scholarly journals AMP-activated protein kinase is essential for the maintenance of energy levels during synaptic activation

2018 ◽  
Author(s):  
Claudia Marinangeli ◽  
Sébastien Didier ◽  
Tariq Ahmed ◽  
Raphaelle Caillerez ◽  
Manon Domise ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Energy Demand ◽  
Metabolic Response ◽  
Energy Levels ◽  
Synaptic Activation ◽  
Total Body Mass ◽  
Leading Role ◽  
Total Body ◽  
Neuronal Energy Metabolism ◽  
Amp Activated Protein Kinase

AbstractWhile accounting for 2% of the total body mass, the brain is the organ that consumes the most energy. Although it is widely acknowledged that neuronal energy metabolism is tightly regulated, the mechanism how neurons meet their energy demand to sustain synaptic transmission remains poorly studied. Here we provide substantial evidence that the AMP-activated protein kinase (AMPK) plays a leading role in this process. Our results show that following synaptic activation, AMPK activation is required to sustain neuronal energy levels particularly through mitochondrial respiration. Further, our studies revealed that this metabolic plasticity regulated by AMPK is required for the expression of immediate early genes, synaptic plasticity and memory formation. These findings are important in the context of neurodegenerative disorders, as AMPK deregulation as it is observed in Alzheimer’s disease, impairs the metabolic response to synaptic activation. Altogether, our data provides the proof of concept that AMPK is an essential player in the regulation of neuroenergetic metabolism plasticity induced in response to synaptic activation.

scholarly journals AMP-Activated Protein Kinase Is Essential for the Maintenance of Energy Levels during Synaptic Activation

iScience ◽  
2018 ◽  
Vol 9 ◽  
pp. 1-13 ◽  
Author(s):  
Claudia Marinangeli ◽  
Sébastien Didier ◽  
Tariq Ahmed ◽  
Raphaelle Caillerez ◽  
Manon Domise ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Energy Levels ◽  
Synaptic Activation ◽  
Amp Activated Protein Kinase

Dealing with energy demand: the AMP-activated protein kinase

1999 ◽  
Vol 24 (1) ◽  
pp. 22-25 ◽  
Author(s):  
Bruce E Kemp ◽  
Ken I Mitchelhill ◽  
David Stapleton ◽  
Belinda J Michell ◽  
Zhi-Ping Chen ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Energy Demand ◽  
Amp Activated Protein Kinase

Isoproterenol stimulates 5′-AMP-activated protein kinase and fatty acid oxidation in neonatal hearts

2010 ◽  
Vol 299 (4) ◽  
pp. H1135-H1145 ◽  
Author(s):  
Jagdip S. Jaswal ◽  
Chad R. Lund ◽  
Wendy Keung ◽  
Donna L. Beker ◽  
Ivan M. Rebeyka ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Protein Kinase ◽  
Fatty Acid Oxidation ◽  
Energy Demand ◽  
Glucose Oxidation ◽  
Acid Oxidation ◽  
Acetyl Coa ◽  
Lactate Oxidation ◽  
Major Energy Source ◽  
Amp Activated Protein Kinase

Isoproterenol increases phosphorylation of LKB, 5′-AMP-activated protein kinase (AMPK), and acetyl-CoA carboxylase (ACC), enzymes involved in regulating fatty acid oxidation. However, inotropic stimulation selectively increases glucose oxidation in adult hearts. In the neonatal heart, fatty acid oxidation becomes a major energy source, while glucose oxidation remains low. This study tested the hypothesis that increased energy demand imposed by isoproterenol originates from fatty acid oxidation, secondary to increased LKB, AMPK, and ACC phosphorylation. Isolated working hearts from 7-day-old rabbits were perfused with Krebs solution (0.4 mM palmitate, 11 mM glucose, 0.5 mM lactate, and 100 mU/l insulin) with or without isoproterenol (300 nM). Isoproterenol increased myocardial O2 consumption (in J·g dry wt−1·min−1; 11.0 ± 1.4, n = 8 vs. 7.5 ± 0.8, n = 6, P < 0.05), and the phosphorylation of LKB (in arbitrary density units; 0.87 ± 0.09, n = 6 vs. 0.59 ± 0.08, n = 6, P < 0.05), AMPK (0.82 ± 0.08, n = 6 vs. 0.51 ± 0.06, n = 6, P < 0.05), and ACC-β (1.47 ± 0.14, n = 6 vs. 0.97 ± 0.07, n = 6, P < 0.05), with a concomitant decrease in malonyl-CoA levels (in nmol/g dry wt; 0.9 ± 0.9, n = 8 vs. 7.5 ± 1.3, n = 8, P < 0.05) and increase in palmitate oxidation (in nmol·g dry wt−1·min−1; 272 ± 45, n = 8 vs. 114 ± 9, n = 6, P < 0.05). Glucose and lactate oxidation were increased (in nmol·g dry wt−1·min−1; 253 ± 75, n = 8 vs. 63 ± 15, n = 9, P < 0.05 and 246 ± 43, n = 8 vs. 82 ± 11, n = 6, P < 0.05, respectively), independent of alterations in pyruvate dehydrogenase phosphorylation, but occurred secondary to a decrease in acetyl-CoA content and acetyl-CoA-to-free CoA ratio. As acetyl-CoA levels decrease in response to isoproterenol, despite an acceleration of the rates of palmitate and carbohydrate oxidation, these data suggest net rates of acetyl-CoA utilization exceed the net rates of acetyl-CoA generation.

Muscle cell depolarization induces a gain in surface GLUT4 via reduced endocytosis independently of AMPK

2006 ◽  
Vol 290 (6) ◽  
pp. E1276-E1286 ◽  
Author(s):  
Nadeeja Wijesekara ◽  
Amanda Tung ◽  
Farah Thong ◽  
Amira Klip
Keyword(s):  
Protein Kinase ◽  
Energy Demand ◽  
Actin Polymerization ◽  
Membrane Depolarization ◽  
Akt Activation ◽  
L6 Myotubes ◽  
Dependent Protein ◽  
Cell Depolarization ◽  
Elevated Surface ◽  
Amp Activated Protein Kinase

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 GLUT4 myc-expressing L6 myotubes devoid of sarcomeres and thus unable to contract. K+-induced membrane depolarization elevated surface GLUT4 myc, 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 GLUT4 myc 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 GLUT4 myc. Interestingly, although 5′-AMP-activated protein kinase (AMPK) was phosphorylated upon depolarization, lowering AMPKα via siRNA did not alter the surface GLUT4 myc 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 GLUT4 myc 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.

scholarly journals AMP-activated protein kinase signaling is upregulated in papillary thyroid cancer

2013 ◽  
Vol 169 (4) ◽  
pp. 521-528 ◽  
Author(s):  
Ana Paula Vidal ◽  
Bruno M Andrade ◽  
Fernanda Vaisman ◽  
Juliana Cazarin ◽  
Luis Felipe Ribeiro Pinto ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Energy Levels ◽  
Staining Intensity ◽  
University Hospital ◽  
Human Thyroid ◽  
Papillary Thyroid ◽  
Thyroid Cells ◽  
Cytoplasmic Staining ◽  
Thyroid Carcinomas ◽  
Amp Activated Protein Kinase

AMP-activated protein kinase (AMPK) is activated by the depletion in cellular energy levels and allows adaptive changes in cell metabolism and cell survival. Recently, our group described that AMPK plays an important role in the regulation of iodide and glucose uptake in thyroid cells. However, AMPK signaling pathway in human thyroid carcinomas has not been investigated so far.ObjectiveTo evaluate the expression and activity of AMPK in papillary thyroid carcinomas.MethodsWe examined total and phosphorylated AMPK (tAMPK and pAMPK) and phosphorylated acetyl-CoA-carboxylase (pACC) expressions through imunohistochemistry, using a tissue microarray block composed of 73 papillary thyroid carcinomas (PAP CA) or microcarcinomas (PAP MCA) and six adenoma (AD) samples from patients followed at the Federal University Hospital. The expression levels were compared with the non-neoplastic tissues from the same patient. Two different pathologists analyzed the samples and attributed scores of staining intensity and the proportion of stained cells. A total index was obtained by multiplying the values of intensity and the proportion of stained cells (INTxPROP).ResultstAMPK, pAMPK, and pACC showed a predominant cytoplasmic staining in papillary carcinomas, adenomas, and non-neoplastic thyroid tissues. However, the intensity and the proportion of stained cells were higher in carcinomas, so that a significant increase was found in the INTxPROP score both in PAP CA and PAP MCA, when compared with their respective controls.ConclusionOur results show unequivocally that AMPK pathway is highly activated in papillary thyroid carcinomas; however, more studies are necessary to understand the pathophysiological significance of AMPK activation in thyroid carcinogenesis.

scholarly journals AMP-activated Protein Kinase Controls Immediate Early Genes Expression Following Synaptic Activation Through the PKA/CREB Pathway

2018 ◽  
Vol 19 (12) ◽  
pp. 3716 ◽  
Author(s):  
Sébastien Didier ◽  
Florent Sauvé ◽  
Manon Domise ◽  
Luc Buée ◽  
Claudia Marinangeli ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Camp Response Element Binding ◽  
Long Term Memory ◽  
Synaptic Activation ◽  
Camp Response Element ◽  
Dependent Protein Kinase ◽  
Dependent Protein ◽  
Amp Activated Protein Kinase ◽  
Creb Pathway

Long-term memory formation depends on the expression of immediate early genes (IEGs). Their expression, which is induced by synaptic activation, is mainly regulated by the 3′,5′-cyclic AMP (cAMP)-dependent protein kinase/cAMP response element binding protein (cAMP-dependent protein kinase (PKA)/ cAMP response element binding (CREB)) signaling pathway. Synaptic activation being highly energy demanding, neurons must maintain their energetic homeostasis in order to successfully induce long-term memory formation. In this context, we previously demonstrated that the expression of IEGs required the activation of AMP-activated protein kinase (AMPK) to sustain the energetic requirements linked to synaptic transmission. Here, we sought to determine the molecular mechanisms by which AMPK regulates the expression of IEGs. To this end, we assessed the involvement of AMPK in the regulation of pathways involved in the expression of IEGs upon synaptic activation in differentiated primary neurons. Our data demonstrated that AMPK regulated IEGs transcription via the PKA/CREB pathway, which relied on the activity of the soluble adenylyl cyclase. Our data highlight the interplay between AMPK and PKA/CREB signaling pathways that allows synaptic activation to be transduced into the expression of IEGs, thus exemplifying how learning and memory mechanisms are under metabolic control.

AMP-activated protein kinase activates transcription of the UCP3 and HKII genes in rat skeletal muscle

2002 ◽  
Vol 283 (6) ◽  
pp. E1239-E1248 ◽  
Author(s):  
James Stoppani ◽  
Audrey L. Hildebrandt ◽  
Kei Sakamoto ◽  
David Cameron-Smith ◽  
Laurie J. Goodyear ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Blood Glucose ◽  
Protein Kinase ◽  
Energy Demand ◽  
Uncoupling Protein ◽  
Hexokinase Ii ◽  
Arterial Infusion ◽  
Ampk Signaling ◽  
Lactate Levels ◽  
Amp Activated Protein Kinase

AMP-activated protein kinase (AMPK) has recently emerged as a key signaling protein in skeletal muscle, coordinating the activation of both glucose and fatty acid metabolism in response to increased cellular energy demand. To determine whether AMPK signaling may also regulate gene transcription in muscle, rats were given a single subcutaneous injection (1 mg/g) of the AMP analog 5-aminoimidazole-4-carboxamide-1-β-d-ribonucleoside (AICAR). AICAR injection activated ( P < 0.05) AMPK-α2 (∼2.5-fold) and transcription of the uncoupling protein-3 (UCP3, ∼4-fold) and hexokinase II (HKII, ∼10-fold) genes in both red and white skeletal muscle. However, AICAR injection also elicited ( P < 0.05) an acute drop (60%) in blood glucose and a sustained (2-h) increase in blood lactate, prompting concern regarding the specificity of AICAR on transcription. To maximize AMPK activation in muscle while minimizing potential systemic counterregulatory responses, a single-leg arterial infusion technique was employed in fully conscious rats. Relative to saline-infused controls, single-leg arterial infusion of AICAR (0.125, 0.5, and 2.5 μg · g−1 · min−1for 60 min) induced a dose-dependent increase (2- to 4-fold, P < 0.05) in UCP3 and HKII transcription in both red and white skeletal muscle. Importantly, AICAR infusion activated transcription only in muscle from the infused leg and had no effect on blood glucose or lactate levels. These data provide evidence that AMPK signaling is linked to the transcriptional regulation of select metabolic genes in skeletal muscle.

scholarly journals Skeletal Muscle AMP-activated Protein Kinase Is Essential for the Metabolic Response to Exercisein Vivo

2009 ◽  
Vol 284 (36) ◽  
pp. 23925-23934 ◽  
Author(s):  
Robert S. Lee-Young ◽  
Susan R. Griffee ◽  
Sara E. Lynes ◽  
Deanna P. Bracy ◽  
Julio E. Ayala ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Metabolic Response ◽  
Amp Activated Protein Kinase

AMP-activated protein kinase — the fat controller of the energy railroadThis paper is one of a selection of papers published in this Special issue, entitled Second Messengers and Phosphoproteins—12th International Conference.

2006 ◽  
Vol 84 (7) ◽  
pp. 655-665 ◽  
Author(s):  
Gregory R. Steinberg ◽  
S. Lance Macaulay ◽  
Mark A Febbraio ◽  
Bruce E. Kemp
Keyword(s):  
Protein Kinase ◽  
Energy Demand ◽  
Second Messengers ◽  
Metabolic Stress ◽  
Special Issue ◽  
Endocrine Control ◽  
Fatty Acid Triglyceride ◽  
Amp Activated Protein Kinase ◽  
Major Mediator ◽  
Selection Of

AMP-activated protein kinase plays an important role in the regulation of lipid metabolism in response to metabolic stress and energy demand. It is also under endocrine control. AMPK acts at multiple steps and has a central role controlling fatty acid, triglyceride, and cholesterol synthesis, as well as the oxidation of fatty acids through direct phosphorylation effects and the control of gene transcription. As such, it can be considered to be the fat controller of the energy railroad. It is thought that AMPK may be a major mediator of the health benefits of exercise in mitigating the development of obesity and age-onset diseases.

The many ways to regulate glucose transporter 4This paper is one of a selection of papers published in this Special Issue, entitled 14th International Biochemistry of Exercise Conference – Muscles as Molecular and Metabolic Machines, and has undergone the Journal’s usual peer review process.

2009 ◽  
Vol 34 (3) ◽  
pp. 481-487 ◽  
Author(s):  
Amira Klip
Keyword(s):  
Protein Kinase ◽  
Glucose Uptake ◽  
Energy Demand ◽  
Glucose Transporter ◽  
Peer Review Process ◽  
Intrinsic Activity ◽  
Hexokinase Ii ◽  
The Many ◽  
Energy Deprivation ◽  
Amp Activated Protein Kinase

Glucose uptake into skeletal muscle is primarily mediated by glucose transporter 4 (GLUT4). The number of GLUT4 polypeptides at the surface of muscle cells rises rapidly in response to insulin, contraction, depolarization, or energy deprivation. However, distinct mechanisms underlie the gain in surface GLUT4 in each case. Insulin promotes its exocytosis to the membrane, regulating vesicle movement, tethering, docking, and fusion. In contrast, muscle contraction, depolarization, and energy demand reduce GLUT4 endocytosis. The signals involved in each case also differ. Insulin utilizes Akt, Rabs, and selective actin remodelling, whereas depolarization and energy deprivation engage AMP-activated protein kinase and Ca2+-dependent signals. GLUT4 internalizes via 2 major routes that involve dynamin, but only one requires clathrin. The clathrin-independent route is slowed down by energy deprivation, and is regulated by AMP-activated protein kinase. In addition to regulation of the exocytic and endocytic movement of GLUT4, glucose uptake is also modulated through changes in the transporter’s intrinsic activity. The glycolytic enzymes glyceraldehyde-3-dehydrogenase and hexokinase II contribute to such regulation, through differential binding to GLUT4.

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