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

AMP-activated protein kinase (AMPK) is an important signaling effector that couples cellular metabolism and function. The effects of AMPK activation on pancreatic beta-cell function remain unresolved. We used 5-amino-imidazole carboxamide riboside (AICAR), an activator of AMPK, to define the signaling mechanisms linking the activation of AMPK with insulin secretion. Application of 300 microM AICAR to mouse islets incubated in 5-14 mM glucose significantly increased AMPK activity and potentiated insulin secretion. AICAR inhibited ATP-sensitive K(+) (K(ATP)) channels and increased the frequency of glucose-induced calcium oscillations in islets incubated in 8-14 mM glucose. At lower glucose concentration (5mM) AICAR did not affect K(ATP) activity or intracellular ([Ca(2+)](i)). AICAR also did not inhibit (86)Rb(+) efflux from islets isolated from Sur1(-/-) mice that lack K(ATP) channels yet significantly potentiated glucose stimulated insulin secretion. Our data suggest that AICAR stimulates insulin secretion by both K(ATP) channel-dependent and -independent pathways.
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PMID:5-amino-imidazole carboxamide riboside acutely potentiates glucose-stimulated insulin secretion from mouse pancreatic islets by KATP channel-dependent and -independent pathways. 1582 53

Contracting skeletal muscles acutely increases glucose transport in both healthy individuals and in people with Type 2 diabetes, and regular physical exercise is a cornerstone in the treatment of the disease. Glucose transport in skeletal muscle is dependent on the translocation of GLUT4 glucose transporters to the cell surface. It has long been believed that there are two major signaling mechanisms leading to GLUT4 translocation. One mechanism is insulin-activated signaling through insulin receptor substrate-1 and phosphatidylinositol 3-kinase. The other is an insulin-independent signaling mechanism that is activated by contractions, but the mediators of this signal are still unknown. Accumulating evidence suggests that the energy-sensing enzyme AMP-activated protein kinase plays an important role in contraction-stimulated glucose transport. However, more recent studies in transgenic and knockout animals show that AMP-activated protein kinase is not the sole mediator of the signal to GLUT4 translocation and suggest that there may be redundant signaling pathways leading to contraction-stimulated glucose transport. The search for other possible signal intermediates is ongoing, and calcium, nitric oxide, bradykinin, and the Akt substrate AS160 have been suggested as possible candidates. Further research is needed because full elucidation of an insulin-independent signal leading to glucose transport would be a promising pharmacological target for the treatment of Type 2 diabetes.
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PMID:Contraction signaling to glucose transport in skeletal muscle. 1603 6

The AMP-activated protein kinase (AMPK) is a critical regulator of energy balance at both the cellular and whole-body levels. Two upstream kinases have been reported to activate AMPK in cell-free assays, i.e., the tumor suppressor LKB1 and calmodulin-dependent protein kinase kinase. However, evidence that this is physiologically relevant currently only exists for LKB1. We now report that there is a significant basal activity and phosphorylation of AMPK in LKB1-deficient cells that can be stimulated by Ca2+ ionophores, and studies using the CaMKK inhibitor STO-609 and isoform-specific siRNAs show that CaMKKbeta is required for this effect. CaMKKbeta also activates AMPK much more rapidly than CaMKKalpha in cell-free assays. K(+)-induced depolarization in rat cerebrocortical slices, which increases intracellular Ca2+ without disturbing cellular adenine nucleotide levels, activates AMPK, and this is blocked by STO-609. Our results suggest a potential Ca(2+)-dependent neuroprotective pathway involving phosphorylation and activation of AMPK by CaMKKbeta.
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PMID:Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase. 1605 95

Though once believed to be regulated exclusively by the cellular energy state, AMPK has now been shown to be activated by a calcium-dependent signaling pathway.
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PMID:Activating AMP-activated protein kinase without AMP. 1606 Nov 73

Specialized O2-sensing cells exhibit a particularly low threshold to regulation by O2 supply and function to maintain arterial pO2 within physiological limits. For example, hypoxic pulmonary vasoconstriction optimizes ventilation-perfusion matching in the lung, whereas carotid body excitation elicits corrective cardio-respiratory reflexes. It is generally accepted that relatively mild hypoxia inhibits mitochondrial oxidative phosphorylation in O2-sensing cells, thereby mediating, in part, cell activation. However, the mechanism by which this process couples to Ca2+ signaling mechanisms remains elusive, and investigation of previous hypotheses has generated contrary data and failed to unite the field. We propose that a rise in the cellular AMP/ATP ratio activates AMP-activated protein kinase and thereby evokes Ca2+ signals in O2-sensing cells. Co-immunoprecipitation identified three possible AMP-activated protein kinase subunit isoform combinations in pulmonary arterial myocytes, with alpha1 beta2 gamma1 predominant. Furthermore, their tissue-specific distribution suggested that the AMP-activated protein kinase-alpha1 catalytic isoform may contribute, via amplification of the metabolic signal, to the pulmonary selectivity required for hypoxic pulmonary vasoconstriction. Immunocytochemistry showed AMP-activated protein kinase-alpha1 to be located throughout the cytoplasm of pulmonary arterial myocytes. In contrast, it was targeted to the plasma membrane in carotid body glomus cells. Consistent with these observations and the effects of hypoxia, stimulation of AMP-activated protein kinase by phenformin or 5-aminoimidazole-4-carboxamide-riboside elicited discrete Ca2+ signaling mechanisms in each cell type, namely cyclic ADP-ribose-dependent Ca2+ mobilization from the sarcoplasmic reticulum via ryanodine receptors in pulmonary arterial myocytes and transmembrane Ca2+ influx into carotid body glomus cells. Thus, metabolic sensing by AMP-activated protein kinase may mediate chemotransduction by hypoxia.
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PMID:Does AMP-activated protein kinase couple inhibition of mitochondrial oxidative phosphorylation by hypoxia to calcium signaling in O2-sensing cells? 1619 27

Contracting skeletal muscle increases glucose uptake to sustain energy demand. This is achieved through a gain in GLUT4 at the membrane, but the traffic mechanisms and regulatory signals involved are unknown. Muscle contraction is elicited by membrane depolarization followed by a rise in cytosolic Ca2+ and actomyosin activation, drawing on ATP stores. It is unknown whether one or more of these events triggers the rise in surface GLUT4. Here, we investigate the effect of membrane depolarization on GLUT4 cycling using GLUT4myc-expressing L6 myotubes devoid of sarcomeres and thus unable to contract. K+-induced membrane depolarization elevated surface GLUT4myc, and this effect was additive to that of insulin, was not prevented by inhibiting phosphatidylinositol 3-kinase (PI3K) or actin polymerization, and did not involve Akt activation. Instead, depolarization elevated cytosolic Ca2+, and the surface GLUT4myc elevation was prevented by dantrolene (an inhibitor of Ca2+ release from sarcoplasmic reticulum) and by extracellular Ca2+ chelation. Ca2+-calmodulin-dependent protein kinase-II (CaMKII) was not phosphorylated after 10 min of K+ depolarization, and the CaMK inhibitor KN62 did not prevent the gain in surface GLUT4myc. Interestingly, although 5'-AMP-activated protein kinase (AMPK) was phosphorylated upon depolarization, lowering AMPKalpha via siRNA did not alter the surface GLUT4myc gain. Conversely, the latter response was abolished by the PKC inhibitors bisindolylmaleimide I and calphostin C. Unlike insulin, K+ depolarization caused only a small increase in GLUT4myc exocytosis and a major reduction in its endocytosis. We propose that K+ depolarization reduces GLUT4 internalization through signals and mechanisms distinct from those engaged by insulin. Such a pathway(s) is largely independent of PI3K, Akt, AMPK, and CaMKII but may involve PKC.
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PMID:Muscle cell depolarization induces a gain in surface GLUT4 via reduced endocytosis independently of AMPK. 1641 6

AMP-activated protein kinase (AMPK) plays a key role in the regulation of energy homeostasis and is activated in response to cellular stress, including hypoxia/ischemia and hyperglycemia. The stress events are accompanied by rapid release of extracellular nucleotides from damaged tissues or activated endothelial cells (EC) and platelets. We demonstrate that extracellular nucleotides (ATP, ADP, and UTP, but not UDP) and adenosine independently induce phosphorylation and activation of AMPK in human umbilical vein EC (HUVEC) by the mechanism that is not linked to changes in AMP:ATP ratio. HUVEC express NTPDases, as well as 5'-nucleotidase; hence, nucleotides can be metabolized to adenosine. However, inhibition of 5'-nucleotidase had no effect on ATP/ADP/UTP-induced phospho- rylation of AMPK, indicating that AMPK activation occurred as a direct response to nucleotides. Nucleotide-evoked phosphorylation of AMPK in HUVEC was mediated by P2Y1, P2Y2, and/or P2Y4 receptors, whereas P2Y6, P2Y11, and P2X receptors were not involved. The nucleotide-induced phosphorylation of AMPK was affected by changes in the concentration of intracellular Ca2+ and by Ca2+/calmodulin-dependent kinase kinase (CaMKK), although most likely it was not dependent on LKB1 kinase. Adenosine-induced phosphorylation of AMPK was not mediated by P1 receptors but required adenosine uptake by equilibrative nucleoside transporters followed by its (intracellular) metabolism to AMP. Moreover, adenosine effect was Ca2+ and CaMKK independent, although probably associated with upstream LKB1. We hypothesize that P2 receptors and adenosine transporters could be novel targets for the pharmacological regulation of AMPK activity and its downstream effects on EC function.
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PMID:Extracellular nucleotides and adenosine independently activate AMP-activated protein kinase in endothelial cells: involvement of P2 receptors and adenosine transporters. 1649 86

AMP-activated protein kinase (AMPK), which functions as a sensor of cellular energy homeostasis, was phosphorylated after norepinephrine stimulation in L6 skeletal muscle cells. This effect was mediated by alpha1-adrenoceptors, with no stimulatory effects due to interactions at alpha2- or beta-adrenoceptors. Alpha1-adrenoceptors are Gq-coupled receptors, and calcium but not phorbol esters could mimic the effect of alpha1-adrenergic stimulation; and we show that protein kinase C is not involved as an upstream signal to AMPK by alpha1-adrenergic stimulation and that the AMP-to-ATP ratio is unaltered after alpha1-adrenergic stimulation. We further show that glucose uptake mediated by alpha1- but not by beta-adrenoceptors can be inhibited by AMPK inhibition. Acetyl-CoA carboxylase (ACC) is phosphorylated at Ser218 by AMPK, and alpha1- but not beta-adrenoceptor stimulation results in phosphorylation of ACC at this residue. These results suggest a novel pathway where alpha1-adrenoceptor activation, independent of protein kinase C, leads to activation of AMPK in skeletal muscle, which contributes to alpha1-adrenoceptor-mediated increases in glucose uptake.
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PMID:AMP-activated protein kinase activation by adrenoceptors in L6 skeletal muscle cells: mediation by alpha1-adrenoceptors causing glucose uptake. 1650 31

The LKB1-->AMPK cascade is switched on by metabolic stresses that either inhibit ATP production (e.g. hypoxia, hypoglycaemia) or that accelerate ATP consumption (e.g. muscle contraction). Any decline in cellular energy status is accompanied by a rise in the cellular AMP: ATP ratio, and this activates AMPK by a complex and sensitive mechanism involving antagonistic binding of the nucleotides to two sites on the regulatory gamma subunits of AMPK. Once activated by metabolic stress, AMPK activates catabolic pathways that generate ATP, while inhibiting cell growth and biosynthesis and other processes that consume ATP. While the AMPK system probably evolved in single-celled eukaryotes to maintain energy balance at the cellular level, in multicellular organisms its role has become adapted so that it is also involved in maintaining whole body energy balance. Thus, it is regulated by hormones and cytokines, especially the adipokines leptin and adiponectin, increasing whole body energy expenditure while regulating food intake. Some hormones may activate AMPK by an LKB1-independent mechanism involving Ca2+/calmodulin dependent protein kinase kinases. Low levels of activation of AMPK are likely to play a role in the current global rise in obesity and Type 2 diabetes, and AMPK is the target for the widely used antidiabetic drug metformin.
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PMID:AMP-activated protein kinase--development of the energy sensor concept. 1664

It is generally accepted that relatively mild hypoxia inhibits mitochondrial oxidative phosphorylation in O2-sensing cells, and thereby mediates, in part, cell activation. However, the mechanism by which this process is coupled to discrete, cell-specific Ca2+ signalling mechanisms remains elusive. We considered the possibility that hypoxia may increase the cellular ATP/AMP ratio, increase the activity of AMP-activated protein kinase (AMPK) and thereby evoke Ca2+ signals in O2-sensing cells. Co-immunoprecipitation identified alpha1beta2gamma1 as the primary AMPK isozyme in pulmonary arterial smooth muscle, whilst the tissue-specific distribution of AMPK activities and their activation by hypoxia suggested that the AMPK-alpha1 catalytic subunit isoform is key to the regulation of O2-sensing cells. Strikingly, 3D reconstruction of immunofluorescence images showed AMPK-alpha1 to be located throughout the cytoplasm of pulmonary arterial smooth muscle cells and, by contrast, targeted to the plasma membrane in carotid body glomus cells. Consistent with these observations Ca2+ imaging, tension recording and electrophysiology demonstrated that AMPK, like hypoxia, activates each cell type via discrete Ca2+ signalling mechanisms: cyclic ADP-ribose-dependent Ca2+ mobilization from the sarcoplasmic reticulum via ryanodine receptors in pulmonary arterial smooth muscle cells and voltage-gated Ca2+ influx into carotid body glomus cells. Thus, metabolic-sensing by AMPK underpins the cell-specific response of O2-sensing cells to hypoxia.
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PMID:AMP-activated protein kinase couples mitochondrial inhibition by hypoxia to cell-specific Ca2+ signalling mechanisms in oxygen-sensing cells. 1668 39


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