate cyclase, and PKC are considered to be involved in learning and memory processes, the result may have clinical implications.
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PMID:Effects of naftidrofuryl oxalate, a 5-HT2 antagonist, on neurotransmission and transduction systems in the gerbil hippocampus. 806 66

To elucidate the mechanism causing the transient accumulation of intracellular cAMP in the FRTL-5 thyroid cell line, the short-term effect of thyroid-stimulating hormone (TSH) on phosphodiesterase (PDE) activity was studied. Together with an increase in cAMP levels, TSH produced a significant increase in total PDE activity as early as 3 min, with a maximal stimulation reached after 15 min. This short-term increase in PDE activity was dependent on the TSH concentration (ED50 = 4 x 10(-11) M TSH). Forskolin and dibutyryl cAMP produced an even larger stimulation than that produced by TSH, suggesting that the effect of TSH is mediated by cAMP. To determine the properties of the PDE forms activated by TSH, antibodies specific for the cAMP-PDEs were used to immunoprecipitate the PDEs present in control cells, and cells incubated for 15 min in the presence of 10 nM TSH. Comparison of the activity recovered in the immunoprecipitation pellets demonstrated that TSH produced more than a 2.5-fold increase in the cAMP-PDE form(s) recognized by this antibody. Conversely, the activity remaining in the supernatants was not affected by the TSH treatment. Most of the activity recovered in the immunoprecipitation pellets (90%) was inhibited by 10 microM Rolipram, an inhibitor specific for the high affinity cAMP-PDEs. No TSH stimulation of the Rolipram-insensitive PDE activity could be observed under these conditions. Western blot analyses with two different cAMP-PDE specific antibodies showed that a 15-min stimulation with TSH induced the appearance of a new band with electrophoretic mobility slower than the polypeptide present in unstimulated cells. The appearance of this band did not require ongoing protein synthesis because it occurred in the presence of cycloheximide. Metabolic [32P]orthophosphate labeling of intact FRTL-5 cells indicated that the TSH treatment caused an increased 32P incorporation into a polypeptide that co-purified with the stimulated PDE activity and had an electrophoretic mobility identical to that of the cAMP-PDE. Okadaic acid, a potent inhibitor of protein phosphatase 1 and protein phosphatase 2A, elicited a potentiation of the TSH-stimulated PDE activity. The stimulating of a PDE with the same immunological properties and Rolipram sensitivity as the cAMP-PDE stimulated by TSH in the intact cells was reproduced, in a cell-free system, by incubating soluble extracts from FRTL-5 cells with the catalytic subunit of cAMP-dependent protein kinase. These data provide evidence that TSH produces a rapid activation of a cAMP-PDE in the FRTL-5 cells through a cAMP-dependent phosphorylation.
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PMID:The short-term activation of a rolipram-sensitive, cAMP-specific phosphodiesterase by thyroid-stimulating hormone in thyroid FRTL-5 cells is mediated by a cAMP-dependent phosphorylation. 813 62

In vascular smooth muscle cells (VSMCs) of rat tail artery, prostaglandin E2 (PGE2) inhibited a voltage-dependent, delayed rectifier K channel current (Ik). The inhibition was concentration-dependent, via a receptor-mediated mechanism involving the activation of G protein(s) (Ren et al., 1995). In this study, we show that the PGE2-induced inhibition of Ik was mediated by activation of protein kinase A (PKA) and possibly protein kinase C (PKC). Pretreatment of the cells with cyclic adenosine 3',5'-monophosphothioate Rp-isomer (Rp-cAMPs), an inhibitor of adenosine 3', 5'-cAMP-dependent protein kinase (PKA), almost completely abolished the PGE2-induced inhibition. Forskolin, dibutyryl cAMP (Db-cAMP) and cyclic adenosine 3',5'cyclic monophosphothioate Sp-isomer (Sp-cAMPs), activators of adenylate cyclase and PKA, mimicked the effect of PGE2 on Ik. Phosphodiesterase inhibition by 3-isobutyl-1-methylxanthine did not alter the PGE2-induced inhibition of Ik. Moreover, we also found that phorbol myristate acetate (PMA), a PKC activator, significantly suppressed Ik. Both the kinase inhibitor staurosporine and down-regulation of PKC by prolonged exposure of the cells to PMA blocked the PGE2-induced inhibition of Ik, but had no effects on the forskolin, Db-cAMP or SpcAMP-induced effect on Ik. Pretreatment of the cells with Rp-cAMPs only partially diminished the degree of Ik inhibition evoked by PMA. Assay of cAMP content indicated that both PGE2 and PMA induced cAMP accumulation. These results strongly suggest that the modulation of Ik by PGE2 in rat tail artery VSMCs involves signal transduction through both PKA and PKC activation. The activation of PKC may potentiate the cAMP-PKA stimulation, whereas the cAMP-PKA cascade did not seem to affect the PKC pathway. These observations suggest that "cross talk" between the two second-messenger systems is involved in the mechanisms that mediate the effect of PGE2.
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PMID:The actions of prostaglandin E2 on potassium currents in rat tail artery vascular smooth muscle cells: regulation by protein kinase A and protein kinase C. 861 46

Memory storage consists of a short-term phase that is independent of new protein synthesis and a long-term phase that requires the synthesis of new proteins and RNA. A cellular representation of these two phases has been demonstrated recently for long-term potentiation (LTP) in both the Schaffer collateral and the mossy fibers of the hippocampus, a structure widely thought to contribute to memory consolidation. By contrast, much less information is available about the medial perforant pathway (MPP), one of the major inputs to the hippocampus. We found that both a short-lasting and a long-lasting potentiation (L-LTP) can be induced in the MPP of rat hippocampal slices by applying repeated tetanization in reduced levels of magnesium. This potentiation was dependent on the activation of NMDA receptors. The early, transient phase of LTP in the MPP did not require either protein or RNA synthesis, and it was independent of protein kinase A activation. By contrast, L-LTP required the synthesis of proteins and RNA, and was selectively blocked by inhibitors of cAMP-dependent protein kinase (PKA). Forskolin, an adenylate cyclase activator, also induced a L-LTP that was attenuated by inhibition of transcription. Our results demonstrate that, like LTP in the Schaffer collateral and mossy fiber pathways, MPP LTP also consists of a late phase that is dependent on protein and RNA synthesis and PKA activity. Thus, cAMP-mediated transcription appears to be a common mechanism for the late form of LTP in all three pathways within the hippocampus.
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PMID:A macromolecular synthesis-dependent late phase of long-term potentiation requiring cAMP in the medial perforant pathway of rat hippocampal slices. 862 57


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