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AMP-activated Protein Kinase (amp-activated + protein_kinase)
Selected AbstractsAMP-activated protein kinase in Sickness and Health , From Molecule to ManACTA PHYSIOLOGICA, Issue 1 2009J. F. P. Wojtaszewski No abstract is available for this article. [source] Structure and function of AMP-activated protein kinaseACTA PHYSIOLOGICA, Issue 1 2009J. S. Oakhill Abstract AMP-activated protein kinase (AMPK) regulates metabolism in response to energy demand and supply. AMPK is activated in response to rises in intracellular AMP or calcium-mediated signalling and is responsible for phosphorylating a wide variety of substrates. Recent structural studies have revealed the architecture of the ,,, subunit interactions as well as the AMP binding pockets on the , subunit. The , catalytic domain (1,280) is autoinhibited by a C-terminal tail (313,335), which is proposed to interact with the small lobe of the catalytic domain by homology modelling with the MARK2 protein structure. Two direct activating drugs have been reported for AMPK, the thienopyridone compound A769662 and PTI, which may activate by distinct mechanisms. [source] The regulation and function of mammalian AMPK-related kinasesACTA PHYSIOLOGICA, Issue 1 2009N. J. Bright Abstract AMP-activated protein kinase (AMPK) is a key regulator of cellular and whole-body energy homeostasis. Recently, 12 AMPK-related kinases (BRSK1, BRSK2, NUAK1, NUAK2, QIK, QSK, SIK, MARK1, MARK2, MARK3, MARK4 and MELK) were identified that are closely related by sequence homology to the catalytic domain of AMPK. The protein kinase LKB1 acts as a master upstream kinase activating AMPK and 11 of the AMPK-related kinases by phosphorylation of a conserved threonine residue in their T-loop region. Further sequence analyses have identified the eight-member SNRK kinase family as distant relatives of AMPK. However, only one of these is phosphorylated and activated by LKB1. Although much is known about AMPK, many of the AMPK-related kinases remain largely uncharacterized. This review outlines the general similarities in structure and function of the AMPK-related kinases before examining the specific characteristics of each, including a brief discussion of the SNRK family. [source] AMP-activated protein kinase: a core signalling pathway in the heartACTA PHYSIOLOGICA, Issue 1 2009A. S. Kim Abstract Over the past decade, AMP-activated protein kinase (AMPK) has emerged as an important intracellular signalling pathway in the heart. Activated AMPK stimulates the production of ATP by regulating key steps in both glucose and fatty acid metabolism. It has an inhibitory effect on cardiac protein synthesis. AMPK also interacts with additional intracellular signalling pathways in a coordinated network that modulates essential cellular processes in the heart. Evidence is accumulating that AMPK may protect the heart from ischaemic injury and limit the development of cardiac myocyte hypertrophy to various stimuli. Heart AMPK is activated by hormones, cytokines and oral hypoglycaemic drugs that are used in the treatment of type 2 diabetes. The tumour suppressor LKB1 is the major regulator of AMPK activity, but additional upstream kinases and protein phosphatases also contribute. Mutations in the regulatory ,2 subunit of AMPK lead to an inherited syndrome of hypertrophic cardiomyopathy and ventricular pre-excitation, which appears to be due to intracellular glycogen accumulation. Future research promises to elucidate the molecular mechanisms responsible for AMPK activation, novel downstream AMPK targets, and the therapeutic potential of targeting AMPK for the prevention and treatment of myocardial ischaemia or cardiac hypertrophy. [source] AMP-activated protein kinase and cancerACTA PHYSIOLOGICA, Issue 1 2009W. Wang Abstract AMP-activated protein kinase (AMPK) is a cellular energy sensor that is conserved in eukaryotes. Elevated AMP/ATP ratio activates AMPK, which inhibits energy-consuming processes and activates energy-producing processes to restore the energy homeostasis inside the cell. AMPK activators, metformin and thiazolidinediones, are used for the treatment of type II diabetes. Recently, reports have indicated that AMPK may also be a beneficial target for cancer treatment. Cancer cells have characteristic metabolic changes different from normal cells and, being a key metabolic regulator, AMPK may regulate the switch. AMPK may act to inhibit tumorigenesis through regulation of cell growth, cell proliferation, autophagy, stress responses and cell polarity. [source] AMP-activated protein kinase in the regulation of hepatic energy metabolism: from physiology to therapeutic perspectivesACTA PHYSIOLOGICA, Issue 1 2009B. Viollet Abstract As the liver is central in the maintenance of glucose homeostasis and energy storage, knowledge of the physiology as well as physiopathology of hepatic energy metabolism is a prerequisite to our understanding of whole-body metabolism. Hepatic fuel metabolism changes considerably depending on physiological circumstances (fed vs. fasted state). In consequence, hepatic carbohydrate, lipid and protein synthesis/utilization are tightly regulated according to needs. Fatty liver and hepatic insulin resistance (both frequently associated with the metabolic syndrome) or increased hepatic glucose production (as observed in type 2 diabetes) resulted from alterations in substrates oxidation/storage balance in the liver. Because AMP-activated protein kinase (AMPK) is considered as a cellular energy sensor, it is important to gain understanding of the mechanism by which hepatic AMPK coordinates hepatic energy metabolism. AMPK has been implicated as a key regulator of physiological energy dynamics by limiting anabolic pathways (to prevent further ATP consumption) and by facilitating catabolic pathways (to increase ATP generation). Activation of hepatic AMPK leads to increased fatty acid oxidation and simultaneously inhibition of hepatic lipogenesis, cholesterol synthesis and glucose production. In addition to a short-term effect on specific enzymes, AMPK also modulates the transcription of genes involved in lipogenesis and mitochondrial biogenesis. The identification of AMPK targets in hepatic metabolism should be useful in developing treatments to reverse metabolic abnormalities of type 2 diabetes and the metabolic syndrome. [source] AMP-activated protein kinase , a sensor of glycogen as well as AMP and ATP?ACTA PHYSIOLOGICA, Issue 1 2009A. McBride Abstract The classical role of the AMP-activated protein kinase (AMPK) is to act as a sensor of the immediate availability of cellular energy, by monitoring the concentrations of AMP and ATP. However, the , subunits of AMPK contain a glycogen-binding domain, and in this review we develop the hypothesis that this is a regulatory domain that allows AMPK to act as a sensor of the status of cellular reserves of energy in the form of glycogen. We argue that the pool of AMPK that is bound to the glycogen particle is in an active state when glycogen particles are fully synthesized, causing phosphorylation of glycogen synthase at site 2 and providing a feedback inhibition of further extension of the outer chains of glycogen. However, when glycogen becomes depleted, the glycogen-bound pool of AMPK becomes inhibited due to binding to ,1,6-linked branch points exposed by the action of phosphorylase and/or debranching enzyme. This allows dephosphorylation of site 2 on glycogen synthase by the glycogen-bound form of protein phosphatase-1, promoting rapid resynthesis of glycogen and replenishment of glycogen stores. This is an extension of the classical role of AMPK as a ,guardian of cellular energy', in which it ensures that cellular energy reserves are adequate for medium-term requirements. The literature concerning AMPK, glycogen structure and glycogen-binding proteins that led us to this concept is reviewed. [source] AMP-activated protein kinase control of fat metabolism in skeletal muscleACTA PHYSIOLOGICA, Issue 1 2009D. M. Thomson Abstract AMP-activated protein kinase (AMPK) has emerged as a key regulator of skeletal muscle fat metabolism. Because abnormalities in skeletal muscle metabolism contribute to a variety of clinical diseases and disorders, understanding AMPK's role in the muscle is important. It was originally shown to stimulate fatty acid (FA) oxidation decades ago, and since then much research has been accomplished describing this role. In this brief review, we summarize much of these data, particularly in relation to changes in FA oxidation that occur during skeletal muscle exercise. Potential roles for AMPK exist in regulating FA transport into the mitochondria via interactions with acetyl-CoA carboxylase, malonyl-CoA decarboxylase, and perhaps FA transporter/CD36 (FAT/CD36). Likewise, AMPK may regulate transport of FAs into the cell through FAT/CD36. AMPK may also regulate capacity for FA oxidation by phosphorylation of transcription factors such as CREB or coactivators such as PGC-1,. [source] AMP-activated protein kinase in contraction regulation of skeletal muscle metabolism: necessary and/or sufficient?ACTA PHYSIOLOGICA, Issue 1 2009T. E. Jensen Abstract In skeletal muscle, the contraction-activated heterotrimeric 5,-AMP-activated protein kinase (AMPK) protein is proposed to regulate the balance between anabolic and catabolic processes by increasing substrate uptake and turnover in addition to regulating the transcription of proteins involved in mitochondrial biogenesis and other aspects of promoting an oxidative muscle phenotype. Here, the current knowledge on the expression of AMPK subunits in human quadriceps muscle and evidence from rodent studies suggesting distinct AMPK subunit expression pattern in different muscle types is reviewed. Then, the intensity and time dependence of AMPK activation in human quadriceps and rodent muscle are evaluated. Subsequently, a major part of this review critically examines the evidence supporting a necessary and/or sufficient role of AMPK in a broad spectrum of skeletal muscle contraction-relevant processes. These include glucose uptake, glycogen synthesis, post-exercise insulin sensitivity, fatty acid (FA) uptake, intramuscular triacylglyceride hydrolysis, FA oxidation, suppression of protein synthesis, proteolysis, autophagy and transcriptional regulation of genes relevant to promoting an oxidative phenotype. [source] AMPK activators , potential therapeutics for metabolic and other diseasesACTA PHYSIOLOGICA, Issue 1 2009G. Zhou Abstract AMP-activated protein kinase (AMPK)-mediated cellular metabolic responses to tissue-specific and whole-body stimuli play a vital role in the control of energy homeostasis. As a cellular energy-sensing mechanism, AMPK activation stimulates glucose uptake and fat oxidation, while it suppresses lipogenesis and gluconeogenesis. The cumulative effects of AMPK activation lead to beneficial metabolic states in liver, muscle and other peripheral tissues that are critical in the pathogenesis of obesity, type 2 diabetes and related metabolic disorders. Activators of AMPK that target selected tissues hold potential as novel therapeutics for diseases in which altered energy metabolism contributes to aetiology. [source] AMP-activated protein kinase: role in metabolism and therapeutic implicationsDIABETES OBESITY & METABOLISM, Issue 6 2006Greg Schimmack AMP-activated protein kinase (AMPK) is an enzyme that works as a fuel gauge which becomes activated in situations of energy consumption. AMPK functions to restore cellular ATP levels by modifying diverse metabolic and cellular pathways. In the skeletal muscle, AMPK is activated during exercise and is involved in contraction-stimulated glucose transport and fatty acid oxidation. In the heart, AMPK activity increases during ischaemia and functions to sustain ATP, cardiac function and myocardial viability. In the liver, AMPK inhibits the production of glucose, cholesterol and triglycerides and stimulates fatty acid oxidation. Recent studies have shown that AMPK is involved in the mechanism of action of metformin and thiazolidinediones, and the adipocytokines leptin and adiponectin. These data, along with evidence that pharmacological activation of AMPK in vivo improves blood glucose homeostasis, cholesterol concentrations and blood pressure in insulin-resistant rodents, make this enzyme an attractive pharmacological target for the treatment of type 2 diabetes, ischaemic heart disease and other metabolic diseases. [source] AMP-activated protein kinase enhances the expression of muscle-specific ubiquitin ligases despite its activation of IGF-1/Akt signaling in C2C12 myotubesJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2009Jun F. Tong Abstract Two muscle-specific ubiquitin ligases (UL), muscle atrophy F box (MAFbx) and muscle RING finger 1 (MuRF1), are crucial for myofibrillar protein breakdown. The insulin like growth factor-1 (IGF-1) pathway inhibits muscle UL expression through Akt-mediated inhibition of FoxO transcription factors, while AMP-activated protein kinase (AMPK) promotes UL expression. The underlying cellular mechanism, however, remains obscure. In this study, the effect of AMPK and its interaction with IGF-1 on ubiquitin ligases expression was investigated. C2C12 myotubes were treated with 0, 0.1, 0.3, and 1.0,mM 5-aminoimidazole-4-carboxamide-1-,- D -ribofuranoside (AICAR) in the presence or absence of 50,ng/ml IGF-1. IGF-1 activated Akt, which enhanced phosphorlytion of FoxO3a at Thr 318/321 and reduced the expression of UL. Intriguingly, though activation of AMPK by 0.3 and 1.0,mM AICAR synergized IGF-1-induced Akt activation, the expression of UL was not attenuated, but strengthened by AMPK activation. AICAR treatment decreased FoxO3a phosphorylation at 318/321 in the cytoplasm and induced FoxO3 nuclear relocation. mTOR inhibition increased basal MAFbx expression and reversed the inhibitory effect of IGF-1 on UL expression. In conclusion, our data show that AMPK activation by AICAR stimulates UL expression despite the activation of Akt signaling, which may be due to the possible antagonistic effect of FoxO phosphorylation by AMPK on phosphorylation by Akt. In addition, AMPK inhibition of mTOR may provide an additional explanation for the enhancement of UL expression by AMPK. J. Cell. Biochem. 108: 458,468, 2009. © 2009 Wiley-Liss, Inc. [source] Exercise intensity-dependent regulation of peroxisome proliferator-activated receptor , coactivator-1, mRNA abundance is associated with differential activation of upstream signalling kinases in human skeletal muscleTHE JOURNAL OF PHYSIOLOGY, Issue 10 2010Brendan Egan Skeletal muscle contraction increases intracellular ATP turnover, calcium flux, and mechanical stress, initiating signal transduction pathways that modulate peroxisome proliferator-activated receptor , coactivator-1, (PGC-1,)-dependent transcriptional programmes. The purpose of this study was to determine if the intensity of exercise regulates PGC-1, expression in human skeletal muscle, coincident with activation of signalling cascades known to regulate PGC-1, transcription. Eight sedentary males expended 400 kcal (1674 kj) during a single bout of cycle ergometer exercise on two separate occasions at either 40% (LO) or 80% (HI) of,. Skeletal muscle biopsies from the m. vastus lateralis were taken at rest and at +0, +3 and +19 h after exercise. Energy expenditure during exercise was similar between trials, but the high intensity bout was shorter in duration (LO, 69.9 ± 4.0 min; HI, 36.0 ± 2.2 min, P < 0.05) and had a higher rate of glycogen utilization (P < 0.05). PGC-1, mRNA abundance increased in an intensity-dependent manner +3 h after exercise (LO, 3.8-fold; HI, 10.2-fold, P < 0.05). AMP-activated protein kinase (AMPK) (2.8-fold, P < 0.05) and calcium/calmodulin-dependent protein kinase II (CaMKII) phosphorylation (84%, P < 0.05) increased immediately after HI but not LO. p38 mitogen-activated protein kinase (MAPK) phosphorylation increased after both trials (,2.0-fold, P < 0.05), but phosphorylation of the downstream transcription factor, activating transcription factor-2 (ATF-2), increased only after HI (2.4-fold, P < 0.05). Cyclic-AMP response element binding protein (CREB) phosphorylation was elevated at +3 h after both trials (,80%, P < 0.05) and class IIa histone deacetylase (HDAC) phosphorylation increased only after HI (2.0-fold, P < 0.05). In conclusion, exercise intensity regulates PGC-1, mRNA abundance in human skeletal muscle in response to a single bout of exercise. This effect is mediated by differential activation of multiple signalling pathways, with ATF-2 and HDAC phosphorylation proposed as key intensity-dependent mediators. [source] Characterization of the porcine AMPK alpha 2 catalytic subunitgene (PRKAA2): genomic structure, polymorphism detection and association studyANIMAL GENETICS, Issue 2 2010L. Lin Summary AMP-activated protein kinase (AMPK), known as a key regulator of cellular energy homeostasis, plays an important role in regulation of glucose and lipid metabolism, and protein synthesis in mammals. The characterization of porcine PRKAA2 encoding the alpha 2 catalytic subunit of AMPK is reported in this study. PRKAA2 was assigned to porcine chromosome 6q by analysis of radiation hybrids (IMpRH panel), and its genomic structure was determined by BAC sequencing. PRKAA2 spans more than 62 kb and consists of nine exons and eight introns. A total of 25 polymorphisms were identified by re-sequencing approximately 7 kb, including all the exons, exon,intron boundaries and 5, and 3, gene flanking regions using twelve founder animals of a Mangalitsa × Piétrain intercross. Neither of two single nucleotide polymorphisms (SNPs) found in the coding region caused an amino acid substitution. Two SNPs (NM_214266.1: c.236+142A>G and NM_214266.1: c.630C>T) in PRKAA2 were genotyped in the Mangalitsa × Piétrain F2 cross (n = 589) and two commercial populations [Piétrain (n = 1173) and German Landrace (n = 536)] and evaluated for association with traits of interest (muscle development and fat deposition). Single SNP and haplotype analyses revealed weak associations between the PRKAA2 genotypes and loin muscle area in the investigated populations. [source] An inhibited conformation for the protein kinase domain of the Saccharomyces cerevisiae AMPK homolog Snf1ACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 9 2010Michael J. Rudolph AMP-activated protein kinase (AMPK) is a master metabolic regulator for controlling cellular energy homeostasis. Its homolog in yeast, SNF1, is activated in response to glucose depletion and other stresses. The catalytic (,) subunit of AMPK/SNF1 in yeast (Snf1) contains a protein Ser/Thr kinase domain (KD), an auto-inhibitory domain (AID) and a region that mediates interactions with the two regulatory (, and ,) subunits. Here, the crystal structure of residues 41,440 of Snf1, which include the KD and AID, is reported at 2.4,Å resolution. The AID is completely disordered in the crystal. A new inhibited conformation of the KD is observed in a DFG-out conformation and with the glycine-rich loop adopting a structure that blocks ATP binding to the active site. [source] 5-Aminoimidazole-4-carboxamide-1-,- d -ribofuranoside Increases Myocardial Glucose Uptake during Reperfusion and Induces Late Pre-conditioning: Potential Role of AMP-Activated Protein KinaseBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 1 2009Steen B. Kristiansen AMP-activated protein kinase (AMPK) is activated by exercise and 5-aminoimidazole-4-carboxamide-1-,- d -ribofuranoside (AICAR). Early pre-conditioning involves AMPK activation and increased myocardial glucose uptake. The aim of the present study was to determine whether AICAR activates myocardial AMPK and induces late pre-conditioning and whether myocardial glucose uptake during reperfusion was modulated. Twenty-four hours after AICAR treatment or exercise, Wistar rats were subjected to ischaemia and reperfusion in a Langendorff model and compared to control rats. AMPK activity increased immediately 2.5-fold in AICAR-treated animals (P < 0.01) and twofold in exercised animals (P < 0.05). AICAR and exercise reduced infarct size by 60% and 50% (both P < 0.01), respectively, and increased myocardial glucose uptake during reperfusion (AICAR; 45%, P < 0.05, exercise; 40%, P < 0.05). In conclusion, AICAR induces late pre-conditioning and increases myocardial glucose uptake during reperfusion in rat hearts. AICAR and exercise activate AMPK, suggesting a role of AMPK in the signalling mechanisms behind late pre-conditioning. [source] Expanding roles for AMP-activated protein kinase in neuronal survival and autophagyBIOESSAYS, Issue 9 2009Jeroen Poels Abstract AMP-activated protein kinase (AMPK) is an evolutionarily conserved cellular switch that activates catabolic pathways and turns off anabolic processes. In this way, AMPK activation can restore the perturbation of cellular energy levels. In physiological situations, AMPK senses energy deficiency (in the form of an increased AMP/ATP ratio), but it is also activated by metabolic insults, such as glucose or oxygen deprivation. Metformin, one of the most widely prescribed anti-diabetic drugs, exerts its actions by AMPK activation. However, while the functions of AMPK as a metabolic regulator are fairly well understood, its actions in neuronal cells only recently gained attention. This review will discuss newly emerged functions of AMPK in neuroprotection and neurodegeneration. Additionally, recent views on the role of AMPK in autophagy, an important catabolic process that is also involved in neurodegeneration and cancer, will be highlighted. [source] Crystallization of the glycogen-binding domain of the AMP-activated protein kinase , subunit and preliminary X-ray analysisACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 1 2005Galina Polekhina AMP-activated protein kinase (AMPK) is an intracellular energy sensor that regulates metabolism in response to energy demand and supply by adjusting the ATP-generating and ATP-consuming pathways. AMPK potentially plays a critical role in diabetes and obesity as it is known to be activated by metforin and rosiglitazone, drugs used for the treatment of type II diabetes. AMPK is a heterotrimer composed of a catalytic , subunit and two regulatory subunits, , and ,. Mutations in the , subunit are known to cause glycogen accumulation, leading to cardiac arrhythmias. Recently, a functional glycogen-binding domain (GBD) has been identified in the , subunit. Here, the crystallization of GBD in the presence of ,-cyclodextrin is reported together with preliminary X-ray data analysis allowing the determination of the structure by single isomorphous replacement and threefold averaging using in-house X-ray data collected from a selenomethionine-substituted protein. [source] | |||||||||||||