AMP-activated protein kinase protects against anoxia in Drosophila melanogaster

AbstractDuring anoxia, proper energy maintenance is essential in order to maintain neural operation. Starvation activates AMP-activated protein kinase (AMPK), an evolutionarily conserved indicator of cellular energy status, in a cascade which modulates ATP production and consumption. We investigated the role of energetic status on anoxia tolerance in Drosophila and discovered that starvation or AMPK activation increases the speed of locomotor recovery from an anoxic coma. Using temporal and spatial genetic targeting we found that AMPK in the fat body contributes to starvation-induced fast locomotor recovery, whereas, under fed conditions, disrupting AMPK in oenocytes prolongs recovery. By evaluating spreading depolarization in the fly brain during anoxia we show that AMPK activation reduces the severity of ionic disruption and prolongs recovery of electrical activity. Further genetic targeting indicates that glial, but not neuronal, AMPK affects locomotor recovery. Together, these findings support a model in which AMPK is neuroprotective in Drosophila.

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AMP-activated protein kinase pathway: a potential therapeutic target in cardiometabolic disease

Clinical Science ◽

10.1042/cs20080066 ◽

2009 ◽

Vol 116 (8) ◽

pp. 607-620 ◽

Cited By ~ 109

Author(s):

Aaron K. F. Wong ◽

Jacqueline Howie ◽

John R. Petrie ◽

Chim C. Lang

Keyword(s):

Protein Kinase ◽

Metabolic Diseases ◽

Elongation Factor ◽

Cardiometabolic Disease ◽

Acid Oxidation ◽

Ampk Activation ◽

Atp Production ◽

Beneficial Effects ◽

Eukaryotic Elongation Factor ◽

Amp Activated Protein Kinase

AMPK (AMP-activated protein kinase) is a heterotrimetric enzyme that is expressed in many tissues, including the heart and vasculature, and plays a central role in the regulation of energy homoeostasis. It is activated in response to stresses that lead to an increase in the cellular AMP/ATP ratio caused either by inhibition of ATP production (i.e. anoxia or ischaemia) or by accelerating ATP consumption (i.e. muscle contraction or fasting). In the heart, AMPK activity increases during ischaemia and functions to sustain ATP, cardiac function and myocardial viability. There is increasing evidence that AMPK is implicated in the pathophysiology of cardiovascular and metabolic diseases. A principle mode of AMPK activation is phosphorylation by upstream kinases [e.g. LKB1 and CaMK (Ca2+/calmodulin-dependent protein kinase], which leads to direct effects on tissues and phosphorylation of various downstream kinases [e.g. eEF2 (eukaryotic elongation factor 2) kinase and p70 S6 kinase]. These upstream and downstream kinases of AMPK have fundamental roles in glucose metabolism, fatty acid oxidation, protein synthesis and tumour suppression; consequently, they have been implicated in cardiac ischaemia, arrhythmias and hypertrophy. Recent mechanistic studies have shown that AMPK has an important role in the mechanism of action of MF (metformin), TDZs (thiazolinediones) and statins. Increased understanding of the beneficial effects of AMPK activation provides the rationale for targeting AMPK in the development of new therapeutic strategies for cardiometabolic disease.

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Energy sensing by the AMP-activated protein kinase and its effects on muscle metabolism

Proceedings of The Nutrition Society ◽

10.1017/s0029665110003915 ◽

2010 ◽

Vol 70 (1) ◽

pp. 92-99 ◽

Cited By ~ 81

Author(s):

D. Grahame Hardie

Keyword(s):

Protein Kinase ◽

Endurance Exercise ◽

Glycogen Synthase ◽

Glycogen Synthesis ◽

Whole Body ◽

Acid Oxidation ◽

Ampk Activation ◽

Energy Status ◽

Cellular Energy ◽

Amp Activated Protein Kinase

The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status, and a regulator of energy balance at both the cellular and whole body levels. Although ubiquitously expressed, its function is best understood in skeletal muscle. AMPK contains sites that reversibly bind AMP or ATP, with an increase in cellular AMP:ATP ratio (signalling a fall in cellular energy status) switching on the kinase. In muscle, AMPK activation is therefore triggered by sustained contraction, and appears to be particularly important in the metabolic changes that occur in the transition from resistance to endurance exercise. Once activated, AMPK switches on catabolic processes that generate ATP, while switching off energy-requiring processes not essential in the short term. Thus, it acutely activates glucose uptake (by promoting translocation of the transporter GLUT4 to the membrane) and fatty acid oxidation, while switching off glycogen synthesis and protein synthesis (the later via inactivation of the mammalian target-of-rapamycin pathway). Prolonged AMPK activation also causes some of the chronic adaptations to endurance exercise, such as increased GLUT4 expression and mitochondrial biogenesis. AMPK contains a glycogen-binding domain that causes a sub-fraction to bind to the surface of the glycogen particle, and it can inhibit glycogen synthesis by phosphorylating glycogen synthase. We have shown that AMPK is inhibited by exposed non-reducing ends in glycogen. We are working on the hypothesis that this ensures that glycogen synthesis is rapidly activated when glycogen becomes depleted after exercise, but is switched off again as soon as glycogen stores are replenished.

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Keeping the home fires burning: AMP-activated protein kinase

Journal of The Royal Society Interface ◽

10.1098/rsif.2017.0774 ◽

2018 ◽

Vol 15 (138) ◽

pp. 20170774 ◽

Cited By ~ 65

Author(s):

D. Grahame Hardie

Keyword(s):

Protein Kinase ◽

Host Cell ◽

Energy Homeostasis ◽

Adenosine Diphosphate ◽

Herbal Remedies ◽

Eukaryotic Cells ◽

Atp Production ◽

Regulatory Systems ◽

Production And Consumption ◽

Amp Activated Protein Kinase

Living cells obtain energy either by oxidizing reduced compounds of organic or mineral origin or by absorbing light. Whichever energy source is used, some of the energy released is conserved by converting adenosine diphosphate (ADP) to adenosine triphosphate (ATP), which are analogous to the chemicals in a rechargeable battery. The energy released by the conversion of ATP back to ADP is used to drive most energy-requiring processes, including cell growth, cell division, communication and movement. It is clearly essential to life that the production and consumption of ATP are always maintained in balance, and the AMP-activated protein kinase (AMPK) is one of the key cellular regulatory systems that ensures this. In eukaryotic cells (cells with nuclei and other internal membrane-bound structures, including human cells), most ATP is produced in mitochondria, which are thought to have been derived by the engulfment of oxidative bacteria by a host cell not previously able to use molecular oxygen. AMPK is activated by increasing AMP or ADP (AMP being generated from ADP whenever ADP rises) coupled with falling ATP. Relatives of AMPK are found in essentially all eukaryotes, and it may have evolved to allow the host cell to monitor the output of the newly acquired mitochondria and step their ATP production up or down according to the demand. Structural studies have illuminated how AMPK achieves the task of detecting small changes in AMP and ADP, despite the presence of much higher concentrations of ATP. Recently, it has been shown that AMPK can also sense the availability of glucose, the primary carbon source for most eukaryotic cells, via a mechanism independent of changes in AMP or ADP. Once activated by energy imbalance or glucose lack, AMPK modifies many target proteins by transferring phosphate groups to them from ATP. By this means, numerous ATP-producing processes are switched on (including the production of new mitochondria) and ATP-consuming processes are switched off, thus restoring energy homeostasis. Drugs that modulate AMPK have great potential in the treatment of metabolic disorders such as obesity and Type 2 diabetes, and even cancer. Indeed, some existing drugs such as metformin and aspirin, which were derived from traditional herbal remedies, appear to work, in part, by activating AMPK.

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Glucose regulates AMP-activated protein kinase activity and gene expression in clonal, hypothalamic neurons expressing proopiomelanocortin: additive effects of leptin or insulin

Journal of Endocrinology ◽

10.1677/joe-06-0080 ◽

2007 ◽

Vol 192 (3) ◽

pp. 605-614 ◽

Cited By ~ 46

Author(s):

Fang Cai ◽

Armen V Gyulkhandanyan ◽

Michael B Wheeler ◽

Denise D Belsham

Keyword(s):

Protein Kinase ◽

Energy Homeostasis ◽

Cell Model ◽

Neuronal Cell ◽

Cell Types ◽

Glucose Sensing ◽

Protein Kinase Activity ◽

Energy Status ◽

Ampk Activity ◽

Amp Activated Protein Kinase

The mammalian hypothalamus comprises an array of phenotypically distinct cell types that interpret peripheral signals of energy status and, in turn, elicits an appropriate response to maintain energy homeostasis. We used a clonal representative hypothalamic cell model expressing proopiomelanocortin (POMC; N-43/5) to study changes in AMP-activated protein kinase (AMPK) activity and glucose responsiveness. We have demonstrated the presence of cellular machinery responsible for glucose sensing in the cell line, including glucokinase, glucose transporters, and appropriate ion channels. ATP-sensitive potassium channels were functional and responded to glucose. The N-43/5 POMC neurons may therefore be an appropriate cell model to study glucose-sensing mechanisms in the hypothalamus. In N-43/5 POMC neurons, increasing glucose concentrations decreased phospho-AMPK activity. As a relevant downstream effect, we found that POMC transcription increased with 2.8 and 16.7 mM glucose. Upon addition of leptin, with either no glucose or with 5 mM glucose, we found that leptin decreased AMPK activity in N-43/5 POMC neurons, but had no significant effect at 25 mM glucose, whereas insulin decreased AMPK activity at only 5 mM glucose. These results demonstrate that individual hypothalamic neuronal cell types, such as the POMC neuron, can have distinct responses to peripheral signals that relay energy status to the brain, and will therefore be activated uniquely to control neuroendocrine function.

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0358: Differential AMP-activated protein kinase (AMPK) activation in platelets, in response to various agonists. Comparison between human and murine platelets

Archives of Cardiovascular Diseases Supplements ◽

10.1016/s1878-6480(14)71420-x ◽

2014 ◽

Vol 6 ◽

pp. 57

Author(s):

Sophie Lepropre ◽

Marie-Blanche Onselaer ◽

Cécile Oury ◽

Luc Bertrand ◽

Jean-Louis Vanoverschelde ◽

...

Keyword(s):

Protein Kinase ◽

Ampk Activation ◽

Amp Activated Protein Kinase

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AMPK: a therapeutic target of heart failure—not only metabolism regulation

Bioscience Reports ◽

10.1042/bsr20181767 ◽

2019 ◽

Vol 39 (1) ◽

Cited By ~ 12

Author(s):

Xuan Li ◽

Jia Liu ◽

Qingguo Lu ◽

Di Ren ◽

Xiaodong Sun ◽

...

Keyword(s):

Heart Failure ◽

Heart Function ◽

Critical Role ◽

Ampk Activation ◽

Atp Production ◽

Metabolism Regulation ◽

Physiological Processes ◽

Clinical Drugs ◽

Serious Disease ◽

Amp Activated Protein Kinase

Abstract Heart failure (HF) is a serious disease with high mortality. The incidence of this disease has continued to increase over the past decade. All cardiovascular diseases causing dysfunction of various physiological processes can result in HF. AMP-activated protein kinase (AMPK), an energy sensor, has pleiotropic cardioprotective effects and plays a critical role in the progression of HF. In this review, we highlight that AMPK can not only improve the energy supply in the failing heart by promoting ATP production, but can also regulate several important physiological processes to restore heart function. In addition, we discuss some aspects of some potential clinical drugs which have effects on AMPK activation and may have value in treating HF. More studies, especially clinical trials, should be done to evaluate manipulation of AMPK activation as a potential means of treating HF.

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AMPK activation with AICAR provokes an acute fall in plasma [K+]

AJP Cell Physiology ◽

10.1152/ajpcell.00464.2007 ◽

2008 ◽

Vol 294 (1) ◽

pp. C126-C135 ◽

Cited By ~ 21

Author(s):

Dan Zheng ◽

Anjana Perianayagam ◽

Donna H. Lee ◽

M. Douglas Brannan ◽

Li E. Yang ◽

...

Keyword(s):

Protein Kinase ◽

Infusion Rate ◽

Extracellular Fluid ◽

Ampk Activation ◽

Conscious Rats ◽

Significant Fall ◽

Ampk Phosphorylation ◽

Atp Levels ◽

Ampk Activity ◽

Amp Activated Protein Kinase

AMP-activated protein kinase (AMPK), activated by an increase in intracellular AMP-to-ATP ratio, stimulates pathways that can restore ATP levels. We tested the hypothesis that AMPK activation influences extracellular fluid (ECF) K+ homeostasis. In conscious rats, AMPK was activated with 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR) infusion: 38.4 mg/kg bolus then 4 mg·kg−1·min−1 infusion. Plasma [K+] and [glucose] both dropped at 1 h of AICAR infusion and [K+] dropped to 3.3 ± 0.04 mM by 3 h, linearly related to the increase in muscle AMPK phosphorylation. AICAR treatment did not increase urinary K+ excretion. AICAR lowered [K+] whether plasma [K+] was chronically elevated or lowered. The K+ infusion rate needed to maintain baseline plasma [K+] reached 15.7 ± 1.3 μmol K+·kg−1·min−1 between 120 and 180 min AICAR infusion. In mice expressing a dominant inhibitory form of AMPK in the muscle (Tg-KD1), baseline [K+] was not different from controls (4.2 ± 0.1 mM), but the fall in plasma [K+] in response to AICAR (0.25 g/kg) was blunted: [K+] fell to 3.6 ± 0.1 in controls and to 3.9 ± 0.1 mM in Tg-KD1, suggesting that ECF K+ redistributes, at least in part, to muscle ICF. In summary, these findings illustrate that activation of AMPK activity with AICAR provokes a significant fall in plasma [K+] and suggest a novel mechanism for redistributing K+ from ECF to ICF.

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Inhibition of hepatic phosphatidylcholine synthesis by AICAR and phenformin is independent of AMP‐activated protein kinase (AMPK) activation.

The FASEB Journal ◽

10.1096/fasebj.20.4.a91-b ◽

2006 ◽

Vol 20 (4) ◽

Author(s):

Susanne Lingrell ◽

René L Jacobs ◽

Jason R.B. Dyck ◽

Dennis E Vance

Keyword(s):

Protein Kinase ◽

Ampk Activation ◽

Amp Activated Protein Kinase ◽

Phosphatidylcholine Synthesis

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Mitochondria-derived ROS activate AMP-activated protein kinase (AMPK) indirectly

Journal of Biological Chemistry ◽

10.1074/jbc.ra118.002579 ◽

2018 ◽

Vol 293 (44) ◽

pp. 17208-17217 ◽

Cited By ~ 77

Author(s):

Elizabeth C. Hinchy ◽

Anja V. Gruszczyk ◽

Robin Willows ◽

Naveenan Navaratnam ◽

Andrew R. Hall ◽

...

Keyword(s):

Protein Kinase ◽

Fluorescent Proteins ◽

Adenine Nucleotide ◽

Direct Action ◽

Cysteine Residues ◽

Ros Production ◽

Α Subunit ◽

Atp Production ◽

Ampk Activity ◽

Amp Activated Protein Kinase

Mitochondrial reactive oxygen species (ROS) production is a tightly regulated redox signal that transmits information from the organelle to the cell. Other mitochondrial signals, such as ATP, are sensed by enzymes, including the key metabolic sensor and regulator, AMP-activated protein kinase (AMPK). AMPK responds to the cellular ATP/AMP and ATP/ADP ratios by matching mitochondrial ATP production to demand. Previous reports proposed that AMPK activity also responds to ROS, by ROS acting on redox-sensitive cysteine residues (Cys-299/Cys-304) on the AMPK α subunit. This suggests an appealing model in which mitochondria fine-tune AMPK activity by both adenine nucleotide–dependent mechanisms and by redox signals. Here we assessed whether physiological levels of ROS directly alter AMPK activity. To this end we added exogenous hydrogen peroxide (H2O2) to cells and utilized the mitochondria-targeted redox cycler MitoParaquat to generate ROS within mitochondria without disrupting oxidative phosphorylation. Mitochondrial and cytosolic thiol oxidation was assessed by measuring peroxiredoxin dimerization and by redox-sensitive fluorescent proteins. Replacing the putative redox-active cysteine residues on AMPK α1 with alanines did not alter the response of AMPK to H2O2. In parallel with measurements of AMPK activity, we measured the cell ATP/ADP ratio. This allowed us to separate the effects on AMPK activity due to ROS production from those caused by changes in this ratio. We conclude that AMPK activity in response to redox changes is not due to direct action on AMPK itself, but is a secondary consequence of redox effects on other processes, such as mitochondrial ATP production.

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