Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.27 (AMPK)
 6,299 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nucleoside diphosphate kinase A (NDPK-A) regulates the alpha1 isoform of the AMP-activated protein kinase (AMPK alpha1) selectively, independent of [AMP] and surrounding [ATP], by a process termed substrate channelling. Here, we show, using a range of empirically validated biochemical techniques, that the muscle form (M-LDH or LDH-A) and the heart form (H-LDH or LDH-B) of lactate dehydrogenase are physically associated with the liver cytosolic substrate-channelling complex such that M-LDH associates with NDPK-A, AMPK alpha1 and casein kinase 2 (CK2), whereas H-LDH associates with local NDPK-B. We find that the species of LDH bound to the substrate-channelling complex regulates the in vivo enzymatic activities of both AMPK and CK2, and has a downstream effect on the phospho-status of acetyl CoA carboxylase, a key regulator of cellular fat metabolism known to be a part of the cytosolic substrate-channelling complex in vivo. We hypothesise that the regulatory presence of LDH in the complex couples the substrate-channelling mechanism to both the glycolytic and redox states of the cell, allowing for efficient sensing of cell metabolic status, interfacing with the substrate-channelling complex and regulating the enzymatic activities of AMPK and CK2, two critical protein kinases.
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PMID:M-LDH serves as a regulatory subunit of the cytosolic substrate-channelling complex in vivo. 1757 40

The carotid body is a peripheral sensory organ that can transduce modest falls in the arterial PO(2) (partial pressure of oxygen) into a neural signal that provides the afferent limb of a set of stereotypic cardiorespiratory reflexes that are graded according to the intensity of the stimulus. The stimulus sensed is tissue PO(2) and this can be estimated to be around 50 mmHg during arterial normoxia, falling to between 10-40 mmHg during hypoxia. The chemoafferent hypoxia stimulus-response curve is exponential, rising in discharge frequency with falling PO(2), and with no absolute threshold apparent in hyperoxia. Although the oxygen sensor has not been definitely identified, it is believed to reside within type I cells of the carotid body, and presently two major hypotheses have been put forward to account for the sensing mechanism. The first relies upon alterations in the cell energy status that is sensed by the cytosolic enzyme AMPK (AMP-activated protein kinase) subsequent to hypoxia-induced increases in the cellular AMP/ATP ratio during hypoxia. AMPK is localized close to the plasma membrane and its activation can inhibit both large conductance, calcium-activated potassium (BK) and background, TASK-like potassium channels, inducing membrane depolarization, voltage-gated calcium entry and neurosecretion of a range of transmitter and modulator substances, including catecholamines, ATP and acetylcholine. The alternative hypothesis considers a role for haemoxygenase-2, which uses oxygen as a substrate and may act to gate an associated BK channel through the action of its products, carbon monoxide and possibly haem. It is likely however, that these and other hypotheses of oxygen transduction are not mutually exclusive and that each plays a role, via its own particular sensitivity, in shaping the full response of this organ between hyperoxia and anoxia.
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PMID:Sensing hypoxia in the carotid body: from stimulus to response. 1770 92

The AMPK (AMP-activated protein kinase) is a highly conserved eukaryotic protein serine/threonine kinase. It mediates a nutrient signalling pathway that senses cellular energy status and was appropriately called the fuel gauge of the cell. At the cellular level, AMPK controls energy homoeostasis by switching on catabolic ATP-generating pathways, while switching off anabolic ATP-consuming processes. Its effect on energy balance extends to whole-body energy homoeostasis, because, in the hypothalamus, it integrates nutritional and hormonal signals that control food intake and body weight. The interest in AMPK also stems from the demonstration of its insulin-independent stimulation of glucose transport in skeletal muscle during exercise. Moreover, the potential importance of AMPK in metabolic diseases is supported by the notion that AMPK mediates the anti-diabetic action of biguanides and thiazolidinediones and that it might be involved in the metabolic syndrome. Finally, the more recent demonstration that AMPK activation could occur independently of changes in cellular energy status, suggests that AMPK action extends to the control of non-metabolic functions.
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PMID:The AMP-activated protein kinase: more than an energy sensor. 1770 97

The cellular slime mold Dictyostelium discoideum has become an increasingly useful model for the study of mitochondrial biology and disease. Dictyostelium is an amoebazoan, a sister clade to the animal and fungal lineages. The mitochondrial biology of Dictyostelium exhibits some features which are unique, others which are common to all eukaryotes, and still others that are otherwise found only in the plant or the animal lineages. The AT-rich mitochondrial genome of Dictyostelium is larger than its mammalian counterpart and contains 56kb (compared to 17kb in mammals) encoding tRNAs, rRNAs, and 33 polypeptides (compared to 13 in mammals). It produces a single primary transcript that is cotranscriptionally processed into multiple monocistronic, dicistronic, and tricistronic mRNAs, tRNAs, and rRNAs. The mitochondrial fission mechanism employed by Dictyostelium involves both the extramitochondrial dynamin-based system used by plant, animal, and fungal mitochondria and the ancient FtsZ-based intramitochondrial fission process inherited from the bacterial ancestor. The mitochondrial protein-import apparatus is homologous to that of other eukaryote, and mitochondria in Dictyostelium play an important role in the programmed cell death pathways. Mitochondrial disease in Dictyostelium has been created both by targeted gene disruptions and by antisense RNA and RNAi inhibition of expression of essential nucleus-encoded mitochondrial proteins. This has revealed a regular pattern of aberrant mitochondrial disease phenotypes caused not by ATP insufficiency per se, but by chronic activation of the universal eukaryotic energy-sensing protein kinase AMPK. This novel insight into the cytopathological mechanisms of mitochondrial dysfunction suggests new possibilities for therapeutic intervention in mitochondrial and neurodegenerative diseases.
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PMID:Mitochondrial biology and disease in Dictyostelium. 1772 68

Berberine, a botanical alkaloid used to control blood glucose in type 2 diabetes in China, has recently been reported to activate AMPK. However, it is not clear how AMPK is activated by berberine. In this study, activity and action mechanism of berberine were investigated in vivo and in vitro. In dietary obese rats, berberine increased insulin sensitivity after 5-wk administration. Fasting insulin and HOMA-IR were decreased by 46 and 48%, respectively, in the rats. In cell lines including 3T3-L1 adipocytes, L6 myotubes, C2C12 myotubes, and H4IIE hepatocytes, berberine was found to increase glucose consumption, 2-deoxyglucose uptake, and to a less degree 3-O-methylglucose (3-OMG) uptake independently of insulin. The insulin-induced glucose uptake was enhanced by berberine in the absence of change in IRS-1 (Ser307/312), Akt, p70 S6, and ERK phosphorylation. AMPK phosphorylation was increased by berberine at 0.5 h, and the increase remained for > or =16 h. Aerobic and anaerobic respiration were determined to understand the mechanism of berberine action. The long-lasting phosphorylation of AMPK was associated with persistent elevation in AMP/ATP ratio and reduction in oxygen consumption. An increase in glycolysis was observed with a rise in lactic acid production. Berberine exhibited no cytotoxicity, and it protected plasma membrane in L6 myotubes in the cell culture. These results suggest that berberine enhances glucose metabolism by stimulation of glycolysis, which is related to inhibition of glucose oxidation in mitochondria. Berberine-induced AMPK activation is likely a consequence of mitochondria inhibition that increases the AMP/ATP ratio.
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PMID:Berberine improves glucose metabolism through induction of glycolysis. 1797 14

Glucose sensing mechanism has been intensively studied in pancreatic cells and neurons. Depolarization of membrane potential by closure of K(ATP) , Kv and TASK channel, and subsequently Ca(2+) entry via L-type voltage gated Ca(2+) channel (VGCC) are implicated to mediate the signal transduction in these cells. However, the mechanism of non-excitable cells, which are lacking VGCC, for sensing glucose remains unclear. In this study, we utilized the calcium ratio measurement and patch clamping technique to study the effects of low glucose on [Ca(2+)](i) and currents in the human embryonic kidney epithelial cells (HEK 293). We found low glucose evoked a significant reversible [Ca(2+)](i) elevation in HEK 293 independent of the closure of Kv channels. This increase of [Ca(2+)](i) was mediated by Ca(2+) entry across plasma membrane and exhibited a dosage dependent behaviour to external glucose concentration. The low glucose-induced entry of Ca(2+) was characterized as a voltage independent behaviour and had cation permeability to Na(+) and Ca(2+). The modulation of PLC, AMPK, tyrosine kinase and cADPribose failed to regulate this glucose-sensitive Ca(2+) entry. In addition, the entry of Ca(2+) was insensitive to nifedipine, 2APB, SKF, La(3+), Gd(3+), and KBR9743, suggesting a novel signal pathway in mediating glucose sensing.
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PMID:Cation channels in human embryonic kidney cells mediating calcium entry in response to extracellular low glucose. 1802 82

Spermidine/spermine N-1-acetyl-transferase (SSAT) is a catabolic enzyme that participates in polyamine metabolism. SSAT has been reported to be induced in some organs subjected to ischemia-reperfusion, but its induction mechanism has not been clarified, and little is known about SSAT regulation by ischemia per se. We induced regional ischemia of rat heart by coronary ligation and found that SSAT expression increased in ischemic myocardium. In neonatal rat cardiomyocytes and HEK293 cells, SSAT was up-regulated at the transcriptional step primarily by ATP depletion rather than oxygen deprivation. Moreover, an AMPK inhibitor compound C and AMPKalpha1-silencing RNAs attenuated the SSAT induction by ATP depletion, and an AMPK activator AICAR induced SSAT expression even without ATP depletion. When SSAT was suppressed using siRNA, the caspase activities and Bax/Bcl-2 ratios further increased in ATP depletion. These results suggest that myocardial SSAT is induced by AMPK signaling and function as a cardioprotectant under ATP-depleted conditions.
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PMID:Myocardial SSAT induction via AMPK signaling and its implication for ischemic injury. 1806 19

The thiazolidinedione anti-diabetic drugs increase activation of endothelial nitric-oxide (NO) synthase by phosphorylation at Ser-1177 and increase NO bioavailability, yet the molecular mechanisms that underlie this remain poorly characterized. Several protein kinases, including AMP-activated protein kinase, have been demonstrated to phosphorylate endothelial NO synthase at Ser-1177. In the current study we determined the role of AMP-activated protein kinase in rosiglitazone-stimulated NO synthesis. Stimulation of human aortic endothelial cells with rosiglitazone resulted in the time- and dose-dependent stimulation of AMP-activated protein kinase activity and NO production with concomitant phosphorylation of endothelial NO synthase at Ser-1177. Rosiglitazone stimulated an increase in the ADP/ATP ratio in endothelial cells, and LKB1 was essential for rosiglitazone-stimulated AMPK activity in HeLa cells. Infection of endothelial cells with a virus encoding a dominant negative AMP-activated protein kinase mutant abrogated rosiglitazone-stimulated Ser-1177 phosphorylation and NO production. Furthermore, the stimulation of AMP-activated protein kinase and NO synthesis by rosiglitazone was unaffected by the peroxisome proliferator-activated receptor-gamma inhibitor GW9662. These studies demonstrate that rosiglitazone is able to acutely stimulate NO synthesis in cultured endothelial cells by an AMP-activated protein kinase-dependent mechanism, likely to be mediated by LKB1.
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PMID:Rosiglitazone stimulates nitric oxide synthesis in human aortic endothelial cells via AMP-activated protein kinase. 1830 14

Metabolic disorders, such as diabetes and obesity, are fundamentally caused by cellular energy imbalance and dysregulation. Therefore, understanding the regulation of cellular fuel and energy metabolism is of great importance to develop effective therapies for metabolic disease. The cellular nutrient and energy sensors, AMPK and TOR, play a key role in maintaining cellular energy homeostasis. Like AMPK and TOR, PAS kinase (PASK) is also a nutrient responsive protein kinase. In yeast, PAS kinase phosphorylates the enzyme Ugp1 and thereby shifts glucose partitioning toward cell wall glucan synthesis at the expense of glycogen synthesis. Consistent with this function, yeast PAS kinase is activated by both cell integrity stress and growth in non-fermentative carbon sources. PASK is also important for proper regulation of glucose metabolism in mammals at both the hormonal and cellular level. In cultured pancreatic beta-cells, PASK is activated by elevated glucose concentrations and is required for glucose-stimulated transcription of the insulin gene. PASK knockdown in cultured myoblasts causes increased glucose oxidation and elevated cellular ATP levels. Mice lacking PASK exhibit increased metabolic rate and resistance to diet-induced obesity. Interestingly, PGC-1 expression and AMPK and TOR activity were not affected in PASK deficient mice, suggesting PASK may exert its metabolic effects through a new mechanism. We propose that PASK plays a significant role in nutrient sensing, metabolic regulation, and energy homeostasis, and is a potential therapeutic target for metabolic disease.
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PMID:The role of PAS kinase in regulating energy metabolism. 1834 4

This study was undertaken to interrogate cancer cell survival during long-term hypoxic stress. Two systems with relevance to carcinogenesis were employed: Fully transformed BJ cells and a renal carcinoma cell line (786-0). The dynamic of AMPK activity was consistent with a prosurvival role during chronic hypoxia. This was further supported by the effects of AMPK agonists and antagonists (AICAR and compound C). Expression of a dominant-negative AMPK alpha resulted in a decreased ATP level and significantly compromised survival in hypoxia. Dose-dependent prosurvival effects of rapamycin were consistent with mTOR inhibition being a critical downstream mediator of AMPK in persistent low oxygen.
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PMID:AMP-activated protein kinase is essential for survival in chronic hypoxia. 1835 90


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