scholarly journals AMPK signaling linked to the schizophrenia-associated 1q21.1 deletion is required for neuronal and sleep maintenance

2018 ◽  
Author(s):  
Stanislav Nagy ◽  
Gianna W. Maurer ◽  
Julie L. Hentze ◽  
Shu Kondo ◽  
Morten Rose ◽  
...  
Keyword(s):  
Nervous System ◽  
Protein Kinase ◽  
Sleep Disturbances ◽  
Deletion Syndrome ◽  
Potential Contribution ◽  
Sleep Maintenance ◽  
Energy Sensor ◽  
Increased Risk ◽  
Amp Activated Protein Kinase ◽  
1Q21.1 Deletion

AbstractThe human 1q21.1 deletion of ten genes is associated with increased risk schizophrenia. The deletion involves the ß-subunit of the AMP-activated protein kinase (AMPK) complex, a key energy sensor in the cell. Although neurons have a high demand for energy and low capacity to store nutrients, the role of AMPK in neuronal physiology is poorly defined. Here we show that AMPK is important in the nervous system for maintaining neuronal integrity and for stress survival and longevity in Drosophila. To understand its impact on behavior and potential contribution to the 1q21.1 deletion syndrome, we focused on sleep, as its main role is proposed to be to reestablish neuronal energy levels that are diminished during energy-demanding wakefulness. Sleep disturbances are one of the most common problems affecting individuals with psychiatric disorders. We show that AMPK is required to maintain proper sleep architecture and for sleep recovery following sleep deprivation. Neuronal AMPKß loss specifically leads to sleep fragmentation and causes dysregulation of genes believed to play a role in sleep homeostasis. Our data also suggest that AMPKß loss may contribute to the increased risk of developing mental disorders and sleep disturbances associated with the human 1q21.1 deletion. Sleep is regulated by circadian and homeostatic processes. While the circadian clock is well studied, the molecular mechanism underlying homeostasis remains largely unknown. Our data suggest that AMPK is required for sleep maintenance and may be involved in the homeostatic process of sleep regulation.Author SummaryThe human 1q21.1 chromosomal deletion is associated with increased risk of schizophrenia. Because this deletion affects only a small number of genes, it provides a unique opportunity to identify the specific disease-causing gene(s) using animal models. Here, we report the use of a Drosophila model to identify the potential contribution of one gene affected by the 1q21.1 deletion – PRKAB2 – to the pathology of the 1q21.1 deletion syndrome. PRKAB2 encodes a subunit of the AMP-activated protein kinase (AMPK) complex, the main cellular energy sensor. We show that AMPK deficiency reduces lifespan and causes structural abnormalities in neuronal dendritic structures, a phenotype which has been linked to schizophrenia. Furthermore, cognitive impairment and altered sleep patterning are some of the most common symptoms of schizophrenia. Therefore, to understand the potential contribution of PRKAB2 to the 1q21.1 syndrome, we tested whether AMPK alterations would cause defects in learning and sleep. Our study shows that lack of PRKAB2 and AMPK-complex activity, in the nervous system leads to reduced learning and to dramatic sleep disturbances. Thus, our data links a single 1q21.1-related gene with phenotypes that resemble common symptoms of schizophrenia, suggesting that this gene, PRKAB2, may contribute to the risk of developing schizophrenia.

scholarly journals VRK-1 extends life span by activation of AMPK via phosphorylation

2020 ◽  
Vol 6 (27) ◽  
pp. eaaw7824
Author(s):  
Sangsoon Park ◽  
Murat Artan ◽  
Seung Hyun Han ◽  
Hae-Eun H. Park ◽  
Yoonji Jung ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Life Span ◽  
Adult Life ◽  
Adult Life Span ◽  
C Elegans ◽  
Energy Sensor ◽  
Evolutionarily Conserved ◽  
Cultured Human Cells ◽  
Germline Proliferation ◽  
Amp Activated Protein Kinase

Vaccinia virus–related kinase (VRK) is an evolutionarily conserved nuclear protein kinase. VRK-1, the single Caenorhabditis elegans VRK ortholog, functions in cell division and germline proliferation. However, the role of VRK-1 in postmitotic cells and adult life span remains unknown. Here, we show that VRK-1 increases organismal longevity by activating the cellular energy sensor, AMP-activated protein kinase (AMPK), via direct phosphorylation. We found that overexpression of vrk-1 in the soma of adult C. elegans increased life span and, conversely, inhibition of vrk-1 decreased life span. In addition, vrk-1 was required for longevity conferred by mutations that inhibit C. elegans mitochondrial respiration, which requires AMPK. VRK-1 directly phosphorylated and up-regulated AMPK in both C. elegans and cultured human cells. Thus, our data show that the somatic nuclear kinase, VRK-1, promotes longevity through AMPK activation, and this function appears to be conserved between C. elegans and humans.

scholarly journals Role of the energy sensor AMP-activated protein kinase in renal physiology and disease

2010 ◽  
Vol 298 (5) ◽  
pp. F1067-F1077 ◽  
Author(s):  
Kenneth R. Hallows ◽  
Peter F. Mount ◽  
Núria M. Pastor-Soler ◽  
David A. Power
Keyword(s):  
Protein Kinase ◽  
Ion Transport ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Renal Physiology ◽  
Renal Diseases ◽  
Renal Hypertrophy ◽  
Energy Sensor ◽  
Energy Consuming ◽  
Amp Activated Protein Kinase

The ultrasensitive energy sensor AMP-activated protein kinase (AMPK) orchestrates the regulation of energy-generating and energy-consuming pathways. AMPK is highly expressed in the kidney where it is reported to be involved in a variety of physiological and pathological processes including ion transport, podocyte function, and diabetic renal hypertrophy. Sodium transport is the major energy-consuming process in the kidney, and AMPK has been proposed to contribute to the coupling of ion transport with cellular energy metabolism. Specifically, AMPK has been identified as a regulator of several ion transporters of significance in renal physiology, including the cystic fibrosis transmembrane conductance regulator (CFTR), the epithelial sodium channel (ENaC), the Na+-K+-2Cl− cotransporter (NKCC), and the vacuolar H+-ATPase (V-ATPase). Identified regulators of AMPK in the kidney include dietary salt, diabetes, adiponectin, and ischemia. Activation of AMPK in response to adiponectin is described in podocytes, where it reduces albuminuria, and in tubular cells, where it reduces glycogen accumulation. Reduced AMPK activity in the diabetic kidney is associated with renal accumulation of triglyceride and glycogen and the pathogenesis of diabetic renal hypertrophy. Acute renal ischemia causes a rapid and powerful activation of AMPK, but the functional significance of this observation remains unclear. Despite the recent advances, there remain significant gaps in the present understanding of both the upstream regulating pathways and the downstream substrates for AMPK in the kidney. A more complete understanding of the AMPK pathway in the kidney offers potential for improved therapies for several renal diseases including diabetic nephropathy, polycystic kidney disease, and ischemia-reperfusion injury.

scholarly journals AMP-Activated Protein Kinase Suppresses Autoimmune Central Nervous System Disease by Regulating M1-Type Macrophage–Th17 Axis

2016 ◽  
Vol 197 (3) ◽  
pp. 747-760 ◽  
Author(s):  
Ashutosh K. Mangalam ◽  
Ramandeep Rattan ◽  
Hamid Suhail ◽  
Jaspreet Singh ◽  
Md Nasrul Hoda ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Protein Kinase ◽  
Central Nervous System Disease ◽  
Nervous System Disease ◽  
System Disease ◽  
Amp Activated Protein Kinase ◽  
M1 Type

scholarly journals β-subunit myristoylation functions as an energy sensor by modulating the dynamics of AMP-activated Protein Kinase

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Nada Ali ◽  
Naomi Ling ◽  
Srinath Krishnamurthy ◽  
Jonathan S. Oakhill ◽  
John W. Scott ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Β Subunit ◽  
Energy Sensor ◽  
Amp Activated Protein Kinase

AMP-activated protein kinase: a cellular energy sensor with a key role in metabolic disorders and in cancer

2011 ◽  
Vol 39 (1) ◽  
pp. 1-13 ◽  
Author(s):  
D. Grahame Hardie
Keyword(s):  
Protein Kinase ◽  
Metabolic Disorders ◽  
Adenine Nucleotides ◽  
Metabolic Stress ◽  
Branch Points ◽  
Atp Production ◽  
Nucleotide Binding Sites ◽  
Anticancer Effects ◽  
Energy Sensor ◽  
Amp Activated Protein Kinase

It is essential to life that a balance is maintained between processes that produce ATP and those that consume it. An obvious way to do this would be to have systems that monitor the levels of ATP and ADP, although because of the adenylate kinase reaction (2ADP↔ATP+AMP), AMP is actually a more sensitive indicator of energy stress than ADP. Following the discoveries that glycogen phosphorylase and phosphofructokinase were regulated by AMP and ATP, Daniel Atkinson proposed that all enzymes at branch points between biosynthesis and degradation would be regulated by adenine nucleotides. This turned out to be correct, but what Atkinson did not anticipate was that sensing of nucleotides would, in most cases, be performed not by the metabolic enzymes themselves, but by a signalling protein, AMPK (AMP-activated protein kinase). AMPK occurs in essentially all eukaryotes and consists of heterotrimeric complexes comprising catalytic α subunits and regulatory β and γ subunits, of which the latter carries the nucleotide-binding sites. Once activated by a metabolic stress, it phosphorylates numerous targets that alter enzyme activity and gene expression to initiate corrective responses. In lower eukaryotes, it is critically involved in the responses to starvation for a carbon source. Because of its ability to switch cellular metabolism from anabolic to catabolic mode, AMPK has become a key drug target to combat metabolic disorders associated with overnutrition such as Type 2 diabetes, and some existing anti-diabetic drugs (e.g. metformin) and many ‘nutraceuticals’ work by activating AMPK, usually via inhibition of mitochondrial ATP production. AMPK activators also potentially have anticancer effects, and there is already evidence that metformin provides protection against the initiation of cancer. Whether AMPK activators can be used to treat existing cancer is less clear, because many tumour cells appear to have been selected for mutations that inactivate the AMPK system. However, if we can identify the various mechanisms by which this occurs, we may be able to find ways of overcoming it.

scholarly journals Nicotine Improves Obesity and Hepatic Steatosis and ER Stress in Diet-Induced Obese Male Rats

Endocrinology ◽  
2014 ◽  
Vol 155 (5) ◽  
pp. 1679-1689 ◽  
Author(s):  
Patricia Seoane-Collazo ◽  
Pablo B. Martínez de Morentin ◽  
Johan Fernø ◽  
Carlos Diéguez ◽  
Rubén Nogueiras ◽  
...  
Keyword(s):  
Nervous System ◽  
Body Weight ◽  
Adipose Tissue ◽  
Energy Balance ◽  
Protein Kinase ◽  
Brown Adipose Tissue ◽  
Male Rats ◽  
Brown Adipose ◽  
Brown Adipose Tissue Thermogenesis ◽  
Amp Activated Protein Kinase

Nicotine, the main addictive component of tobacco, promotes body weight reduction in humans and rodents. Recent evidence has suggested that nicotine acts in the central nervous system to modulate energy balance. Specifically, nicotine modulates hypothalamic AMP-activated protein kinase to decrease feeding and to increase brown adipose tissue thermogenesis through the sympathetic nervous system, leading to weight loss. Of note, most of this evidence has been obtained in animal models fed with normal diet or low-fat diet (LFD). However, its effectiveness in obese models remains elusive. Because obesity causes resistance towards many factors involved in energy homeostasis, the aim of this study has been to compare the effect of nicotine in a diet-induced obese (DIO) model, namely rats fed a high-fat diet, with rats fed a LFD. Our data show that chronic peripheral nicotine treatment reduced body weight by decreasing food intake and increasing brown adipose tissue thermogenesis in both LFD and DIO rats. This overall negative energy balance was associated to decreased activation of hypothalamic AMP-activated protein kinase in both models. Furthermore, nicotine improved serum lipid profile, decreased insulin serum levels, as well as reduced steatosis, inflammation, and endoplasmic reticulum stress in the liver of DIO rats but not in LFD rats. Overall, this evidence suggests that nicotine diminishes body weight and improves metabolic disorders linked to DIO and might offer a clear-cut strategy to develop new therapeutic approaches against obesity and its metabolic complications.

scholarly journals AMP-activated protein kinase, stress responses and cardiovascular diseases

2012 ◽  
Vol 122 (12) ◽  
pp. 555-573 ◽  
Author(s):  
Shaobin Wang ◽  
Ping Song ◽  
Ming-Hui Zou
Keyword(s):  
Cell Proliferation ◽  
Protein Kinase ◽  
Stress Responses ◽  
Recent Literature ◽  
Redox Balance ◽  
Cellular Polarity ◽  
Pathological Conditions ◽  
Energy Sensor ◽  
Intracellular Energy ◽  
Amp Activated Protein Kinase

AMPK (AMP-activated protein kinase) is one of the key players in maintaining intracellular homoeostasis. AMPK is well known as an energy sensor and can be activated by increased intracellular AMP levels. Generally, the activation of AMPK turns on catabolic pathways that generate ATP, while inhibiting cell proliferation and biosynthetic processes that consume ATP. In recent years, intensive investigations on the regulation and the function of AMPK indicates that AMPK not only functions as an intracellular energy sensor and regulator, but is also a general stress sensor that is important in maintaining intracellular homoeostasis during many kinds of stress challenges. In the present paper, we will review recent literature showing that AMPK functions far beyond its proposed energy sensor and regulator function. AMPK regulates ROS (reactive oxygen species)/redox balance, autophagy, cell proliferation, cell apoptosis, cellular polarity, mitochondrial function and genotoxic response, either directly or indirectly via numerous downstream pathways under physiological and pathological conditions.

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