Ca2+/calmodulin-dependent protein kinase kinase-β acts upstream of AMP-activated protein kinase in mammalian cells

Woods, Angela; Dickerson, Kristina; Heath, Richard B.; Hong, Seungpyo; Momcilovic, Milica; Johnstone, Stephen R.; Carlson, Marian; Carling, David

doi:10.1016/j.cmet.2005.06.005

Cited by 1,243 publications

(1,012 citation statements)

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“…Recently neuronal over-expression of the Ca 2+ /calmodulin dependent protein kinase (CaMKK) was shown to protect mice from high fat diet-induced weight gain, insulin resistance and glucose homeostasis. CaMKK is activated by the change of the intracellular Ca 2+ [62-64] and acts as an upstream activator of AMPK, independent of AMP levels. In hypothalamic neurons, CaMKK regulates orexigenic NPY production [65, 66].…”

Section: Role Of Calcium/calcium Binding Proteins In the Hypothalamusmentioning

confidence: 99%

Oxidative Stress in the Hypothalamus: the Importance of Calcium Signaling and Mitochondrial ROS in Body Weight Regulation

Gyengési

Paxinos

Andrews³

2012

Current Neuropharmacology

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A considerable amount of evidence shows that reactive oxygen species (ROS) in the mammalian brain are directly responsible for cell and tissue function and dysfunction. Excessive reactive oxygen species contribute to various conditions including inflammation, diabetes mellitus, neurodegenerative diseases, tumor formation, and mental disorders such as depression. Increased intracellular calcium levels have toxic roles leading to cell death. However, the exact connection between reactive oxygen production and high calcium stress is not yet fully understood. In this review, we focus on the role of reactive oxygen species and calcium stress in hypothalamic arcuate neurons controlling feeding. We revisit the role of NPY and POMC neurons in the regulation of appetite and energy homeostasis, and consider how ROS and intracellular calcium levels affect these neurons. These novel insights give a new direction to research on hypothalamic mechanisms regulating energy homeostasis and may offer novel treatment strategies for obesity and type-2 diabetes.

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Section: Role Of Calcium/calcium Binding Proteins In the Hypothalamusmentioning

confidence: 99%

Oxidative Stress in the Hypothalamus: the Importance of Calcium Signaling and Mitochondrial ROS in Body Weight Regulation

Gyengési

Paxinos

Andrews³

2012

Current Neuropharmacology

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“…The catalytic α subunit contains a conventional serine/threonine protein kinase domain, and phosphorylation of the Thr 172 residue within the activation loop of the α subunit by upstream kinases is essential for the activity of the heterotrimer (reviewed by Carling [3]). Two kinases have been established as upstream activators of AMPK: the protein kinase serine/threonine 11 (LKB1)/ STE20-related kinase adaptor alpha (STRAD)/calcium binding protein 39 (MO25) complex [4] and the calcium/ calmodulin-dependent protein kinase kinase β (CAMKKβ) [5]. Once phosphorylated at Thr 172 , AMPK can further be activated by allosteric binding of AMP to the regulatory γ subunit [6].…”

Section: Introductionmentioning

confidence: 99%

AMP-activated protein kinase inhibits IL-6-stimulated inflammatory response in human liver cells by suppressing phosphorylation of signal transducer and activator of transcription 3 (STAT3)

et al. 2010

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Aim/hypothesis The aim of the study was to examine the possible role of AMP-activated protein kinase (AMPK) in the regulation of the inflammatory response induced by cytokine action in human liver cells. Methods IL-6-stimulated expression of the genes for acutephase response markers serum amyloid A (SAA1, SAA2) and haptoglobin (HP) in the human hepatocarcinoma cell line HepG2 were quantified after modulation of AMPK activity by pharmacological agonists (5-amino-4-imidazolecarboxamideriboside [AICAR], metformin) or by using small interfering (si) RNA transfection. The intracellular signalling pathway mediating the effect of AMPK on IL-6-stimulated acute-phase marker expression was characterised by assessing the phosphorylation levels of the candidate protein signal transducer and activator of transcription 3 (STAT3) in response to AMPK agonists. Results AICAR and metformin markedly blunt the IL-6-stimulated expression of SAA cluster genes as well as of haptoglobin in a dose-dependent manner. Moreover, the repression of AMPK activity by siRNA significantly reversed the inhibition of SAA expression by both AICAR and metformin, indicating that the effect of the agonists is dependent on AMPK. For the first time we show that AMPK appears to regulate IL-6 signalling by directly inhibiting the activation of the main downstream target of IL-6, STAT3. Conclusions/interpretation We provide evidence for a key function of AMPK in suppression of the acute-phase response caused by the action of IL-6 in liver, suggesting that AMPK may act as an intracellular link between chronic low-grade inflammation and metabolic regulation in peripheral metabolic tissues.

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“…Thr-172 can also be phosphorylated by the Ca 2 + -activated kinase calmodulindependent kinase kinase-b, which can trigger the activation of AMPK in response to agents that increase intracellular Ca 2 + (Fig. 1), even in the absence of a rise in AMP (8,9) . AMPK occurs universally as heterotrimeric complexes, i.e.…”

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confidence: 99%

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

Hardie

2010

Proc. Nutr. Soc.

119

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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-ofrapamycin 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. Muscle: Exercise: Type 2 diabetes: NutraceuticalsAnimal cells take up fuel molecules such as glucose or fatty acids, and oxidise them to CO 2 via the process of catabolism. Much of the energy released during this process is used to convert ADP to ATP, which can be likened to the chemicals in a rechargeable battery. Extending this analogy, catabolism charges up the battery by converting ADP to ATP, whereas most other cellular activities (e.g. growth, division, secretion and movement) require energy and are driven by the conversion of ATP back to ADP, thus draining the battery. Just as machines that utilise rechargeable batteries (such as laptop computers or electric cars) require systems to monitor the state of the battery, cells require systems to monitor their ATP : ADP ratio and match the rates of uptake and consumption of carbon nutrients to the rate of ATP utilisation. The topic of this review is the AMP-activated protein kinase (AMPK), which is the major system responsible for achieving this task in eukaryotes. Researchers who wish to understand disorders of energy balance, such as obesity and type-2 diabetes, have been particularly interested in the system. Protein kinases, including AMPK, are signalling enzymes that modify the function of target proteins by transferring phosphate groups from ATP to side chains of specific amino acids, usually serine o...

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Ca2+/calmodulin-dependent protein kinase kinase-β acts upstream of AMP-activated protein kinase in mammalian cells

Cited by 1,243 publications

References 50 publications

Oxidative Stress in the Hypothalamus: the Importance of Calcium Signaling and Mitochondrial ROS in Body Weight Regulation

Oxidative Stress in the Hypothalamus: the Importance of Calcium Signaling and Mitochondrial ROS in Body Weight Regulation

AMP-activated protein kinase inhibits IL-6-stimulated inflammatory response in human liver cells by suppressing phosphorylation of signal transducer and activator of transcription 3 (STAT3)

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

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