AMP-activated protein kinase

5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase is an

• α –
  PRKAA1, PRKAA2
• β – PRKAB1, PRKAB2
• γ – PRKAG1, PRKAG2, PRKAG3

The crystal structure of mammalian AMPK regulatory core domain (α C terminal, β C terminal, γ) has been solved in complex with AMP,^[13] ADP ^[14] or ATP.^[15]

Regulation

Due to the presence of isoforms of its components, there are 12 versions of AMPK in mammals, each of which can have different tissue localizations, and different functions under different conditions.^[16] AMPK is regulated allosterically and by post-translational modification, which work together.^[16]

If residue Thr-172 of AMPK's α1-subunit (or Thr-174 of AMPK's α2-subunit) is phosphorylated, AMPK is activated around 100-fold;

AMPK is regulated allosterically mostly by competitive binding to the CBS sites on its γ subunit between ATP (which allows phosphatase access to Thr-172) and AMP or ADP (each of which blocks access to phosphatases).^[1] It thus appears that AMPK is a sensor of AMP/ATP or ADP/ATP ratios and thus cell energy level.^[16] AMPK undergoes a large conformational change upon ATP binding. A region on the α subunit known as the kinase domain (KD) dissociates from its active-state conformation and loosely associates with the γ subunit ~100Å away. The KD also rotates ~180° in the conformational change. Upon KD dissociation, the active loop (AL) of the α subunit which contains the critical phosphorylated Thr residue is fully exposed to upstream phosphatases. This conformational change represents a plausible mechanism for AMPK modulation. When cellular energy states are low (high AMP/ATP or ADP/ATP levels), AMPK adopts the KD-associated conformation and AMPK is protected from dephosphorylation and remains activated. When cellular energy states are high, AMPK adopts the KD-displaced conformation, the AL is exposed to upstream phosphatases, and AMPK is deactivated.^[6]

The pharmacological compounds Merck Compound 991 and Abbott A769662 bind to the allosteric drug and metabolism site (ADaM) on the β subunit and have been shown to activate AMPK up to 10-fold.^[6][18] ADaM site binding may have roles in AMPK activation as well as protection against dephosphorylation.^[19]

There are other mechanisms by which AMPK is inhibited or activated by insulin, leptin, and

AMPK may be inhibited or activated by various tissue-specific ubiquitinations.^[16]

It is also regulated by several protein-protein interactions, and may either be activated or inhibited by oxidative factors; the role of oxidation in regulating AMPK was controversial as of 2016.^[16]

Function

When AMPK phosphorylates acetyl-CoA carboxylase 1 (ACC1) or sterol regulatory element-binding protein 1c (SREBP1c), it inhibits synthesis of fatty acids, cholesterol, and triglycerides, and activates fatty acid uptake and β-oxidation.^[16]

AMPK stimulates glucose uptake in skeletal muscle by phosphorylating Rab-GTPase-activating protein TBC1D1, which ultimately induces fusion of GLUT1 vesicles with the plasma membrane.^[16] AMPK stimulates glycolysis by activating phosphorylation of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2/3 and activating phosphorylation of glycogen phosphorylase, and it inhibits glycogen synthesis through inhibitory phosphorylation of glycogen synthase.^[16] In the liver, AMPK inhibits gluconeogenesis by inhibiting transcription factors including hepatocyte nuclear factor 4 (HNF4) and CREB regulated transcription coactivator 2 (CRTC2).^[16]

AMPK inhibits the energy-intensive

Mutations in the skeletal muscle calcium release channel (RYR1) underlies a life- threatening response to heat in patients with malignant hyperthermia susceptibility (MHS). Upon acute exposure to heat, these mutations cause uncontrolled Ca²⁺ release from the sarcoplasmic reticulum, leading to sustained muscle contractures, severe hyperthermia, and sudden death.^[38] At basal conditions, the temperature-dependent Ca²⁺ leak also leads to increased energy demand and activation of energy sensing AMP kinase (AMPK) in skeletal muscle.^[38] The activated AMPK increases muscle metabolic activity, including glycolysis, which leads to marked elevation of circulating lactate.^[38]

AMPK activity increases with exercise and the LKB1/MO25/STRAD

Although AMPKα2 activation has been thought to be important for mitochondrial adaptations to exercise training, a recent study investigating the response to exercise training in AMPKα2 knockout mice opposes this idea.[45] Their study compared the response to exercise training of several proteins and enzymes in wild type and AMPKα2 knockout mice. And even though the knockout mice had lower basal markers of mitochondrial density (COX-1, CS, and HAD), these markers increased similarly to the wild type mice after exercise training. These findings are supported by another study also showing no difference in mitochondrial adaptations to exercise training between wild type and knockout mice.^[46]

Maximum life span

The

Loss of AMPK has been reported to alter the sensitivity of glucose sensing cells, through poorly defined mechanisms. Loss of the AMPKα2 subunit in pancreatic β-cells and hypothalamic neurons decreases the sensitivity of these cells to changes in extracellular glucose concentration.[58]^[59][60][61] Moreover, exposure of rats to recurrent bouts of insulin induced hypoglycemia/glucopenia, reduces the activation of AMPK within the hypothalamus, whilst also suppressing the counterregulatory response to hypoglycemia. ^[62][63] Pharmacological activation of AMPK by delivery of AMPK activating drug AICAR, directly into the hypothalamus can increase the counterregulatory response to hypoglycaemia.^[64]

Lysosomal damage, inflammatory diseases and metformin

AMPK is recruited to lysosomes and regulated at the lysosomes via several systems of clinical significance. This includes the

Tumor suppression and promotion

Some evidence indicates that AMPK may have a role in tumor suppression. Studies have found that AMPK may exert most, or even all of, the tumor suppressing properties of liver kinase B1 (LKB1).^[17] Additionally, studies where the AMPK activator metformin was used to treat diabetes found a correlation with a reduced risk of cancer, compared to other medications. Gene knockout and knockdown studies with mice found that mice without the gene to express AMPK had greater risks of developing lymphomas, though as the gene was knocked out globally instead of just in B cells, it was impossible to conclude that AMP knockout had cell-autonomous effects within tumor progenitor cells.^[73]

In contrast, some studies have linked AMPK with a role as a tumor promoter by protecting cancer cells from stress. Thus, once cancerous cells have formed in an organism, AMPK may swap from protecting against cancer to protecting the cancer itself. Studies have found that tumor cells with AMPK knockout are more susceptible to death by glucose starvation or extracellular matrix detachment, which may indicate AMPK has a role in preventing these two outcomes. There is no direct evidence that inhibiting AMPK would be an effective cancer treatment in humans.^[73]

Controversy over role in adaption to exercise/training

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A seemingly

• Salicylic acid
• Aspirin
• Salsalate

Notes

References