Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.31 (AMP-activated protein kinase)
 13,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated here whether adiponectin can exhibit an inhibitory effect on tumor necrosis factor-alpha (TNF-alpha)- and receptor activator of nuclear factor-kappaB ligand (RANKL)-induced osteoclastogenesis by using RAW264 cell D clone with a high efficiency to form osteoclasts. Globular adiponectin (gAd) strongly inhibited TNF-alpha/RANKL-induced differentiation of osteoclasts by interfering with TNF receptor-associated factor 6 production and calcium signaling; consequently, the induction of nuclear factor of activated T cells c1 (NFATc1) was strongly inhibited. Moreover, we observed that inhibition of AMP-activated protein kinase abrogated gAd inhibition for TNF-alpha/RANKL-induced NFATc1 expression. Our data suggest that adiponectin acts as a potent regulator of bone resorption observed in diseases associated with cytokine activation.
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PMID:Adiponectin inhibits induction of TNF-alpha/RANKL-stimulated NFATc1 via the AMPK signaling. 1820 70

We have investigated the mechanism of the changes in the profile of metabolic enzyme expression that occur in association with fast-to-slow transformation of rabbit skeletal muscle. The hypotheses assessed are: do 1) lowered intracellular ATP concentration or 2) reduction of the muscular glycogen stores act as triggers of metabolic transformation? We find that 3 days of decreased cytosolic ATP content have no impact on the investigated metabolic markers, whereas incubation of the cells with little or no glucose leads to decreases in glycogen in conjunction with decreases in glyceraldehyde-3-phosphate dehydrogenase (GAPDH) promoter activity, GAPDH mRNA and specific GAPDH enzyme activity (indicators of the anaerobic glycolytic pathway), and furthermore to increases in mitochondrial acetoacetyl-CoA thiolase (MAT, also known as ACAT) promoter activity, peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) expression and citrate synthase (CS) specific enzyme activity (all indicators of oxidative metabolic pathways). The AMP-activated protein kinase (AMPK) activity under these conditions is reduced compared to controls. In experiments with two inhibitors of glycogen degradation we show that the observed metabolic transformation caused by low glucose takes place even if intracellular glycogen content is high. These findings for the first time provide evidence that metabolic adaptation of skeletal muscle cells from rabbit in primary culture can be induced not only by elevation of intracellular calcium concentration or by a rise of AMPK activity, but also by reduction of glucose supply. Contrary to expectations, neither an increase in phospho-AMPK nor a reduction of muscular glycogen content are crucial events in the glucose-dependent induction of metabolic transformation in the muscle cell culture system studied.
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PMID:Metabolic transformation of rabbit skeletal muscle cells in primary culture in response to low glucose. 1821 29

Calcium-calmodulin/dependent protein kinase II (CaMKII), AMP-activated protein kinase (AMPK), and extracellular signal-regulated kinase (ERK1/2) have each been implicated in the regulation of substrate metabolism during exercise. The purpose of this study was to determine whether CaMKII is involved in the regulation of FA uptake and oxidation and, if it is involved, whether it does so independently of AMPK and ERK1/2. Rat hindquarters were perfused at rest with (n = 16) or without (n = 10) 3 mM caffeine, or during electrical stimulation (n = 14). For each condition, rats were subdivided and treated with 10 muM of either KN92 or KN93, inactive and active CaMKII inhibitors, respectively. Both caffeine treatment and electrical stimulation significantly increased FA uptake and oxidation. KN93 abolished caffeine-induced FA uptake, decreased contraction-induced FA uptake by 33%, and abolished both caffeine- and contraction-induced FA oxidation (P < 0.05). Caffeine had no effect on ERK1/2 phosphorylation (P > 0.05) and increased alpha(2)-AMPK activity by 68% (P < 0.05). Electrical stimulation increased ERK1/2 phosphorylation and alpha(2)-AMPK activity by 51% and 3.4-fold, respectively (P < 0.05). KN93 had no effect on caffeine-induced alpha(2)-AMPK activity, ERK1/2 phosphorylation, or contraction-induced ERK1/2 phosphorylation (P > 0.05). Alternatively, it decreased contraction-induced alpha(2)-AMPK activity by 51% (P < 0.05), suggesting that CaMKII lies upstream of AMPK. These results demonstrate that regulation of contraction-induced FA uptake and oxidation occurs in part via Ca(2+)-independent activation of ERK1/2 as well as Ca(2+)-dependent activation of CaMKII and AMPK.
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PMID:Evidence for the involvement of CaMKII and AMPK in Ca2+-dependent signaling pathways regulating FA uptake and oxidation in contracting rodent muscle. 1830 92

Inhibition of mitochondrial permeability transition pore (MPTP) opening at reperfusion is critical for cardioprotection by ischemic preconditioning (IP). Some studies have implicated mitochondrial protein phosphorylation in this effect. Here we confirm that mitochondria rapidly isolated from preischemic control and IP hearts show no significant difference in calcium-mediated MPTP opening, whereas IP inhibits MPTP opening in mitochondria isolated from IP hearts following 30 minutes of global normothermic ischemia or 3 minutes of reperfusion. Analysis of protein phosphorylation in density-gradient purified mitochondria was performed using both 2D and 1D electrophoresis, with detection of phosphoproteins using Pro-Q Diamond or phospho-amino-specific antibodies. Several phosphoproteins were detected, including voltage-dependent anion channels isoforms 1 and 2, but none showed significant IP-mediated changes either before ischemia or during ischemia and reperfusion, and neither Western blotting nor 2D fluorescence difference gel electrophoresis detected translocation of protein kinase C (alpha, epsilon, or delta isoforms), glycogen synthase kinase 3beta, or Akt to the mitochondria following IP. In freeze-clamped hearts, changes in phosphorylation of GSK3beta, Akt, and AMP-activated protein kinase were detected following ischemia and reperfusion but no IP-mediated changes correlated with MPTP inhibition or cardioprotection. However, measurement of mitochondrial protein carbonylation, a surrogate marker for oxidative stress, suggested that a reduction in mitochondrial oxidative stress at the end of ischemia and during reperfusion may account for IP-mediated inhibition of MPTP. The signaling pathways mediating this effect and maintaining it during reperfusion are discussed.
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PMID:Inhibition of mitochondrial permeability transition pore opening by ischemic preconditioning is probably mediated by reduction of oxidative stress rather than mitochondrial protein phosphorylation. 1835 42

Although Panax ginseng has been widely used in oriental countries for pharmacological effects such as anti-diabetic, anti-inflammatory, adaptogenic and anti-fatigue activities, the active ingredient is not yet fully identified. In our preliminary studies, protopanaxadiol ginsenosides showed the insulin secretion-stimulating activity. In HIT-T15 cells, Rg3 enhanced the insulin secretion in a concentration dependent manner. This effect, however, was almost completely abolished in the presence of diazoxide (K+ channel opener) or nifedipine (Ca2+ channel blocker). Oral glucose tolerance test (OGTT) was also performed using ICR mice and Rg3 suppressed the blood glucose levels from rising by enhancing an insulin secretion at 30 min after administration. From these studies, we may conclude that Rg3 lowered the plasma glucose level by stimulating an insulin secretion and this action was presumably associated with ATP sensitive K+ channel. Next, to explore the hypothesis that ginsenoside Rg3 epimers may exhibit differential effects, glucose-stimulated insulin secretion activity and phosphorylation of AMP-activated protein kinase (AMPK) were compared between 20(S)- and 20(R)-ginsenoside Rg3. 5 microM of 20(S)-Rg3 enhanced the glucose-stimulated insulin secretion by 58% compared to the control, but 20(R)-Rg3 did not show any effect. In C2C12 myotubes, 20(S)- and 20(R)-Rg3 both markedly phosphorylated AMPK and acetyl-CoA carboxylase (ACC), although 20(R)-Rg3 showed a little less effect. Taken together, our results suggest that ginsenoside Rg3 epimers showed differential activities, and 20(S)-Rg3 epimer exhibited the higher pharmacological effects in insulin secretion and AMPK activation than 20(R)-Rg3. The novel characteristics of 20(S)-Rg3 may be a valuable candidate for anti-diabetic agent.
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PMID:20(S)-ginsenoside Rg3 enhances glucose-stimulated insulin secretion and activates AMPK. 1837 76

Muscle contraction acutely increases glucose transport in both healthy and type 2 diabetic individuals. Since glucose uptake during muscle contraction has been observed in the absence of insulin, the existence of an insulin-independent pathway has been suggested to explain this phenomenon. However, the exact mechanism behind the translocation of GLUT4 vesicles through the sarcolemma during muscle contraction is still unknown. Some substances, such as AMPK and calcium activated proteins, have been suggested as potential mediators but the exact mechanisms of their involvement remain to be elucidated. A hypothetical convergence point between the insulin cascade and the potential pathways triggered by muscle contraction has been suggested. Therefore, the earliest concept that two different routes exist in skeletal muscle has been progressively modified to the notion that glucose uptake is induced by muscle contraction via components of the insulin pathway. With further consideration, increased glucose uptake and enhanced insulin sensitivity observed during/after exercise might be explained by a metabolic- and calcium-dependent activation of several intermediate molecules of the insulin cascade. This paper aimed to review the literature in order to examine in detail these concepts behind muscle contraction-induced glucose uptake.
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PMID:Skeletal muscle pathways of contraction-enhanced glucose uptake. 1840 5

Smooth muscle contraction is initiated by a rise in intracellular calcium, leading to activation of smooth muscle myosin light chain kinase (MLCK) via calcium/calmodulin (CaM). Activated MLCK then phosphorylates the regulatory myosin light chains, triggering cross-bridge cycling and contraction. Here, we show that MLCK is a substrate of AMP-activated protein kinase (AMPK). The phosphorylation site in chicken MLCK was identified by mass spectrometry to be located in the CaM-binding domain at Ser(815). Phosphorylation by AMPK desensitized MLCK by increasing the concentration of CaM required for half-maximal activation. In primary cultures of rat aortic smooth muscle cells, vasoconstrictors activated AMPK in a calcium-dependent manner via CaM-dependent protein kinase kinase-beta, a known upstream kinase of AMPK. Indeed, vasoconstrictor-induced AMPK activation was abrogated by the STO-609 CaM-dependent protein kinase kinase-beta inhibitor. Myosin light chain phosphorylation was increased under these conditions, suggesting that contraction would be potentiated by ablation of AMPK. Indeed, in aortic rings from mice in which alpha1, the major catalytic subunit isoform in arterial smooth muscle, had been deleted, KCl- or phenylephrine-induced contraction was increased. The findings suggest that AMPK attenuates contraction by phosphorylating and inactivating MLCK. This might contribute to reduced ATP turnover in the tonic phase of smooth muscle contraction.
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PMID:AMP-activated protein kinase phosphorylates and desensitizes smooth muscle myosin light chain kinase. 1842 92

Metabolic syndrome accelerates the atherosclerotic process, and the earliest event of which is endothelial dysfunction. Ghrelin, a newly discovered gastric peptide, improves endothelial function and inhibits proatherogenic changes. In particular, low ghrelin concentration has been associated with several features of metabolic syndrome, including obesity, insulin resistance, and high blood pressure. However, the molecular mechanisms underlying ghrelin vascular actions remain largely unclear. Here, we showed that ghrelin activated endothelial nitric oxide (NO) synthase (eNOS) in cultured endothelial cells (ECs) and in intact vessels. Specifically, ghrelin rapidly induced phosphorylation of eNOS on an activation site and production of NO in human umbilical vein ECs and bovine aortic ECs. The eNOS phosphorylation was also observed in mouse aortas ex vivo perfused with ghrelin and in aortic tissues isolated from mice injected with ghrelin. Mechanistically, ghrelin stimulated AMP-activated protein kinase (AMPK) and Akt activation in cultured ECs and intact vessels. Inhibiting AMPK and Akt with their pharmacological inhibitors, small interference RNA and adenoviruses carried dominant-negative mutants, markedly attenuated ghrelin-induced eNOS activation, and NO production. Furthermore, ghrelin receptor/Gq protein/calcium-dependent pathway mediates activation of AMPK, Akt, and eNOS, and calmodulin-dependent kinase kinase is a potential convergent point to regulate Akt and AMPK activation in ghrelin signaling. Importantly, eNOS activation is critical for ghrelin inhibition of vascular inflammation. Together, both in vitro and in vivo data demonstrate a new role of ghrelin signaling for eNOS activation, and highlight the therapeutic potential for ghrelin to correct endothelial dysfunction associated with atherosclerotic vascular diseases and metabolic syndrome.
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PMID:Molecular mechanisms of ghrelin-mediated endothelial nitric oxide synthase activation. 1845 Sep 53

Reproduction is accurately regulated by metabolic states in mammals. Adiponectin regulates luteinizing hormone (LH) secretion in the pituitary and energy homeostasis in the hypothalamus. We further investigated the gonadotropin-releasing hormone (GnRH) secretion regulation by adiponectin and its related molecular and electrophysiological mechanisms. The results showed that adiponectin receptors (AdipR1 and 2) were expressed in GT1-7 cells derived from hypothalamus neurons. GnRH secretion was inhibited via activation of AMP-activated protein kinase (AMPK). Moreover, we revealed that hyperpolarization of plasma membrane potentials and reduction of calcium influx was also caused by adiponectin.
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PMID:Globular adiponectin inhibits GnRH secretion from GT1-7 hypothalamic GnRH neurons by induction of hyperpolarization of membrane potential. 1846 65

AMPK is a metabolic "master" controller activated in skeletal muscle by exercise in a time and intensity dependent manner, and has been implicated in regulating metabolic pathways in muscle during physical exercise. AMPK signaling in skeletal muscle is regulated by several systemic and intracellular factors and the regulation of skeletal muscle AMPK in response to exercise is the focus of this review. Specifically, the role of LKB1 and phosphatase PP2C in nucleotide-dependent activation of AMPK, and ionized calcium in CaMKK-dependent activation of AMPK in working muscle is discussed. We also discuss the influence of reactive oxygen species produced within the muscle as well as muscle glycogen and TAK1 in regulating AMPK during exercise. Currently, during intensive contraction, activation of alpha2-AMPK seems mainly to rely on AMP accumulating from ATP-hydrolysis whereas calcium signaling may have some importance during more gentle contraction conditions. Factors that regulate alpha1-AMPK during exercise are less clear but it appears, at least to some extent, to rely on an adenine nucleotide-dependent mechanism.
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PMID:How is AMPK activity regulated in skeletal muscles during exercise? 1850 8


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