AMPK - a nutrient and energy sensor that maintains energy homeostasis

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Nat Rev Mol Cell Biol

. Author manuscript; available in PMC: 2017 Dec 12.

Published in final edited form as: Nat Rev Mol Cell Biol. 2012 Mar 22;13(4):251–262. doi: 10.1038/nrm3311

AMPK - a nutrient and energy sensor that maintains energy homeostasis

D Grahame Hardie 1, Fiona A Ross 1, Simon A Hawley 1

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PMCID: PMC5726489  EMSID: EMS75237  PMID: 22436748

The publisher's version of this article is available at Nat Rev Mol Cell Biol

핵심 포인트

• AMP 활성화 단백질 키나제(AMPK)는 ATP, ADP, AMP의 농도를 감지하여 세포 에너지 상태를 모니터링하는 이종 삼량체 단백질 복합체로 존재합니다.
• ADP 또는 AMP가 AMPK γ-서브유닛의 한 위치에서 ATP를 대체하면, 키나아제 도메인의 활성화 루프 내 보존된 Thr 잔기에서 순수 인산화가 촉진되어 >100배의 활성화가 발생합니다. AMP가 γ-서브유닛의 두 번째 위치에서 ATP 또는 ADP를 대체하면 추가로 10배의 알로스테릭 활성화가 발생하여 전체적으로 최대 1,000배의 활성화가 달성됩니다.
• AMPK는 미토콘드리아 ATP 생산을 억제하거나 ATP 소비를 가속화하는 대사 스트레스에 의해 활성화됩니다. 또한 많은 약물과 외인성 물질에 의해 활성화되며, 대부분은 미토콘드리아 기능을 억제하는 방식으로 작용합니다.
• 에너지 스트레스에 의해 활성화된 AMPK는 ATP 생성 경로를 활성화하고 ATP 소비 경로를 억제함으로써 세포 내 에너지 균형을 회복합니다.
• 포유류에서 AMPK는 주로 뇌의 시상하부에 작용하여 식욕 증가와 에너지 소비 증가를 통해 전신 에너지 균형을 조절합니다.
• AMPK는 세포 주기 진행과 신경 세포막의 흥분성 등 대사 과정과 무관한 과정도 조절하며, 이는 전반적으로 ATP를 절약하는 것을 목적으로 합니다.

Preface

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 behavior. Finally, recent studies reveal that AMPK conserves ATP levels through the regulation of processes other than metabolism, such regulation of the cell cycle and neuronal membrane excitability.

서론

AMP 활성화 단백질 키나제(AMPK)는 

세포 내 에너지 감지기의 핵심 역할을 합니다. 

에너지 상태가 저하되면 활성화되어 

분해 과정에 관여하는 단백질의 활성 또는 발현을 증가시켜 ATP 생성을 촉진하며,

 동시에 생합성 경로를 차단하여 ATP를 보존합니다. 

AMPK는 

또한 전신 수준에서 대사 에너지 균형을 조절합니다. 

예를 들어, 

시상하부에 작용하여 식욕을 촉진하는 약물의 효과를 매개하며, 

대사 및 식욕 행동의 일주기 리듬을 동기화합니다. 

최근 연구에서는

AMPK가 대사 이외의 과정, 예를 들어

세포 주기 조절 및 신경 세포막 흥분성 조절을 통해

ATP 수준을 보존한다는 것이 밝혀졌습니다.

Introduction

Just like a mobile electronic device, every living cell contains a “rechargeable battery” formed by pairs of interconvertible chemicals. The key chemicals within the cell are ATP and ADP, interconverted by the reaction ATP ↔ ADP + phosphate. This reaction is maintained by catabolism many orders of magnitude away from equilibrium, yielding a high ratio of ATP to ADP that is used to drive energy-requiring processes. In animal cells ATP is mainly generated via the mitochondrial ATP synthase, thus “charging the battery”. Almost every other function that cells perform requires energy, and most are driven by the hydrolysis of ATP back to ADP and phosphate, thus “discharging the battery”. Clearly, ATP generation needs to remain in balance with ATP consumption, and regulatory proteins that sense ATP and ADP levels would be a logical way to achieve this. However, all eukaryotic cells express high levels of adenylate kinase, and the reversible reaction it catalyzes (2ADP ↔ ATP + AMP) is usually maintained close to equilibrium. This means that any rise in the ADP:ATP ratio, which signifies falling energy status, causes the adenylate kinase reaction to be displaced towards ATP and AMP production. Thus, falling cellular energy is associated with increases not only in ADP, but also AMP. The relative increase in concentration is always much greater for AMP than ADP, although its absolute concentration remains lower than that of ADP unless energy stress becomes quite severe (Fig. 1). Thus, it seems logical that proteins sensing cellular energy status should monitor either the ADP:ATP or AMP:ATP ratio, or both. A small number of metabolic enzymes do directly sense the AMP:ATP ratio, including the muscle isoforms of glycogen phosphorylase [G] and phosphofructokinase [G] (which are involved in glycogen breakdown and glycolysis, and are activated by an increasing AMP:ATP ratio), and fructose-1,6-bisphosphatase (which is involved in gluconeogenesis, and is inhibited by an increasing AMP:ATP ratio). However, the principal energy sensor in most eukaryotic cells appears to be the AMP-activated protein kinase (AMPK)1. In support of this, increases in AMP:ATP and ADP:ATP ratios during stresses such as muscle contraction2, ischemia in cardiac muscle3, or treatment of hepatocytes with metformin4 are larger in cells or tissues in which AMPK, or its essential activating upstream kinase liver kinase B1 (LKB1), have been knocked out. In this Review article, we describe how AMPK monitors cellular energy status by sensing increases in the ratios of AMP:ATP and ADP:ATP, as well as other signals. Moreover, we examine how it regulates energy balance at the cellular level, by activating catabolic pathways that generate ATP, while conserving ATP by down-regulating anabolic pathways. Finally, we discuss results showing that AMPK also regulates metabolism and energy balance at the whole body level, especially via effects on the hypothalamus, as well as recent findings suggesting that AMPK conserves energy by regulating non-metabolic processes, such as the cell cycle and neuronal membrane excitability.

소개

모바일 전자기기처럼 모든 살아있는 세포는

상호 변환 가능한 화학물질 쌍으로 구성된

'재충전 가능한 배터리'를 포함하고 있습니다.

세포 내 주요 화학물질은

ATP와 ADP로, ATP ↔ ADP + 인산염 반응을 통해 상호 변환됩니다.

이 반응은

평형 상태에서 수십억 배나 멀리 떨어진 상태에서 분해 작용에 의해 유지되며,

ATP와 ADP의 높은 비율을 생성해 에너지 소비 과정에 에너지를 공급합니다.

동물 세포에서 ATP는

주로 미토콘드리아의 ATP 합성효소에 의해 생성되어

“배터리를 충전”합니다.

세포가 수행하는 거의 모든 기능은 에너지를 필요로 하며,

대부분은 ATP가 ADP와 인산으로 가수분해되는 과정에서

“배터리를 방전”함으로써 이루어집니다.

따라서

ATP 생성량은 ATP 소비량과 균형을 유지해야 하며,

ATP와 ADP 농도를 감지하는 조절 단백질이 이를 달성하는 논리적인 방법일 것입니다.

그러나

모든 진핵세포는 아데닐산 키나아제(adenylate kinase)를 고농도로 발현하며,

이 단백질이 촉매하는 가역 반응(2ADP ↔ ATP + AMP)은

일반적으로 평형 상태에 가깝게 유지됩니다.

이는 ADP:ATP 비율이 상승해 에너지 상태가 저하되면

아데닐산 키나아제 반응이 ATP와 AMP 생성을 향해 이동함을 의미합니다.

따라서

세포 에너지 감소는

ADP뿐만 아니라 AMP의 증가와도 연관됩니다.

상대적 농도 증가율은

항상 AMP가 ADP보다 훨씬 크지만,

절대 농도는 에너지 스트레스가 매우 심해지지 않는 한 ADP보다 낮습니다(그림 1).

따라서

세포 에너지 상태를 감지하는 단백질은

ADP:ATP 또는 AMP:ATP 비율, 또는 둘 다를 모니터링해야 한다는 것이 논리적입니다.

소수의 대사 효소는

AMP:ATP 비율을 직접 감지합니다.

이에는 글리코겐 분해와 글리코lysis에 관여하며 AMP:ATP 비율이 증가함에 따라 활성화되는 글리코겐 포스포릴레이스 [G]와 포스포프루토키나제 [G]의 근육 이소형, 그리고 글루코네오게네시스(gluconeogenesis)에 관여하며 AMP:ATP 비율이 증가함에 따라 억제되는 프럭토스-1,6-비스포스파타제(fructose-1,6-bisphosphatase)가 포함됩니다.

그러나 대부분의 진핵세포에서 주요 에너지 센서는 AMP 활성화 단백질 키나제(AMPK)1인 것으로 보입니다. 이를 뒷받침하는 증거로, 근육 수축2, 심장 근육의 허혈3, 또는 간세포에 메트포르민을 투여한 경우와 같은 스트레스 상황에서 AMP:ATP 및 ADP:ATP 비율이 증가하는 현상이 AMPK 또는 그 필수 활성화 상류 키나제인 간 키나제 B1(LKB1)이 결손된 세포나 조직에서 더 크게 나타납니다. 이 리뷰 논문에서 우리는 AMPK가 AMP:ATP 및 ADP:ATP 비율의 증가를 감지함으로써 세포 에너지 상태를 모니터링하는 메커니즘을 설명합니다. 또한 AMPK가 ATP를 생성하는 분해 경로를 활성화하면서 ATP를 보존하기 위해 합성 경로를 억제함으로써 세포 수준에서 에너지 균형을 조절하는 방식을 탐구합니다. 마지막으로, AMPK가 특히 뇌하수체에 미치는 영향을 통해 전신 수준에서 대사 및 에너지 균형을 조절한다는 결과를 논의하며, AMPK가 세포 주기 및 신경 세포막 흥분성 등 비대사적 과정을 조절함으로써 에너지를 보존한다는 최근 연구 결과도 소개합니다.

Figure 1.

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Model for the mechanism by which AMPK is activated by increases in AMP and ADP (top), as the cellular concentrations of ATP, ADP and AMP change (bottom). The model at the top represents different states of the three subunits of AMPK (see Fig. 2 for details of domains). The graph at the bottom shows changes in the predicted concentrations of ATP, ADP and AMP on going from an unstressed, fully charged cell (left) to a cell undergoing a severe energy stress (right), corresponding to a 10-fold increase in ADP:ATP ratio. The graph was generated by assuming that the adenylate kinase reaction was at equilibrium. Note that in a fully charged cell (left), AMP concentration is very low, but that its % change in concentration as ADP/ATP increases is always much greater than those of ATP or ADP. In the model at the top, the basal state (top left) has sites 1 and 3 in the γ subunit occupied by ATP (site 4 is always occupied by AMP). Replacement of ATP by ADP (or AMP) at site 3 during moderate stress (top centre) promotes phosphorylation of Thr172 (bottom centre), causing a 100-fold increase in activity (indicated by two stars). Replacement of ATP by AMP at site 1 during more severe stress causes a further 10-fold allosteric activation (indicated by a third star, bottom right). As cellular energy status returns to normal, AMP at site 1 and ADP or AMP at site 3 are progressively replaced by ATP (moving from right to left on the bottom row). This promotes the dephosphorylation of Thr-172 and a return to the basal state.

AMPK – subunits and regulation

Genes encoding AMPK subunits are found in essentially all eukaryotes. AMPK and its orthologs appear to exist universally as heterotrimeric complexes comprising a catalytic α subunit and regulatory β and γ subunits, the domain organization of which are summarized in Fig. 2. The kinase activity of the αβγ complexes, in animals from nematodes to humans, is instantaneously increased by AMP by as much as 10-fold, although due to technical limitations with the assay5 the effect observed is usually smaller. It has been argued that this allosteric activation [G] by AMP (which gave the kinase its name) may not be relevant under physiological conditions because of competition at the allosteric site by ADP and ATP6. However, as shown in Fig. 1, an increase in the ADP:ATP ratio of only 10-fold is sufficient for the cellular concentrations of the three adenine nucleotides to become equal. Although this would represent quite a severe stress and might only occur in pathological states (such as ischemia) rather than under more physiological conditions (such as exercise), the ATP:ADP ratio would still be still many orders of magnitude away from equilibrium and could still drive energy-requiring processes.

Figure 2.

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Domain map of typical mammalian AMPK. Colour coding of domains are similar to those in Figs. 1 and 3. AMPK complexes are heterotrimers composed of α, β and γ subunits in a 1:1:1 ratio. Key to acronyms: N-lobe, N-terminal lobe of kinase domain; C-lobe, C-terminal lobe of kinase domain; AID, auto-inhibitory domain; α-CTD, α subunit C-terminal domain; CBM, carbohydrate-binding module; β-CTD, β subunit C-terminal domain; CBS1-4, CBS repeats in γ subunit. The β-CTD forms the core of the complex, binding to the α-CTD and the N-terminus of the γ subunit prior to CBS1.

AMPK catalytic subunits contain a conventional serine/threonine kinase domain at the N-terminus. In all species, the activity of the complex increases more than 100-fold5 when a conserved threonine residue in the activation loop [G] (which is conventionally referred to as Thr172 due to its position in the original rat sequence7)is phosphorylated by upstream kinases. In mammals the major upstream kinases are the LKB1:STRAD:MO25 complex [G] 8–10 (originally identified genetically as a tumor suppressor) and the Ca2+/calmodulin-activated protein kinases kinases, especially CaMKKβ11–13.

The LKB1 complex provides a high basal level of phosphorylation at Thr-172 that is modulated by the binding of AMP to the AMPK-γ subunit, which promotes phosphorylation and inhibits dephosphorylation14, 15. Although allosteric activation is only caused by AMP, it has recently been found that the effects on phosphorylation and dephosphorylation can also be produced by ADP16, 17. The effects of AMP and ADP on phosphorylation require N-terminal myristylation [G] of the β subunit 17, 18. Since AMP and ADP bind the γ subunits of AMPK with similar affinity to ATP16 (which does not cause activation), and ADP is usually present in cells at higher concentrations than AMP (Fig. 1), ADP may be the key activating signal that promotes net Thr-172 phosphorylation during moderate energy stress. However, allosteric activation by AMP would further amplify activation during a more severe stress. This complex mechanism (Fig. 1) allows the system to provide a graded response of AMPK activity over a wide range of stress levels.

The alternative activating pathway, involving CaMKKβ, triggers activation of AMPK in response to increases in cell Ca2+ without necessarily requiring any change in AMP or ADP levels. In tumor cells that have lost the tumor suppressor LKB1 due to somatic mutations, treatments that increase AMP and ADP levels do not normally activate AMPK8, because basal CaMKKβ activity is too low for the effects of nucleotide binding on phosphorylation status to become evident. However, these treatments can cause AMPK activation in such cells if intracellular Ca2+ is also elevated19. This emphasizes that the effects of AMP and/or ADP on Thr172 phosphorylation status are a result of their binding to AMPK, and are independent of the upstream kinases and phosphatases that phosphorylate or dephosphorylate Thr172.

AMPK - structure

Although there is not yet a structure for a complete AMPK heterotrimer, the structures of various combinations of domains have been determined by X-ray crystallography. At the N-terminus of the α subunit is a conventional kinase domain immediately followed by an auto-inhibitory domain (AID), so-called because constructs containing the kinase domain plus the AID are much less active than those containing the kinase domain alone20, 21. The AID is followed by an extended “linker peptide” that connects the AID to the C-terminal domain (α-CTD). A recent structure16 showed that this linker (colored red in Figs. 2 and 3) wraps around the γ subunit as if holding it in a tight embrace.

Figure 3.

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Two views of a crystal structure of a partial heterotrimeric complex of mammalian AMPK16; the right-hand view is rotated about 180° about the y axis compared to the left-hand view. The constructs crystallized contained only the C-terminal domain of the β subunit and also lacked a flexible loop in the C-terminal domain of the α subunit. The α subunit AID was present but was not resolved in this crystal form; in the left-hand view, its approximate location would just to the right of the junction between the αsubunit C-lobe (green) and the α-linker (red). The crystals contained AMP bound at sites 3 and 4. Note how in this structure, access to the Thr172 site is restricted by the close association of the α-CTD with the kinase domain (left-hand view). In addition, note how AMP bound in site 3 is not visible because it is covered by the “α-hook” structure of the linker peptide (right-hand view, linker peptide in red). Key to acronyms: N-lobe, N-terminal lobe of kinase domain; C-lobe, C-terminal lobe of kinase domain; γ-NTD, N-terminal region of γ subunit; α-CTD, α subunit C-terminal domain; β-CTD, β subunit C-terminal domain; γ-CBS1-4, CBS repeats in γ subunit.

The β subunits contain a carbohydrate-binding module or CBM (absent in the constructs used to generate the structure in Fig. 3), which causes mammalian AMPK to associate with glycogen particles22, 23. The functional significance of this remains uncertain, although it may serve to co-localize AMPK with downstream targets located in the glycogen particle, such as glycogen synthase. The β subunit C-terminal domain (β-CTD) interacts with both the α-CTD and the γ subunit, thus forming the core of the complex. The γ subunits contain four tandem repeats, numbered CBS1 through CBS4 in Figs. 2 and 3, of a sequence motif termed a CBS repeat [G] 24. These occur in a small number of other proteins (including cystathionine β-synthase (CBS)), usually as just two repeats that assemble to form a Bateman domain [G]25, with ligand-binding sites in the cleft between the repeats26. Most Bateman domains bind adenosine-containing ligands, usually ATP but in one case S-adenosyl methionine27, and mutations in them are associated with several human diseases, including a heart disease caused by mutations affecting the AMPK-γ2 subunit26, 27. In AMPK the four CBS repeats in the γ subunits form a flattened disk with one repeat in each quadrant (seen from two different sides in Fig. 3), containing four potential ligand-binding sites in the centre. These sites are numbered 1-4 according to the number of the repeat carrying a conserved aspartate residue involved in ligand binding6, and have variable occupancies in the crystal structures of partial complexes from mammals and fungi16, 28–30. In the mammalian γ1 subunit, site 2 appears to be always empty, site 4 to have a tightly-bound AMP, whereas sites 1 and 3 represent the regulatory sites that bind AMP, ADP or ATP in competition. AMP binding to site 1 appears to cause allosteric activation, while binding of AMP or ADP to site 3 appears to modulate the phosphorylation state of Thr-17216. A model16 that can explain how binding of AMP or ADP, but not ATP, protects Thr-172 against dephosphorylation has been discussed previously31.

One long-standing puzzle has been the identity of the signals that activate AMPK orthologs in fungi and plants, which are not allosterically activated by AMP32, 33. Under conditions where the S. cerevisiae SNF1 complex is activated, such as during glucose starvation, there are very large increases in AMP:ATP and ADP:ATP ratios32. The γ subunits in fungi and plants contain four CBS repeats as in mammals, and crystal structures of partial complexes from S. pombe have been solved with AMP, ADP and/or ATP bound at different sites30, 34. These observations support the idea that the activating signal is an adenine nucleotide in fungi as in mammals, and it was recently reported that ADP inhibits dephosphorylation and inactivation of the S. cerevisiae complex35, with AMP having a smaller effect36. AMP had already been shown to inhibit dephosphorylation of a plant SnRK1 complex37. These results suggest that ADP and/or AMP may be the elusive signals that activate the fungal and plant enzymes, but that they work only via effects on the phosphorylation state of the kinase, and not via the additional allosteric mechanism.

Regulation of AMPK in intact cells

In mammalian cells, AMPK is activated by many different types of metabolic stress, drugs and xenobiotics by the mechanisms described above, involving increases in cellular AMP, ADP or Ca2+. These can now be regarded as the classical or “canonical” AMPK activation mechanisms. However, recent work suggests that other stimuli activate AMPK via mechanisms that do not involve changes in the levels of AMP, ADP and Ca2+, which can therefore be termed “non-canonical” mechanisms. These distinct types of mechanism are addressed below.

Activation by metabolic stresses, drugs and xenobiotics

The canonical mechanisms of activation of mammalian AMPK, which involve increases in AMP and ADP (Fig. 1) explain why AMPK is activated by stresses that inhibit the catabolic production of ATP, such as starvation for glucose38 or oxygen39 or addition of a metabolic poison40, as well as by stresses that increase ATP consumption such as muscle contraction41. AMPK is also switched on by numerous drugs and xenobiotics, including anti-diabetic drugs (such as metformin, phenformin and thiazolidinediones42, 43), plant products reputed to have health-promoting properties (resveratrol from grapes and red wine44, epigallocatechin gallate from green tea, capsaicin from peppers45, curcumin from turmeric46, and even garlic47), and plant products used in traditional Chinese medicine (berberine48 and hispidulin49). Metformin, which is now prescribed to more than 100 million people with type 2 diabetes worldwide, was derived from the natural product galegine extracted from Galega officinalis, a plant reputedly used to treat diabetes-like conditions in medieval Europe. Although metformin activates AMPK, this may not explain all of the therapeutic effects of the drug. In fact, AMPK-α1 knockout mice that also carry a liver-specific deletion of AMPK-α2 display a normal hypoglycemic response to metformin, and the acute effects of metformin on glucose production in isolated hepatocytes are also preserved4. The latter effect may be explained by metformin causing an increase in AMP that directly inhibits the gluconeogenic enzyme fructose-1,6-bisphosphatase. One caveat in the interpretation of these experiments is that the fall in ATP (and hence the increase in AMP) caused by metformin was larger in cells lacking AMPK than in wild type cells4, suggesting that the inhibition of fructose-1,6-bisphosphatase by AMP may be accentuated in the absence of AMPK. Thus, although not completely ruling out a role for AMPK in metformin action, these results do indicate that other targets, such as fructose-1,6-bisphosphatase, are also important.

It has been suggested that metformin activates AMPK in L6 cells by inhibiting AMP deaminase (the enzyme that breaks down AMP) thus causing AMP to accumulate50. While this is an interesting proposal, the concentration of metformin used to inhibit AMP deaminase (10 mM) was very high. The same study also reported that the effect of metformin to activate AMPK was not reduced by siRNA knockdown of adenylate kinase. However, only the “cytosolic” AK1 isoform was knocked down, and not the mitochondrial isoform, AK2, which might be the more relevant isoform when studying effects of a mitochondrial inhibitor. Also, we now know that increased phosphorylation of AMPK can be triggered by an increase in ADP alone, obviating any requirement for adenylate kinase to generate AMP.

Intriguingly, some of the AMPK activators described above, including resveratrol and metformin, extend healthy lifespan in C. elegans, and genetic studies show that the AMPK ortholog is required for these effects, as well as for the life-extending effects of dietary restriction51, 52. In both C. elegans and mammalian cells, AMPK up-regulates genes involved in oxidative metabolism and oxidative stress resistance by regulating transcription factors of the DAF-16/FOXO family53, 54. This might contribute to its effects on healthy lifespan.

An important question is how these drugs and xenobiotics all manage to activate AMPK, despite the fact that their structures are so varied. Most modulate AMPK in intact cells but not in cell-free assays, suggesting that they activate AMPK indirectly. Using a cell line that expresses an AMP- and ADP-insensitive AMPK mutant, it has been shown that many of them, including metformin and resveratrol, activate AMPK indirectly by increasing cellular AMP and ADP, usually by inhibiting mitochondrial ATP synthesis55. Many of these natural products appear to be defensive compounds produced by plants to deter infection by pathogens, or grazing by insect or mammalian herbivores. Consistent with this, resveratrol is produced in grapes in response to fungal infection56, while Galega officinalis is classed as a noxious weed in the USA because it is poisonous to herbivores. Since the mitochondrial respiratory chain and ATP synthase contain several large multiprotein complexes, they might have many potential binding sites for hydrophobic xenobiotics that might inhibit their function. Production of mitochondrial poisons would be a useful general strategy for plants to deter pathogens or herbivores, with the side effect that plants would provide a rich source of AMPK activators. One could argue that, by inhibiting mitochondrial ATP synthesis, these xenobiotics are acting in animals as mimetics of dietary restriction and/or exercise, both of which can decrease cellular energy status and have favorable effects on healthy lifespan.

Activation by oxidative stress and genotoxic treatments

There are increasing indications that some types of cellular stress activate AMPK by “non-canonical” mechanisms that may not involve increases in AMP, ADP or Ca2+ levels. In cultured cells, AMPK is activated by reactive oxygen species (ROS) such as H2O2. At high ROS concentrations, AMPK activation may be secondary to the inhibition of mitochondrial ATP synthesis, with consequent rises in AMP and ADP levels55. However, it has been suggested that there is also a more direct mechanism involving oxidation or glutathionylation [G] of two conserved cysteine residues in the AMPK-α subunit57. It has also been suggested that H2O2 can activate AMPK via a third mechanism involving a cytoplasmic form of the PI-3 kinase-like kinase, Ataxia-Telangiectasia Mutated (ATM)58, the product of the gene mutated in human ataxia-telangiectasia [G]. Nuclear ATM is activated by double strand breaks in DNA and is part of a key DNA damage-sensing pathway. However, it has recently become clear that there is also a cytoplasmic pool of ATM that has a role in the response to oxidative stress59. AMPK activation by low concentrations of H2O2 is reduced in fibroblasts from ataxia-telangiectasia patients or mouse embryo fibroblasts lacking ATM. ATM-dependent activation of AMPK by oxidative stress seems to require LKB1, since it is attenuated in cells lacking this upstream kinase58. Interestingly, ATM can phosphorylate LKB1, although it is not clear that this has any effect on LKB1 activity60.

Another class of factors that activate AMPK are genotoxic, DNA-damaging treatments such as etoposide61, doxorubicin62 and ionizing radiation63, which activate AMPK initially in the nucleus63. There is evidence that these effects also require ATM but, surprisingly, they do not require LKB1 because the pathway is functional in LKB1-null cells61, 63. The detailed mechanism for this effect remains unclear. Finally, a recent genome-wide association study identified a strong association between single nucleotide polymorphisms that mapped to the Atm gene on chromosome 11 and enhanced hypoglycemic response to metformin treatment in humans64. Although the molecular explanation for this association remains unclear, it provides another tantalizing link between metformin, ATM and AMPK.

To summarize this section, AMPK is activated in intact cells both by “canonical” pathways involving increases in AMP, ADP or Ca2+, and by “non-canonical” pathways such as those triggered by ROS and DNA damaging agents. The latter may involve the PI-3-like kinase ATM, although the detailed mechanisms involved remain unclear.

Regulation of cellular energy metabolism

AMPK and its orthologs phosphorylate downstream targets at serine/threonine residues within a characteristic sequence motif, which has hydrophobic residues at the -5 and +4 positions and basic residues at -4 and -3, or both65, 66. Another basic residue at -6 is an additional positive determinant, while the best substrates (such as acetyl-CoA carboxylase-1/-α) have additional hydrophobic residues forming an amphipathic helix N-terminal to the -5 position67. The principal effects of AMPK activation on cell metabolism are summarized in Fig. 4. Consistent with a role in maintaining energy homeostasis, when AMPK is activated by energetic stress it switches on catabolic pathways that generate ATP, while switching off biosynthetic pathways that consume ATP.

Figure 4.

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Summary of effects of AMPK activation on cellular metabolism. The likely protein targets that mediate the metabolic effects of AMPK, as well as the final metabolic outcomes, are depicted. Proteins shown on the inner wheel with question marks may not be directly phosphorylated by AMPK. Catabolic pathways, including glucose uptake via GLUT4 and GLUT1, glycolysis, fatty acid uptake via CD36, fatty acid oxidation, mitochondrial biogenesis and autophagy are invariably activated by AMPK. Anabolic pathways, including fatty acid synthesis, transcription of lipogenic enzymes, triglyceride synthesis, cholesterol synthesis, transcription of gluconeogenic enzymes, glycogen synthesis, protein synthesis and rRNA synthesis, are invariably inhibited by AMPK.

Regulation of glucose uptake by the glucose transporter GLUT4

Catabolic events mediated by AMPK include enhanced glucose uptake during muscle contraction, when the major metabolic fate of the glucose is catabolism to generate ATP. Muscle glucose uptake is also promoted by the hormone insulin, although this mainly occurs in resting muscle when the major metabolic fate of the glucose is glycogen synthesis, an anabolic process. In both cases, enhanced glucose uptake is mediated through translocation of the glucose transporter GLUT4 from intracellular storage vesicles to the plasma membrane. Fusion of these vesicles with the plasma membrane requires members of the Rab family of G proteins to be in their GTP-bound state68. Under basal conditions Rabs are held in an inactive GDP-bound state by Rab-GAPs such as AS160 (also known as TBC1D4) and TBC1D1, which are associated with the GLUT4 storage vesicles. The insulin-activated kinase Akt phosphorylates AS160 in muscle and adipocytes, triggering its association with 14-3-3 proteins and its consequent dissociation from the vesicles69–71. Similarly, AMPK phosphorylates TBC1D1 in contracting muscle, with similar effects72, 73. In either case, dissociation of these Rab-GAPs triggers the conversion of Rabs to their active, GTP forms and the consequent fusion of the vesicles, carrying their GLUT4 cargo, with the plasma membrane. Consistent with this model, mice with a knock-in mutation (T649A) at a key Akt phosphorylation site in AS160 show impaired glucose disposal in vivo and impaired insulin-stimulated glucose uptake with isolated muscle71. It would be very interesting to perform similar experiments with the AMPK site on TBC1D1, to confirm‎ the mechanism by which AMPK regulates glucose uptake in contracting muscle.

Whether AMPK, working via phosphorylation of TBC1D1 and perhaps other targets, entirely accounts for the acute effects of contraction on muscle glucose transport has been a matter of some controversy. In mouse knockouts of AMPK-α2 (the major catalytic subunit isoform in muscle), the stimulatory effects of the AMPK activator 5-aminoimidazole-4-carboxamide riboside (AICAR) on glucose uptake were lost, but the effects of contraction were normal. In AMPK-α1 knockout mice, both responses were normal74. By contrast, in mice with muscles lacking the upstream kinase LKB1 (in which activation of both AMPK-α1 and AMPK-α2 complexes by contraction was abolished), the effects of both AICAR and contraction on glucose uptake were lost2. One explanation for these discrepancies is that AMPK-α1 may be able to compensate for AMPK-α2 when the latter is absent. Recent results with muscle-specific AMPK-β1-/- AMPK-β2-/- double knockout mice, which lack any detectable AMPK activity, have supported the idea that AMPK activation is crucial during muscle contraction. The running speed and endurance of these mice was dramatically reduced, and they exhibited blunted muscle glucose uptake in response to treadmill exercise, and markedly impaired contraction-stimulated glucose uptake in isolated muscles75. These results are consistent with the idea that AMPK represents the primary signalling pathway responsible for contraction-induced glucose uptake, although TBC1D1 may not be the only downstream target that mediates this effect.

Regulation of other catabolic pathways

AMPK also promotes glucose uptake into cells expressing only GLUT1 (which includes most cells other than those in muscle, liver and adipose tissue), via a mechanism that involves activation of GLUT1 that is already located at the plasma membrane76. Moreover, it promotes fatty acid uptake into cardiac myocytes via translocation of vesicles containing the fatty acid transporter CD36 to the plasma membrane77. The direct targets for AMPK that mediate these effects remain unknown. Once they have entered the cell, AMPK can promote the catabolism of glucose via glycolysis, and of fatty acids by enhancing their uptake into mitochondria and their consequent breakdown by the β-oxidation pathway. Activation of glycolysis occurs via phosphorylation of 6-phosphofructo-2-kinase (PFK2), which catalyzes the generation of fructose-2,6-bisphosphate, a key allosteric activator of the glycolytic enzyme 6-phosphofructo-1-kinase. However, this only occurs in cells expressing the PFKFB2 isoform of PFK2, such as cardiac myocytes39, or the PFKFB3 isoform, such as monocytes and macrophages78. Uptake of fatty acids into mitochondria, which appears to be the rate-limiting step in β-oxidation, is promoted by AMPK via phosphorylation and inactivation of the ACC2/ACCβ isoform of acetyl-CoA carboxylase. This results in a drop in concentration of the acetyl-CoA carboxylase product, malonyl-CoA, an inhibitor of fatty acid entry into mitochondria mediated by the carnitine-palmitoyl-CoA transferase-1 (CPT1) system79.

Regulation of mitochondrial biogenesis and mitophagy

Another critical process activated by AMPK is mitochondrial biogenesis (Fig. 4), which in the longer term generates increased capacity for the oxidative catabolism of both glucose and fatty acids. Repeated daily dosing of rats with AICAR results in increased expression‎ of mitochondrial genes in muscle80 as well as increased exercise endurance81 (the latter finding prompted the World Anti-Doping Agency to ban the use of AICAR in competitive sports). The AMPK-β1-/- AMPK-β2-/- double knockout mice mentioned above, which lack any AMPK activity in muscle, also had greatly reduced muscle mitochondrial content75. The “master regulator” of mitochondrial biogenesis is PGC-1α, a co-activator that enhances the activity of several transcription factors acting on nuclear-encoded mitochondrial genes82. AMPK directly phosphorylates PGC-1α, which has been proposed to cause activation of its own transcription via a positive feedback loop83. An alternative mechanism by which AMPK has been proposed to activate PGC-1α is through promotion of its deacetylation, by increasing the concentration of NAD, the co-substrate for the deacetylase SIRT184.

As well as increasing mitochondrial biogenesis, AMPK is involved in the turnover of mitochondria via the special form of autophagy termed mitophagy (Fig. 4). ULK1 and ULK2, the mammalian orthologs of the yeast Atg1 kinase that initiates the autophagy cascade, form stable complexes with AMPK85, and AMPK phosphorylates and activates ULK1, thus triggering autophagy86, 87. In cells in which endogenous ULK1 was replaced by a kinase-inactive mutant, or by a mutant in which the AMPK phosphorylation sites were substituted by alanine, mitochondria with aberrant morphology and reduced membrane potential accumulated following nutrient starvation86. This supports the idea that phosphorylation of ULK1 by AMPK is required for the clearance of dysfunctional mitochondria. Mitochondria are the main site of production of reactive oxygen species in the cell, and are particularly susceptible to oxidative damage. By recycling components of damaged mitochondria, mitophagy may be as important in maintaining a healthy cellular ATP-generating capacity as is the production of new mitochondria.

Regulation of anabolic pathways

Consistent with its role in cellular energy homeostasis, AMPK also conserves ATP by switching off almost all anabolic pathways, including the biosynthesis of lipids, carbohydrates, proteins and ribosomal RNA. It achieves this in part by phosphorylating and/or regulating enzymes or regulatory proteins directly involved in these pathways, including acetyl-CoA carboxylase88 (ACC1/ACCα isoform, involved in fatty acid synthesis), glycerol phosphate acyl-transferase89 (triglyceride/phospholipid synthesis), HMG-CoA reductase90 (cholesterol synthesis), glycogen synthase91 (glycogen synthesis), TSC292 and RAPTOR66 (regulators of the target-of-rapamycin (TOR) kinase, which promotes protein synthesis) and TIF-IA/RRN393 (a transcription factor for RNA polymerase I, responsible for ribosomal RNA synthesis). In many cases, AMPK also down-regulates expression‎ of the proteins involved in these pathways, including ACC1/ACCα and other lipogenic enzymes (probably via phosphorylation of the lipogenic transcription factor SREBP-1C94) and the gluconeogenic enzymes phosphoenolpyruvate carboxykinase and glucose-6-phosphatase (by phosphorylation of the transcriptional co-activator CRTC2, formerly known as TORC295, and/or by phosphorylation and nuclear exclusion of the Class IIa HDAC family, which deacetylate and activate FOXO family transcription factors96). With the exception of gluconeogenesis, most of these anabolic pathways are required for cell growth, and in many cases expression‎ of the enzymes involved is up-regulated in tumors. By down-regulating these pathways, AMPK not only conserves ATP, but also exerts a cytostatic, anti-tumor effect, consistent with the hypothesis that it exerts most, if not all, of the tumor suppressor effects of its upstream kinase, LKB1.

Regulation of whole body energy metabolism

In mammals, AMPK can also influence metabolism and energy balance at the whole body level, particularly through its actions in the hypothalamus of the brain.

AMPK and control of appetite

The primary appetite control centre is the arcuate nucleus [G] of the hypothalamus, in which increased electrical activity in neuropeptide Y and agouti-related protein-expressing neurons (NPY/AgRP neurons) [G] induces feeding, while increased activity in neurons expressing pro-opiomelanocortin (POMC neurons) [G] inhibits feeding97. Kinase assays in dissected hypothalamic regions from rodents show that hormones that inhibit feeding, such as the adipokine leptin, inhibit the α2 isoform of AMPK98, whereas those that promote it, such as the hormone ghrelin [G] from the stomach, the adipokine adiponectin, or cannabinoids, activate AMPK (the specific isoform was not determined)98–101. Direct injection into the hypothalamus of pharmacological activators of AMPK, or DNAs encoding activated mutants, also promotes feeding98, 99.

Although leptin inhibits AMPK-α2 in the hypothalamus98, mice in which AMPK-α2 was specifically knocked out in NPY/AgRP neurons or POMC neurons displayed only minor changes in food intake, and still exhibited decreased food intake in response to leptin102. A possible explanation for this anomaly was provided by a recent report suggesting that it is in presynaptic neurons [G] upstream of NPY/AgRP neurons, rather than in the NPY/AgRP or POMC neurons themselves, that regulation of AMPK is critical103. The frequency of miniature excitatory postsynaptic currents [G] in the NPY/AgRP neurons was used as a measure of neurotransmitter release from presynaptic neurons acting upstream. Using various pharmacological agents, evidence was obtained for a model in which ghrelin, which is released from the stomach during fasting, activates AMPK in presynaptic neurons via GHSR1 receptors (Fig. 5a). These receptors activate heterotrimeric G proteins containing Gq/G11, which trigger intracellular Ca2+ release and therefore lead to the activation of AMPK by the CaMKKβ pathway104. Consistent with this, CaMKKβ-deficient mice show reduced expression‎ of NPY and AgRP, but not POMC, in the hypothalamus, and fail to increase their food intake in response to ghrelin105. Although the critical downstream target(s) for AMPK in the presynaptic neurons remain unclear, its activation appears to initiate a positive feedback loop in which Ca2+ release via ryanodine receptors [G] causes sustained activation of AMPK and release of Ca2+, and consequent neurotransmitter release onto the NPY/AgRP neurons. This in turn promotes sustained feeding, which due to the positive feedback loop continues even after ghrelin stimulation has ceased. According to this model, feeding only stops when leptin released by adipocytes stimulates release from neighbouring POMC neurons of opioids, which act via µ-opioid receptors in the presynaptic neurons upstream of the NPY/AgRP neurons to inhibit AMPK (the mechanism for this latter effect remains unknown) (Fig. 5b). An interesting parallel exists between this proposed neural circuit and the “reset-set” or “flip-flop” memory storage circuits used in electronic devices. These circuits are switched on by signals coming in via the “set” input, and remain switched on even in the absence of further stimulation until a signal is received on the “reset” input. By analogy, hunger signals such as ghrelin represent the “set” inputs that switch on AgRP neurons and trigger feeding, and feeding would continue until the satiety signal, leptin, resets the circuit by acting on the POMC neuron. This model is consistent with observed diurnal patterns of plasma ghrelin and leptin in humans eating normal meals106. If excess food is available, it may have survival value to continue eating until the leptin signal coming from adipocytes indicates that fat stores have been replenished, rather than stopping eating as soon as the hunger signal from the stomach (ghrelin) had ceased.

Figure 5.

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AMPK-regulated control of feeding behavior by modulation of neuropeptide Y-and agouti-related protein-expressing neurons (NPY/AgRP neurons) and pro-opiomelanocortin neurons (POMC neurons), as proposed by Yang et al103. A) in the fasted state ghrelin, a “hunger signal” derived from the stomach, activates AMPK in the presynaptic neurons acting upstream of NPY/AgRP neurons via the CaMKKβ pathway. This causes release of Ca2+ by Ca2+-induced release from intercellular stores via ryanodine receptors, creating a feedback loop that causes continued release of neurotransmitter onto the NPY/AgRP neuron, even when ghrelin stimulation ceases. The NPY/AgRP neurons promote feeding (and inhibits the POMC neurons, which inhibit feeding). b) Feeding continues (even in the absence of ghrelin) until the POMC neurons are stimulated by the “satiety signal”, leptin. Activity of these neurons inhibits feeding and also promotes release of opioids that inhibit AMPK in the presynaptic neurons upstream of the NPY/AgRP neurons, switching them back to an inactive state.

Role of AMPK in glucose sensing and modulation of the sympathetic nervous system

AMPK in the neighboring ventromedial hypothalamus also appears to have important roles in controlling whole body energy balance. There is evidence that it is involved in sensing of low blood glucose, promoting release of counter-regulatory hormones (epinephrine and glucagon) that stimulate glucose production by the liver107. Thyroid hormones also inhibit AMPK in this region108, increasing the activity of sympathetic nerves, which increase energy expenditure by promoting fat oxidation in muscle or brown adipose tissue108. Interestingly, in whole body mouse knock-outs of AMPK-α2 there is elevated production of catecholamines109, consistent with the idea that inhibition of AMPK can promote activity of the sympathetic nervous system.

AMPK and circadian rhythms

In most mammals, whole body metabolism exhibits circadian rhythms, via which the timing of feeding and metabolism are synchronized with the daily cycle of light and darkness. The suprachiasmatic nucleus [G] of the hypothalamus is the site of the “master clock” that generates these rhythms. However, the proteins involved in establishing these rhythms are also expressed at peripheral sites such as the liver, forming “slave clocks” that can oscillate independently under certain circumstances110. These proteins include the transcription factors Bmal1 and Clock, which form a heterodimer that activates the expression‎ of many genes, two of which are the Per (period) and Cry (cryptochrome) genes. Once synthesized, Per and Cry proteins bind to each other, become phosphorylated and then enter the nucleus, where they inhibit the Clock:Bmal1 complex. This delayed negative feedback loop results in the rhythmic expression‎ not only of Per and Cry themselves, but also of numerous other genes driven by Bmal1/Clock. AMPK has been found to phosphorylate Cry1, reducing its association with Per2 and instead increasing its binding to FBXL3, a ubiquitin ligase that promotes Cry1 ubiquitylation and degradation111. This would have the effect of extending the period of the endogenous rhythm. In mouse embryo fibroblasts synchronized by serum starvation, treatment with low glucose or the AMPK activator AICAR reduced the amplitude, and increased the period, of the circadian rhythm of a luciferase reporter gene driven by the Bmal1/Clock promoter; these effects were lost in cells lacking LKB1 or AMPK. It has been known for many years that the phosphorylation of AMPK targets such as acetyl-CoA carboxylase follows a circadian rhythm in rodent liver linked to the times of feeding88. The more recent results111 suggest that AMPK may have a crucial role in determining these circadian rhythms.

AMPK functions beyond metabolism

Although AMPK is best known for its effects on metabolism, it has recently become clear that is mediates other effects not directly related to metabolism. Two of these are regulation of the cell cycle and modulation of membrane excitability.

Regulation of the cell cycle

Both DNA replication (in S phase) and mitosis (in M phase) are energy-requiring processes, and it would make little sense for cells that are deficient in energy to execute them. Consistent with this, activation of AMPK in cycling cells causes a G1 arrest prior to S phase112. This is associated with phosphorylation of p53 at Ser-15 (although it is not clear that this is a direct target for AMPK) and up-regulation of expression‎ of the G1 cyclin-dependent kinase inhibitor p21WAF1, a product of a p53-activated gene112, 113. AMPK has also been reported to phosphorylate the C-terminal residue of another cyclin-dependent kinase inhibitor, p27KIP1, causing its stabilization114. These effects may explain, at least in part, the ability of AMPK to cause cell cycle arrest.

Surprisingly, other studies suggest that AMPK activity is required for completion of mitosis. An elegant chemical genetic screen, involving expression‎ of AMPK-α2 with a mutation in the catalytic site that allowed it to utilize a chemically modified ATP, identified several novel targets for AMPK, all of which conformed with the established AMPK recognition motif65, 66. Many of these novel targets had roles in mitosis and cytokinesis, including components of the anaphase promoting complex (APC1 and CDC27), three of the regulatory subunits (PPP1R12A/B/C) that target protein phosphatase-1 to dephosphorylate myosin regulatory light chain (MRLC) at Ser19, and the protein kinase PAK2, which phosphorylates MRLC at Ser19115. The phosphorylation of both AMPK (Thr172) and PPP1R12C at the AMPK site (Ser452) were elevated in mitotic cells, and stable expression‎ of a S452A mutant PPP1R12C led to an increase in the proportion of multinucleated cells, indicating a defect in mitosis or cytokinesis. Relevant to this are findings that AMPK phosphorylated at Thr172 is specifically localized at several places within the mitotic apparatus in mitotic cells116. Intriguingly, Drosophila embryos carrying AMPK-null mutations also display a high frequency of multinucleate or polyploid cells, and this could be rescued by expressing MRLC with phosphomimetic mutations at the sites equivalent to Thr18 and Ser19 in human MRLC117.

It is not immediately apparent why a kinase activated by energy stress should be required for passage through mitosis. Perhaps mitosis is accelerated by AMPK in cells undergoing stress in order that an orderly cell cycle arrest may occur in the ensuing G1 phase. However, it may be that this is an ancillary function of AMPK unrelated to its role as an energy sensor.

Regulation of membrane excitability

Remarkably, ATP turnover in the grey matter of brain is comparable with that in leg muscle during marathon running, explaining why an organ contributing only 2% of body weight can account for >20% of resting metabolism118. It has been estimated that the firing of action potentials accounts for 25–50% of this energy consumption, with synaptic transmission (which is triggered by action potentials) contributing most of the remainder118, 119. A mechanism that down-regulated the firing of neuronal action potentials would therefore conserve a considerable amount of energy. Recent studies with HEK-293 cells stably expressing the potassium channel Kv2.1 showed that AMPK activation was found to activate these potassium channels by causing a shift in voltage gating to more negative membrane potentials. Identical effects were observed when activated AMPK (thiophosphorylated at Thr172 to make it resistant to phosphatases), but not an inactive mutant, was introduced into the cells via the patch pipette120. AMPK phosphorylates purified Kv2.1 at two sites in its cytoplasmic C-terminal tail, and the effect of AMPK activation on voltage gating was lost in cells in which one of these (Ser440) was substituted with a non-phosphorylatable alanine120. Kv2.1 accounts for a large proportion of the delayed rectifier K+ channels [G] in central neurons, and their activation has been proposed to reduce the firing of action potentials down the axon121. Interestingly, introduction of active thiophosphorylated AMPK, but not an inactive mutant, into cultured rat hippocampal neurons via the patch pipette caused a progressive decrease in the frequency of action potentials induced by a current pulse120. These results support the idea that AMPK activation may exert a neuroprotective role by limiting the rate of firing of action potentials, thus conserving energy when the energy status of neuronal tissue is compromised.

Conclusions and outstanding questions

There are now around one thousand papers on AMPK and its orthologs published every year, and in this review we have only been able to cover a small number that we found particularly interesting. The classical pathways by which AMPK is activated by increases in AMP:ATP or ADP:ATP ratios, or increases in Ca2+, are now becoming well understood, although our understanding of the protein phosphatases that dephosphorylate Thr-172 remains incomplete. The “non-canonical” mechanisms by which oxidative stress and genotoxic agents activate AMPK are another area that needs further investigation. Although AMPK is perhaps best known for its effects to regulate metabolism at the cellular level, in mammals it also regulates metabolism and helps to maintain energy balance at the whole body level. It does this by mediating effects of hormones and other agents acting on neurons in different hypothalamic regions, which regulate intake of food (and hence energy) and energy expenditure. AMPK also regulates diurnal rhythms of feeding and metabolism. By switching off biosynthetic pathways required for cell growth, AMPK activation would exert a cytostatic effect, helping to explain why its upstream activator, LKB1, is a tumor suppressor. Commensurate with its role in preserving cellular energy homeostasis, AMPK also down-regulates ATP-requiring processes outside of metabolism, including progress through the cell cycle (another potential tumor suppressor effect) and firing of action potentials in neurons. Although it might be said that the AMPK field is approaching maturity, it seems certain that many exciting findings about the pathway remain to be discovered, and these insights might lead to novel drugs and other means of exploiting this knowledge.

결론 및 미해결 문제

현재 AMPK 및 그 동형체에 관한 논문은 

매년 약 1,000편이 발표되고 있으며, 

본 리뷰에서는 그 중 특히 흥미로운 일부만 다루었습니다. 

AMPK가 

AMP:ATP 또는 ADP:ATP 비율의 증가나 

Ca2+ 농도 증가에 의해 활성화되는 고전적인 경로는 이제 잘 이해되고 있지만, 

Thr-172를 탈인산화하는 단백질 인산화효소에 대한 이해는 여전히 불완전합니다. 

산화 스트레스와 유전독성 물질이 AMPK를 활성화하는 “비전형적” 메커니즘은 추가 연구가 필요한 또 다른 분야입니다. 

AMPK는 

세포 수준에서 대사 조절로 가장 잘 알려져 있지만, 

포유류에서는 호르몬 및 기타 신경전달물질이 시상하부 다양한 영역의 신경세포에 작용하여

 음식 섭취(그리고 따라서 에너지 섭취)와 에너지 소비를 조절함으로써 

대사 조절과 에너지 균형 유지에 기여합니다. 

AMPK는 

또한 식사와 대사 과정의 일일 리듬을 조절합니다. 

세포 성장에 필요한 생합성 경로를 차단함으로써 

AMPK 활성화는 세포 증식을 억제하는 효과를 발휘하며, 

이는 그 상위 활성화인자 LKB1이 종양 억제인자라는 점을 설명하는 데 기여합니다. 

세포 에너지 균형 유지라는 역할에 부합하게, AMPK는 대사 외부의 ATP 요구 과정도 억제합니다. 

이는 세포 주기 진행(또 다른 잠재적 종양 억제 효과)과 신경세포의 활동 전위 발사 등을 포함합니다. AMPK 분야가 성숙 단계에 접어들고 있다고 할 수 있지만, 이 경로에 대한 흥미로운 발견이 여전히 많이 남아 있으며, 이러한 통찰은 새로운 약물 및 이 지식을 활용하는 다른 방법 개발로 이어질 수 있습니다.

Acknowledgements

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

Glossaryactivation loop

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

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

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

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); caused by mutation of the ATM gene, encoding a protein kinase of the phosphatidylinositol-3- kinase-like kinase (PIKK) family

Bateman domain

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

CBS repeat

sequence motif usually occurring as two tandem repeats that form a Bateman domain; named after cystathionine β-synthase, in which the Bateman domain binds S-adenosyl methionine

circadian rhythm

a biological rhythm that follows 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

delayed rectifier K+ channels

a group of voltage-gated K+ channels that open and close slowly in response to membrane depolarization; by allowing K+ ions to flow out of cells down their concentration gradient and thus oppose subsequent depolarization, these channels regulate the frequency of action potentials

fructose-1,6-bisphosphatase

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

ghrelin

a 28 amino acid peptide that is released by cells of the stomach and represents a “hunger signal”

glutathionylation

the covalent attachment of glutathione to a protein, via the formation of a mixed disulfide between the cysteine moiety of glutathione and a cysteine side chain of the protein

glycogen phosphorylase

the primary enzyme that mobilizes stores of glucose in glycogen, catalyzing the release of glucose-1-phosphate from the non-reducing ends of glycogen by a phosphorylysis reaction

LKB1:STRAD:MO25 complex

a heterotrimeric complex containing the tumor suppressor protein kinase, LKB1, and the accessory subunits STRAD and MO25; LKB1 was discovered as the gene mutated in a form of inherited cancer susceptibility (Peutz-Jeghers syndrome), and is also lost due to somatic mutation in many human cancers

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

miniature excitatory postsynaptic currents

small depolarizing currents measured by patch clamping of a neuron, due to release of packets of neurotransmitter from a presynaptic neuron upstream of that neuron; they can be observed by applying tetrodotoxin to inhibit the firing of action potentials in the neuron

mitophagy

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

NPY/AgRP neuron

a neuron that expresses the neuropeptides neuropeptide Y and agouti-related protein

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 methionine

phosphofructokinase

enzyme that catalyzes a key regulatory step in glycolysis, the transfer of phosphate from ATP to fructose-6-phosphate to generate fructose-1,6-bisphosphate

POMC neuron

a neuron that expresses the neuropeptide pro-opiomelanocortin

presynaptic neuron

a neuron acting immediately upstream of the neuron under study, which releases neurotransmitters directly onto that neuron

Rab-GAP

protein carrying a Rab-GTPase activator protein function, i.e. 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

ryanodine receptors

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

ventromedial nucleus

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

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