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

C1q may participate in the loss of connective tissue occurring in chronic inflammatory lesions. The hypothesis of a detrimental role of C1q on cell proliferation was tested on primary cultures of human fibroblasts (HFs). C1q suppressed the DNA synthesis of HF in response to platelet-derived growth factor (PDGF) with an IC(50) of 20 microg/ml, and blocked 78% of the cycling cells in G(1) phase. The C1q block did not involve production of inhibitory prostaglandin by the cells. Given that C1q elicits signals of the adenylyl cyclase pathway in HF, we examined cAMP-dependent mechanisms to understand how C1q inhibited the PDGF response. Whereas the C1q block was enhanced by agonist dibutyryl-adenosine 3', 5'-cyclic mono-phosphate (db-cAMP), antagonist adenosine 3', 5'-cyclic monophosphorotioate triethylammonium salt (Rp-cAMP) minimized it. C1q increased the level of cAMP-dependent protein kinase I (PKA-I) 4.5-fold, without altering the activation of the extracellular-regulated protein kinase (ERK) pathway. These results demonstrate that the interactions of C1q with HF cause growth arrest at the G(1) phase through mechanisms associated with a PKA-I dependent pathway.
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PMID:C1q arrests the cell cycle progression of fibroblasts in G(1) phase: role of the cAMP/PKA-I pathway. 1125 56

Although it was shown earlier that phosphorylation of Na,K-ATPase by cAMP-dependent protein kinase (PKA) occurs in intact cells, the purified enzyme in vitro is phosphorylated by PKA only after treatment by detergent. This is accompanied by an unfortunate side effect of the detergent that results in complete loss of Na,K-ATPase activity. To reveal the effect of Na,K-ATPase phosphorylation by PKA on the enzyme activity in vitro, the effects of different detergents and ligands on the stoichiometry of the phosphorylation and activity of Na,K-ATPase from duck salt glands (alpha1beta1-isoenzyme) were comparatively studied. Chaps was shown to cause the least inhibition of the enzyme. In the presence of 0.4% Chaps at 1 : 10 protein/detergent ratio in medium containing 100 mM KCl and 0.3 mM ATP, PKA phosphorylates serine residue(s) of the Na,K-ATPase with stoichiometry 0.6 mol Pi/mol of alpha-subunit. Phosphorylation of Na,K-ATPase by PKA in the presence of the detergent inhibits the Na,K-ATPase. A correlation was found between the inclusion of P(i) into the alpha-subunit and the loss of activity of the Na,K-ATPase.
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PMID:Phosphorylation of the alpha-subunit of Na,K-ATPase from duck salt glands by cAMP-dependent protein kinase inhibits the enzyme activity. 1156 56

This study tested the hypothesis that nitric oxide (NO) production contributes to relaxation induced by 3',5'-cyclic adenylate monophosphate (cAMP)-elevating agents and that high salt diet impairs this mechanism of relaxation. Relaxation response to isoproterenol but not sodium nitroprusside, a NO donor, was reduced in the thoracic aorta from rats that were placed on a high salt diet (8% NaCl; 60+/-4%, P<0.001). 1H-[1,2,4]oxadiazolol [4,3,-alpha]quinoxalin-1-one (ODQ, 10 microM), a soluble guanylate cyclase inhibitor, but not N(omega)-nitro-L-arginine methyl ester (L-NAME, 100 microM), an inhibitor of NO synthase (NOS), attenuated the relaxation to isoproterenol (59+/-16%, P<0.01). High salt diet also impaired the relaxation responses to forskolin, an activator of adenylate cyclase, or 8-Bromo-cAMP (8-Br-cAMP). (N-[2-((p-bromocinnamyl)aminoethyl]-5-isoquinolinesulfonamide hydrochloride (H-89) (8 microM), an inhibitor of cAMP-dependent protein kinase, did not affect the relaxation produced by isoproterenol. These data suggest that high salt diet impairs relaxation response to isoproterenol by a dual mechanism involving diminished NO/NOS pathway linked to cGMP pathway and diminished cAMP pathway that is independent of protein kinase A.
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PMID:High salt diet modulates cAMP- and nitric oxide-mediated relaxation responses to isoproterenol in the rat aorta. 1292 69

StubGAL83 is a potato gene that encodes the beta-subunit of a protein kinase complex similar to the yeast SNF1, and the mammalian AMPK complexes that are modulated by changes in the cellular AMP/ATP ratio and are important regulators of metabolic and stress responses. Here we show that the expression of StubGAL83 in potato foliage is much higher in the dark than in the light and can be repressed by metabolisable sugars in the dark. The amounts of StubGAL83 mRNA are higher in sink than in source leaves. To unravel the role of StubGAL83, transgenic potato plants expressing a part of the StubGAL83 cDNA in antisense orientation under the control of the constitutive CaMV35S promoter were generated. Northern analysis revealed a reduction up to 90-95% in StubGAL83 mRNA accumulation in leaves of seven lines. Five out of these seven lines exhibited a reduction of StubGAL83 mRNA levels also in root and tuber tissues. Independent on the type of repression, the transgenic lines showed a delay in rooting and an increased sensitivity to salt stress. The roots were stunted and possessed less pronounced tap roots than the controls albeit with different severity in the different transgenic lines. The root cells were smaller and some of them had irregular shape. Tuberisation of the antisense-StubGAL83 lines was delayed, the size of the tubers was reduced while the number of tubers per plant was increased. These results together suggest that StubGAL83 affects root and tuber development probably by altering the metabolic status of the leaves.
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PMID:Antisense repression of StubGAL83 affects root and tuber development in potato. 1294 48

Thiazolidinediones have been shown to activate AMP-activated protein kinase activity in cultured cells. Whether they have a similar effect in vivo and if so whether it is physiologically relevant is not known. To assess these questions, we examined the effects of pioglitazone, administered orally to intact rats, on AMPK phosphorylation (AMPK-P) (a measure of its activation) and acetyl CoA carboxylase (ACC) activity and malonyl CoA concentration in rat liver and adipose tissue. In the first study, measurements were made in the Dahl-salt-sensitive rat (Dahl-S), a strain of Sprague-Dawley rat with endogenous hypertriglyceridemia and high levels of malonyl CoA that are restored to control values by pioglitazone. Treatment with pioglitazone (20mg/kg bw/day for 3 weeks) did not significantly increase either P-AMPK or P-ACC (which varies inversely with ACC activity) in control rats. However, in the Dahl-S rats values for AMPK-P and ACC-P were 50% lower than in control rats and were doubled by pioglitazone treatment. In a second study, the effects of two weeks treatment with pioglitazone (3mg/kg bw/day administered orally) were evaluated in Wistar rats. Under basal conditions (no manipulation of the animals), pioglitazone increased AMPK phosphorylation by twofold and decreased ACC activity and the concentration of malonyl CoA by 50% in liver. Following a euglycemic-hyperinsulinemic clamp (6h), 50% decreases in AMPK and ACC phosphorylation (indicating an increase in its activity) and comparable increases in malonyl CoA concentration were observed in liver and adipose tissue. In both tissues, pre-treatment with pioglitazone prevented these changes. Where studied (in Wistar rats under basal conditions) treatment with pioglitazone decreased the concentration of ATP by 1/3 and increased the concentration of ADP and AMP in liver. The results indicate that treatment with pioglitazone can increase AMPK activity in rat liver and adipose tissue in a variety of circumstances. They also suggest that this activation of AMPK may be mediated by a change in cellular energy state. Whether these effects of pioglitazone contribute to its insulin-sensitizing and other actions in vivo remains to be determined.
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PMID:Pioglitazone treatment activates AMP-activated protein kinase in rat liver and adipose tissue in vivo. 1473 47

Phospholamban (PLB) is a major target of the beta-adrenergic cascade in the heart, functioning to modulate contractile force by altering the rate of calcium re-sequestration by the Ca-ATPase. Functionally, inhibition by PLB binding is manifested by shifts in the calcium dependence of Ca-ATPase activation toward higher calcium levels; phosphorylation of PLB by PKA reverses the inhibitory action of PLB. To investigate structural changes in the cytoplasmic portion of PLB that result from either the phosphorylation of PLB by cAMP-dependent protein kinase (PKA) or calcium binding to the Ca-ATPase, we have used frequency-domain fluorescence spectroscopy to measure the spatial separation and conformational heterogeneity between N-(1-pyrenyl)maleimide, covalently bound to a single cysteine (Cys(24)) engineered near the membrane surface of the transmembrane domain of PLB, and Tyr(6) in the cytosolic domain. Irrespective of calcium activation of the Ca-ATPase or phosphorylation of Ser(16) in PLB by PKA, we find that PLB remains tightly associated with the Ca-ATPase in a well-defined conformation. However, calcium activation of the Ca-ATPase induces an increase in the overall dimensions of the cytoplasmic portion of bound PLB, whereas PLB phosphorylation results in a more compact structure, consistent with increased helical content induced by a salt link between phospho-Ser(16) and Arg(13). Thus, enzyme activation of the Ca-ATPase may occur through different mechanisms: calcium binding to high-affinity sites within the Ca-ATPase functions to overcome conformational constraints imposed by PLB on the N-domain of the Ca-ATPase; alternatively, phosphorylation stabilizes the backbone fold of PLB to release inhibitory interactions with the Ca-ATPase.
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PMID:Conformational changes within the cytosolic portion of phospholamban upon release of Ca-ATPase inhibition. 1504 94

The involvement of the extracellular signal-regulated kinase 1/2 (ERK1/2) cascade in long-lasting potentiation of synaptic transmission, induced by tetraethylammonium (TEA) or by elevated extracellular calcium concentration, was investigated in layer V horizontal connections within motor cortex in rat brain slices. Brief application of TEA (25 mM) resulted in a long-lasting potentiation of field potentials by 54+/-12%. A transient exposure of slices to elevated extracellular calcium (5 mM) induced long-lasting potentiation of responses reaching 30+/-8%. The induction of both forms of potentiation was prevented by the exposure of slices to inhibitors of the upstream activator of ERK 1/2, MEK (ERK kinase), U0126 (20 microM) and PD 98059 (50 microM). PhosphoERK2 immunoreactivity was transiently increased above baseline levels 15 min after termination of the exposure of slices to either TEA or elevated calcium concentration. Both forms of potentiation were partially occluded by Sp-adenosine 3',5'-cyclic monophosphorothioate triethylammonium salt (Sp-cAMPS; 100 microM), an activator of cAMP-dependent protein kinase (PKA), and they were blocked after preincubation with Rp-adenosine 3',5'-cyclic monophosphorothioate triethylammonium salt (Rp-cAMPS; 100 microM), a specific inhibitor of PKA activation by cAMP. It has previously been shown that TEA-induced potentiation represents a N-methyl-d-aspartate (NMDA) receptor-independent form of persistent synaptic enhancement, and, on the contrary, calcium-induced potentiation depends on NMDA receptors. Thus, the activation of PKA and the ERK1/2 cascade are required for two forms of chemically induced long-lasting increases of synaptic efficacy in slices of rat motor cortex.
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PMID:Chemically-induced long-term potentiation in rat motor cortex involves activation of extracellular signal-regulated kinase cascade. 1534 67

SNARK is a member of the AMPK subfamily of serine/threonine protein kinases. In this study, we examined the regulation of SNARK activity in kidney (BHK, HEK293), pancreatic beta-cell insulinoma (INS-1), hepatocarcinoma (H4IIE) and keratinocyte (NRKC)-derived cell lines in response to diverse cellular stresses. We show that SNARK activity is regulated by glucose- or glutamine-deprivation, induction of endoplasmic reticulum stress by homocysteine or DTT, elevation of cellular AMP and/or depletion of ATP, hyperosmotic stress, salt stress, ultraviolet B radiation and oxidative stress caused by hydrogen peroxide. Moreover, the regulation of SNARK activity in response to cellular stresses depends greatly upon cell type. Furthermore, SNARK activity is downregulated by metformin in a dose- and time-dependent manner in H4IIE cells. These observations support a role for SNARK as a molecular component of the cellular stress response.
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PMID:Regulation of SNARK activity in response to cellular stresses. 1589 79

In cholangiocytes, bile salt (BS) uptake via the apical sodium-dependent bile acid transporter (ASBT) may evoke ductular flow by enhancing cAMP-mediated signaling to the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. We considered that ASBT-mediated BS uptake in the distal ileum might also modulate intestinal fluid secretion. Taurocholate (TC) induced a biphasic rise in the short circuit current across ileal tissue, reflecting transepithelial electrogenic ion transport. This response was sensitive to bumetanide and largely abrogated in Cftr-null mice, indicating that it predominantly reflects CFTR-mediated Cl- secretion. The residual response in Cftr-null mice could be attributed to electrogenic ASBT activity, as it matched the TC-coupled absorptive Na+ flux. TC-evoked Cl- secretion required ASBT-mediated TC uptake, because it was blocked by a selective ASBT inhibitor and was restricted to the distal ileum. Suppression of neurotransmitter or prostaglandin release, blocking of the histamine H1 receptor, or pretreatment with 5-hydroxytryptamine did not abrogate the TC response, suggesting that neurocrine or immune mediators of Cl- secretion are not involved. Responses to TC were retained after carbachol treatment and after permeabilization of the basolateral membrane with nystatin, indicating that BS modulate CFTR channel gating rather than the driving force for Cl- exit. TC-induced Cl- secretion was maintained in cGMP-dependent protein kinase II-deficient mice and only partially inhibited by the cAMP-dependent protein kinase inhibitor H89, suggesting a mechanism of CFTR activation different from cAMP or cGMP signaling. We conclude that active BS absorption in the ileum triggers CFTR activation and, consequently, local salt and water secretion, which may serve to prevent intestinal obstruction in the postprandial state.
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PMID:Activation of CFTR by ASBT-mediated bile salt absorption. 1603 45

Glu230, one of the acidic residues that cluster around the active site of the catalytic subunit of cAMP-dependent protein kinase, plays an important role in substrate recognition. Specifically, its side chain forms a direct salt-bridge interaction with the substrate's P-2 Arg. Previous studies showed that mutation of Glu230 to Gln (E230Q) caused significant decreases not only in substrate binding but also in the rate of phosphoryl transfer. To better understand the importance of Glu230 for structure and function, we solved the crystal structure of the E230Q mutant at 2.8 A resolution. Surprisingly, the mutant preferred an open conformation with no bound ligands observed, even though the crystals were grown in the presence of MgATP and the inhibitor peptide, IP20. This is in contrast to the wild-type protein that, under the same conditions, prefers the closed conformation of a ternary complex. The structure highlights the importance of the electrostatic surface not only for substrate binding and catalysis, but also for the mechanism for closing the active site cleft. This surface mutation clearly disrupts the recognition and binding of substrate peptide so that the enzyme prefers an open conformation that cannot trap ATP. This is consistent with the reinforcing concepts of conformational dynamics and the synergistic binding of ATP and substrate peptide. Another unusual feature of the structure is the observation of the entire N terminus (Gly1-Thr32) assumes an extended alpha-helix conformation. Finally, based on temperature factors, this mutant structure is more stable than the wild-type C-subunit in the apo state.
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PMID:Crystal structure of the E230Q mutant of cAMP-dependent protein kinase reveals an unexpected apoenzyme conformation and an extended N-terminal A helix. 1625 59


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