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AMPK: a nutrient and energy sensor that maintains energy homeostasis

Key Points

  • AMP-activated protein kinase (AMPK) occurs as heterotrimeric protein complexes that monitor cellular energy status by sensing the concentrations of ATP, ADP and AMP.

  • Displacement of ATP by ADP or AMP at one site on the AMPK γ-subunit promotes the net phosphorylation of a conserved Thr residue within the activation loop of the kinase domain, causing >100-fold activation. Displacement of ATP or ADP by AMP at a second site on the γ-subunit causes a further tenfold allosteric activation, yielding up to 1,000-fold activation overall.

  • AMPK is activated by metabolic stresses that inhibit mitochondrial ATP production or that accelerate ATP consumption. It is also activated by many drugs and xenobiotics, most of which act by inhibiting mitochondrial function.

  • Once activated by energy stress, AMPK restores cellular energy balance by switching on catabolic, ATP-generating pathways while switching off anabolic, ATP-consuming pathways.

  • In mammals, AMPK also regulates whole-body energy balance, mainly by increasing food intake and energy expenditure through effects on the hypothalamus of the brain.

  • AMPK also regulates non-metabolic processes, such as progress through the cell cycle and excitability of neuronal membranes, with the overall purpose of sparing ATP.

Abstract

AMP-activated protein kinase (AMPK) is a crucial cellular energy sensor. Once activated by falling energy status, it promotes ATP production by increasing the activity or expression of proteins involved in catabolism while conserving ATP by switching off biosynthetic pathways. AMPK also regulates metabolic energy balance at the whole-body level. For example, it mediates the effects of agents acting on the hypothalamus that promote feeding and entrains circadian rhythms of metabolism and feeding behaviour. Finally, recent studies reveal that AMPK conserves ATP levels through the regulation of processes other than metabolism, such as the cell cycle and neuronal membrane excitability.

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Figure 1: Model for the mechanism of activation of AMPK.
Figure 2: Domain map of typical mammalian AMPK.
Figure 3: Two views of a crystal structure of a partial heterotrimeric complex of mammalian AMPK.
Figure 4: Effects of activation of AMPK on cellular metabolism.
Figure 5: AMPK-regulated control of feeding behaviour.

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Acknowledgements

Studies described that were carried out in the authors' laboratory were supported by the Wellcome Trust.

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Glossary

Glycogen phosphorylase

The primary enzyme that mobilizes stores of glucose in glycogen, catalysing the release of glucose-1-phosphate from the non-reducing ends of glycogen by a phosphorolysis reaction.

Phosphofructokinase

Enzyme that catalyses a key regulatory step in glycolysis: the transfer of phosphate from ATP to fructose-6-phosphate to generate fructose-1,6-bisphosphate.

Fructose-1,6-bisphosphatase

Enzyme that catalyses a key regulatory step in gluconeogenesis (hydrolysis of fructose-1,6-bisphosphate to fructose-6-phosphate) in the liver and kidney.

Membrane excitability

Some biological membranes, such as the plasma membranes of neurons, are excitable because they contain voltage-gated Na+ channels that open in response to depolarization, allowing Na+ ions to flood into the cell down their concentration gradient; this amplifies the depolarization and causes a wave of depolarization (an action potential) to travel along the membrane.

Allosteric activation

The activation of an enzyme by non-covalent binding of a ligand (an allosteric activator) that binds at a site distinct from the catalytic site.

Activation loop

A sequence segment in the C-terminal lobe of protein kinases that often plays a key part in switching the kinase on; in many cases, the kinase is only active after phosphorylation of this loop.

LKB1–STRAD–MO25 complex

A heterotrimeric complex containing the tumour suppressor protein kinase LKB1 (liver kinase B1) and the accessory subunits STRAD (STE20-related kinase adapter protein) and MO25 (also known as calcium-binding protein 39). LKB1 was found to be the gene that is mutated in a form of inherited cancer susceptibility (Peutz–Jeghers syndrome) and is also lost owing to somatic mutation in many human cancers.

N-terminal myristylation

The covalent attachment of 14 carbon saturated fatty acid (myristic acid), usually to the N terminus of a protein following cleavage of the initiating Met.

CBS repeat

Sequence motif usually occurring as two tandem repeats that form a Bateman domain. They are named after cystathionine β-synthase, in which the Bateman domain binds S-adenosyl Met.

Bateman domain

A domain formed by two tandem CBS repeats that associate together with central clefts that bind small molecules, especially adenosine derivatives.

Glutathionylation

The covalent attachment of glutathione to a protein via the formation of a mixed disulphide between the Cys moiety of glutathione and a Cys side chain of the protein.

Ataxia telangiectasia

An inherited human disorder of which the clinical signs include ataxia (uncoordinated movement) and telangiectasia (dilated blood vessels in the skin or mucous membranes). It is caused by mutation of the ataxia telangiectasia mutated (ATM) gene, which encodes a protein kinase of the phosphoinositide 3-kinase-like kinase (PIKK) family.

RAB-GAPs

Proteins carrying a RAB-GTPase activator protein function — that is, the ability to promote conversion of small G proteins of the RAB family from their active RAB-GTP state to their inactive RAB-GDP state.

Mitophagy

The special form of autophagy by which mitochondria (probably in a damaged or defective state) are engulfed by autophagosomes and degraded, and their contents recycled for re-use.

Arcuate nucleus

An anatomical region of the hypothalamus at the base of the brain that appears to have a particular role in feeding and appetite.

Ghrelin

A 28-amino-acid peptide that is released by cells of the stomach and represents a 'hunger signal'.

Presynaptic neurons

Neurons acting immediately upstream of the neurons under study. Presynaptic neurons release neurotransmitters directly onto the neurons of interest.

Miniature excitatory postsynaptic currents

Small depolarizing currents that can be measured by patch clamping of a neuron. The currents are generated by packets of neurotransmitters released from a presynaptic neuron upstream of the patch-clamped neuron. These currents can be observed by applying tetrodotoxin to inhibit the firing of action potentials in the neuron.

Ryanodine receptors

Ca2+ release channels in the sarcoplasmic/endoplasmic reticulum of muscle cells and neurons. These receptors are activated by Ca2+ and blocked by the plant product ryanodine.

Ventromedial hypothalamus

An anatomical region of the hypothalamus at the base of the brain that appears to have a role in glucose sensing and activation of the sympathetic nervous system.

Circadian rhythms

Biological rhythms that follow the normal 24 hour cycle; although endogenously driven and thus continuing in the absence of external cues, they are often entrained or modified by external stimuli such as light or food availability.

Suprachiasmatic nucleus

A hypothalamic bilateral structure that is the central pacemaker of circadian rhythms in mammals.

Delayed rectifier potassium channels

A group of voltage-gated potassium channels that open and close slowly in response to membrane depolarization. By allowing potassium ions to flow out of cells down their concentration gradient and thus oppose subsequent depolarization, these channels regulate the frequency of action potentials.

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Hardie, D., Ross, F. & Hawley, S. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 13, 251–262 (2012). https://doi.org/10.1038/nrm3311

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