EC:2.7.11.31 - FACTA Search

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)

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.
...
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

Cells aggressively defend adenosine nucleotide homeostasis; intracellular biosensors detect variations in energetic status and communicate with other cellular networks to initiate adaptive responses. Here, we demonstrate some new elements of this communication process, and we show that this networking is compromised by off-target, bioenergetic effects of some popular pharmacological tools. Treatment of cells with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), so as to simulate elevated AMP levels, reduced the synthesis of bis-diphosphoinositol tetrakisphosphate ([PP](2)-InsP(4)), an intracellular signal that phosphorylates proteins in a kinase-independent reaction. This was a selective effect; levels of other inositol phosphates were unaffected by AICAR. By genetically manipulating cellular AMP-activated protein kinase activity, we showed that it did not mediate these effects of AICAR. Instead, we conclude that the simulation of deteriorating adenosine nucleotide balance itself inhibited [PP](2)-InsP(4) synthesis. This conclusion is consistent with our demonstrating that oligomycin elevated cellular [AMP] and selectively inhibited [PP](2)-InsP(4) synthesis without affecting other inositol phosphates. In addition, we report that the shortterm increases in [PP](2)-InsP(4) levels normally seen during hyperosmotic stress were attenuated by 2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamide (PD184352). The latter is typically considered an exquisitely specific mitogen-activated protein kinase kinase (MEK) inhibitor, but small interfering RNA against MEK or extracellular signal-regulated kinase revealed that this mitogen-activated protein kinase pathway was not involved. Instead, we demonstrate that [PP](2)-InsP(4) synthesis was inhibited by PD184352 through its nonspecific effects on cellular energy balance. Two other MEK inhibitors, 1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene (U0126) and 2'-amino-3'-methoxyflavone (PD98059), had similar off-target effects. We conclude that the levels and hence the signaling strength of [PP](2)-InsP(4) is supervised by cellular adenosine nucleotide balance, signifying a new link between signaling and bioenergetic networks.
...
PMID:Cellular energetic status supervises the synthesis of bis-diphosphoinositol tetrakisphosphate independently of AMP-activated protein kinase. 1846 Jun 7

We previously found that the phosphorylation of ERK1/2 by submaximal concentrations of the muscarinic receptor ligand carbachol was potentiated in rat parotid acinar cells exposed to ouabain, a cardiac glycoside that inhibits the Na-K-ATPase. We now report that this signaling phenomenon involves the prevention of negative regulation of extracellular signal-regulated kinase-1/2 (ERK1/2) that is normally mediated by AMP-activated protein kinase (AMPK). Carbachol increases the turnover of the ATP-consuming Na-K-ATPase, reducing intracellular ATP and promoting the phosphorylation/activation of the energy sensor AMPK. Ouabain blocks the reduction in ATP and subsequent AMPK phosphorylation, which is regulated by the AMP-to-ATP ratio. The ouabain-promoted enhancement of ERK1/2 phosphorylation was not reproduced in Par-C10 cells, an immortalized rat parotid cell line that did not respond to carbachol with an ATP reduction and that employs an upstream AMPK kinase (Ca(2+)/calmodulin-dependent protein kinase kinase, CaMKK) different from that (LKB1) in native cells. In native parotid cells, inhibitory effects of AMPK on ERK1/2 signaling were examined by activating AMPK with 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR), which is converted to an AMP mimetic but does not alter parotid ATP levels. AICAR-treated cells display increases in AMPK phosphorylation and a reduced phosphorylation of ERK1/2 subsequent to activation of muscarinic and P2X(7) receptors, which promote increases in Na-K-ATPase turnover, but not upon epidermal growth factor receptor activation. These results suggest that carbachol-initiated AMPK activation can produce a negative feedback on ERK1/2 signaling in response to submaximal muscarinic receptor activation and that increases in fluid secretion can modulate receptor-initiated signaling events indirectly by producing ion transport-dependent decreases in ATP.
...
PMID:Regulation of ERK1/2 by ouabain and Na-K-ATPase-dependent energy utilization and AMPK activation in parotid acinar cells. 1868 86

Endurance training represents one extreme in the continuum of skeletal muscle plasticity. The molecular signals elicited in response to acute and chronic exercise and the integration of multiple intracellular pathways are incompletely understood. We determined the effect of 10 days of intensified cycle training on signal transduction in nine inactive males in response to a 1-h acute bout of cycling at the same absolute workload (164 +/- 9 W). Muscle biopsies were taken at rest and immediately and 3 h after the acute exercise. The metabolic signaling pathways, including AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR), demonstrated divergent regulation by exercise after training. AMPK phosphorylation increased in response to exercise ( approximately 16-fold; P < 0.05), which was abrogated posttraining (P < 0.01). In contrast, mTOR phosphorylation increased in response to exercise ( approximately 2-fold; P < 0.01), which was augmented posttraining (P < 0.01) in the presence of increased mTOR expression (P < 0.05). Exercise elicited divergent effects on mitogen-activated protein kinase (MAPK) pathways after training, with exercise-induced extracellular signal-regulated kinase (ERK) 1/2 phosphorylation being abolished (P < 0.01) and p38 MAPK maintained. Finally, calmodulin kinase II (CaMKII) exercise-induced phosphorylation and activity were maintained (P < 0.01), despite increased expression ( approximately 2-fold; P < 0.05). In conclusion, 10 days of intensified endurance training attenuated AMPK, ERK1/2, and mTOR, but not CaMKII and p38 MAPK signaling, highlighting molecular pathways important for rapid functional adaptations and maintenance in response to intensified endurance exercise and training.
...
PMID:Divergent cell signaling after short-term intensified endurance training in human skeletal muscle. 1882 72

AMP-activated protein kinase (AMPK) and Rho kinase (ROK) are known to modulate the mevalonate pathway. Activation of AMPK suppresses 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase. ROK acts downstream of HMG-CoA reductase, and its inhibition exerts antiatherosclerosis effects. However, whether or not these enzymes are involved in bone metabolism is unclear. The present study was undertaken to investigate the effects of an AMPK activator, 5-aminoimidazole-4-carboxamide1-beta-d-ribonucleoside (AICAR), and a ROK inhibitor, fasudil hydrochrolide, on the mineralization of osteoblastic MC3T3-E1 cells. Real-time PCR and mineralization stainings revealed that both AICAR and fasudil significantly stimulated endothelial nitric oxide synthase (eNOS), bone morphogenetic protein-2 (BMP-2), and osteocalcin mRNA expression as well as mineralization in the cells. Supplementation of either mevalonate or geranyl-geranyl pyrophosphate, the downstream molecules of HMG-CoA reductase, or coincubation with either a nitric oxide synthase inhibitor, N(G)-nitro-l-arginine methyl ester, or a BMP-2 antagonist, noggin, significantly reversed these AICAR-induced reactions. Western blot analysis showed that AICAR activated protein kinase B and extracellular signal-regulated kinase (ERK). ERK inhibitor significantly reversed the AICAR-induced increase in eNOS and BMP-2 mRNA expression. Measurement of ROK activities by enzyme-linked immunosorbent assay revealed that both AICAR and fasudil significantly suppressed the phosphorylation of the myosin-binding subunit of myosin phosphate, a ROK substrate. These findings suggest that the AMPK activator and the ROK inhibitor are able to stimulate the mineralization of osteoblasts through modulating the mevalonate pathway. These agents could be candidate drugs that promote bone formation for the treatment of osteoporosis.
...
PMID:Activation of AMP kinase and inhibition of Rho kinase induce the mineralization of osteoblastic MC3T3-E1 cells through endothelial NOS and BMP-2 expression. 1900 47

Adiponectin, an adipocyte-derived hormone, has been proposed to show antiatherogenic properties through the inhibitory effects against various growth factors. Insulin-like growth factor-1 (IGF-1) is one of the potent mitogens, which has been considered to play important roles in both atherogenesis and plaque stabilization in accordance to the phase of atherosclerosis. The aim of this study is to elucidate the adiponectin effects on IGF-1-induced cell migration and its intracellular signaling pathways in vascular smooth muscle cells (VSMCs). In this study, we assessed cell migration and several kinase activities in cultured rat aortic smooth muscle cells (RASMCs). Adiponectin pretreatment suppressed IGF-1-induced cell migration and extracellular signal-regulated kinase (ERK)1/2 activation, which is one of the major mediators for IGF-1-induced cell migration. In RASMCs, adiponectin and 5-aminoimidazole-4-carboxamide riboside (AICAR), a 5'-AMP-activated protein kinase (AMPK) activator, stimulated AMPK activation. AMPK activation by AICAR inhibited IGF-1-induced ERK1/2 activation and cell migration in RASMCs. On the other hand, phosphorylation of Akt and Bad, proapoptotic molecules of the Bcl-2 family, which were increased by IGF-1 stimulation, was not diminished by the pretreatment with adiponectin. It was shown that adiponectin inhibited IGF-1-induced VSMC migration through suppression of ERK1/2 activation, which might be implicated in AMPK activation. Furthermore, adiponectin selectively inhibited ERK1/2 pathway, not Akt-Bad pathway, stimulated by IGF-1. From these findings, it was implied that adiponectin suppressed IGF-1-induced VSMC migration and its signaling selectivity.
...
PMID:Adiponectin inhibits insulin-like growth factor-1-induced cell migration by the suppression of extracellular signal-regulated kinase 1/2 activation, but not Akt in vascular smooth muscle cells. 1926 81

5-[5-(2-Nitrophenyl) furfuryliodine]-1,3-diphenyl-2-thiobarbituric acid (UCF-101) is a protease inhibitor which was reported to protect against ischaemic heart damage and apoptosis. This study evaluated the impact of UCF-101 on steptozotocin (STZ)-induced diabetic cardiomyocyte dysfunction. Adult FVB mice were made diabetic with a single injection of STZ (200 mg kg(1)). Two weeks after STZ injection, cardiomyocytes from control and STZ-treated mice were isolated and treated with UCF-101 (20 mum for 1 h). Cardiomyocyte contractile properties were analysed, including peak shortening (PS), maximal velocity of shortening/relengthening (+/-dL/dt), time to PS (TPS) and time to 90% relengthening (TR(90)). Steptozotocin-induced diabetes depressed PS and +/-dL/dt and prolonged TPS and TR(90) in cardiomyocytes, all of which were significantly alleviated by UCF-101. Immunoblotting analysis showed that UCF-101 significantly alleviated STZ-induced loss of phospholamban phosphorylation without affecting sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2a) and phospholamban. Steptozotocin reduced AMP-activated protein kinase (AMPK) phosphorylation at Thr172 of the catalytic subunit without affecting total AMPK expression, which was restored by UCF-101. Short-term exposure to UCF-101 did not change the expression of X-linked inhibitor of apoptosis protein (XIAP) and Omi stress-regulated endoprotease, high temperature requirement protein A2 (Omi/HtrA2), favouring an apoptosis-independent mechanism. Both the AMPK activator resveratrol and the antioxidant N-acetylcysteine mimicked the UCF-101-induced beneficial effect in STZ-induced diabetic cardiomyocytes. In addition, UCF-101 promoted the phosphorylation of p38 mitogen-activated protein kinases and c-Jun N-terminal kinase (JNK) after 15 min of incubation, while it failed to affect the phosphorylation of extracellular signal-regulated kinase (ERK) and glycogen synthase kinase-3beta (GSK-3beta) within 120 min in H9C2 myoblasts. Taken together, these results indicate that UCF-101 protects against STZ-induced cardiomyocyte contractile dysfunction, possibly via an AMPK-associated mechanism.
...
PMID:The protease inhibitor UCF-101 ameliorates streptozotocin-induced mouse cardiomyocyte contractile dysfunction in vitro: role of AMP-activated protein kinase. 2751 Jun 42

The favorable effects of the peroxisome proliferator-activated receptor-gamma ligand pioglitazone on glucose metabolism are associated with an increase in the fat-derived hormone adiponectin in the bloodstream. A recent clinical trial, Prospective Pioglitazone Clinical Trial in Macrovascular Events, demonstrated that pioglitazone improved cardiovascular outcomes in patients with type 2 diabetes mellitus. However, the functional role of adiponectin in cardioprotection by pioglitazone has not been examined experimentally. Here we investigated the effect of pioglitazone on angiotensin II (Ang II)-induced cardiac hypertrophy and assessed the potential contribution of adiponectin to the action of pioglitazone on the heart. Wild-type or adiponectin-deficient mice were treated with pioglitazone as food admixture at a concentration of 0.01% for 1 week followed by 2 weeks of infusion with Ang II at 3.2 mg/kg per day. Ang II infusion in wild-type mice resulted in exacerbated myocyte hypertrophy and increased interstitial fibrosis, which were accompanied by elevated phosphorylation of extracellular signal-regulated kinase and expression of transforming growth factor-beta1 in the heart. Treatment of wild-type mice with pioglitazone attenuated cardiac hypertrophy and fibrosis, extracellular signal-regulated kinase phosphorylation, and transforming growth factor-beta1 expression in response to Ang II. Pioglitazone also increased the plasma adiponectin level and phosphorylation of cardiac AMP-activated protein kinase in wild-type mice in the presence of Ang II. The suppressive effects of pioglitazone on Ang II-induced cardiac hypertrophy and fibrosis were diminished in adiponectin-deficient mice. Furthermore, pioglitazone had no effects on the phosphorylation of extracellular signal-regulated kinase and AMP-activated protein kinase in the Ang II-infused heart of adiponectin-deficient mice. These data provide direct evidence that pioglitazone protects against Ang II-induced pathological cardiac remodeling via an adiponectin-dependent mechanism.
...
PMID:Evidence for the importance of adiponectin in the cardioprotective effects of pioglitazone. 1993 24

The Rendement Napole (RN) genotype widely exists in Hampshire pigs. Recently, RN gene was identified as a R200Q mutation in AMP-activated protein kinase (AMPK) gamma3 subunit. The effect of RN genotype on the growth performance of animals and the underlying mechanisms remain controversial. Using transgenic mice carrying an analogous R225Q mutation, the objective of this study was to study the role of RN gene in the growth performance of animals at different energy levels. Wild-type (WT) mice and those with the RN mutation were assigned to 4 groups: 1) WT plus normal diet, 2) RN plus normal diet, 3) WT plus high-energy diet, and 4) RN plus high-energy diet. Mice were weaned at 21 d old and fed the trial diets for 1 mo and then killed for carcass measurements. The pH of postmortem muscle from RN mice was less (P < 0.01) than that from WT mice. No difference in growth performance was observed when mice were fed a normal diet. When fed a high-energy diet, RN mice showed a greater fat accumulation (WT vs. RN, 1.11 vs. 1.63 g for gonadal fat and 1.40 vs. 1.84 g for subcutaneous fat; P < 0.05). Muscle weight was also increased (WT vs. RN, 0.27 vs. 0.30 g for gastrocnemius muscle; P < 0.05). The food consumption was greater in RN compared with WT mice (2.95 vs. 2.49 g; P < 0.05). The AMPK content and its downstream target, acetyl-CoA carboxylase (ACC), content were greater in RN mice (P < 0.05). The phosphorylation of ACC at Ser 79, a site exclusively phosphorylated by AMPK, was increased (P < 0.05), showing greater AMPK activity in RN mouse muscle. No difference in muscle fiber composition and mitochondrial content was observed between WT and RN mice. High fat diet downregulates protein kinase B but upregulates extracellular signal-regulated kinase signaling. In conclusion, the R225Q mutation has no major effect on the growth performance of animals fed a normal diet; a high-energy diet increased fatness in RN mice, likely due to their greater consumption of feed compared with WT mice.
...
PMID:Mouse AMP-activated protein kinase gamma3 subunit R225Q mutation affecting mouse growth performance when fed a high-energy diet. 2002 37

Mitogen-activated protein kinase (MAPK) pathways are involved in the regulation of cellular responses, including cell proliferation, differentiation, cell growth, and apoptosis. Because these responses are tightly related to cellular energy level, AMP-activated protein kinase (AMPK), which plays an essential role in energy homeostasis, has emerged as another key regulator. In the present study, we demonstrate a novel signal network between AMPK and MAPK in HCT116 human colon carcinoma. Glucose deprivation activated AMPK and three MAPK subfamilies, extracellular signal-regulated kinase (ERK), c-Jun NH(2)-terminal kinase (JNK), and p38 MAPK. Under these conditions, inhibition of endogenous AMPK by expressing a dominant-negative form significantly potentiated ERK activation, indicating that glucose deprivation-induced AMPK is specifically antagonizing ERK activity in HCT116 cells. Moreover, we provide novel evidence that AMPK activity is critical for p53-dependent expression of dual-specificity phosphatase (DUSP) 1 & 2, which are negative regulators of ERK. Notably, ERK exhibits pro-apoptotic effects in HCT116 cells under glucose deprivation. Collectively, our data suggest that AMPK protects HCT116 cancer cells from glucose deprivation, in part, via inducing DUSPs, which suppresses pro-apoptotic ERK, further implying that a signal network between AMPK and ERK is a critical regulatory point in coupling the energy status of the cell to the regulation of cell survival.
...
PMID:AMP-activated protein kinase antagonizes pro-apoptotic extracellular signal-regulated kinase activation by inducing dual-specificity protein phosphatases in response to glucose deprivation in HCT116 carcinoma. 3044 2

<< Previous 1 2 3 4 5 6 7 8 9 Next >>