AMP-activated protein kinase
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'''5'AMP-activated protein kinase''' or '''AMPK''' consists of three proteins ([[subunits]]) that together make a functional [[enzyme]], conserved from yeast to humans, that plays a role in cellular energy homeostasis. <!-- Image with unknown copyright status removed: [[Image:Spg 1.gif|thumb|right|'''Some Metabolic Effects of AMPK''']] -->It is expressed in a number of tissues, including the [[liver]], [[brain]], and [[skeletal muscle]]. The net effect of AMPK activation is stimulation of [[hepatic]] fatty acid oxidation and [[ketogenesis]], inhibition of [[cholesterol]] synthesis, [[lipogenesis]], and [[triglyceride]] synthesis, inhibition of adipocyte [[lipolysis]] and lipogenesis, stimulation of skeletal muscle fatty acid oxidation and muscle glucose uptake, and modulation of insulin secretion by [[pancreatic]] [[beta-cells]](4).
==Structure==
The [[wiktionary:heterotrimeric|heterotrimeric]] protein AMPK is formed by α, β, and γ subunits. Each of these three subunits takes on a specific role for both the stability and activity of AMPK (11). Specifically, the γ subunit includes four particular [[Cystathione]] [[Beta]] [[Synthase]] (CBS) domains giving AMPK its ability to sensitively detect shifts in the [[Adenosine monophosphate|AMP]]:[[adenosine triphosphate|ATP]] ratio. The four CBS domains create two binding sites for AMP commonly referred to as Bateman domains. Binding of one [[AMP]] to a [[Bateman domain]] cooperatively increases the binding [[affinity]] of the second AMP to the other Bateman domain (49). As AMP binds both Bateman domains the γ subunit undergoes a conformational change which exposes the [[catalytic]] domain found on the α subunit. It is in this catalytic domain where AMPK becomes activated when [[phosphorylation]] takes place at [[threonine]]-172 by an [[upstream]] AMPK [[kinase]] ([[AMPKK]]) (19). The α, β, and γ subunits can also be found in different isoforms: the γ subunit can exist as either the γ1, γ2 or γ3 [[isoform]]; the β subunit can exist as either the β1 or β2 isoform; and the α subunit can exist as either the α1 or α2 isoform. Although the most common isoforms expressed in most cells are the α1, β1, and γ1 isoforms, it has been demonstrated that the α2, β2, γ2, and γ3 isoforms are also expressed in [[cardiac]] and [[skeletal muscle]] (11, 12, 13).
== Function ==
AMPK acts as a [[metabolic]] [[master switch]] regulating several [[intracellular]] systems including the cellular uptake of [[glucose]], the [[β-oxidation]] of [[fatty acids]] and the [[biogenesis]] of glucose transporter 4 ([[GLUT4]]) and [[mitochondria]] (1, 2, 4, 5, 36). The energy-sensing capability of AMPK can be attributed to its ability to detect and react to fluctuations in the AMP:ATP ratio that take place during [[rest]] and [[exercise]] (muscle stimulation). During [[muscle]] stimulation, AMP increases while ATP decreases, which changes AMPK into a good substrate for activation via an upstream kinase complex, AMPKK, or better, where binding of AMP renders activated AMPK that is phosphorylated at Thr-172 a worse substrate for protein kinase 2Calpha (54). AMPKK is a complex of three proteins, [[STE-related adaptor]] ([[STRAD]]), [[mouse protein 25]] ([[MO25]]), and [[LKB1]] (a [[serine]]/threonine kinase). During a bout of exercise, AMPK activity increases while the muscle cell experiences metabolic [[Stress (medicine)|stress]] brought about by an extreme cellular demand for ATP. Upon activation, AMPK increases cellular energy levels by inhibiting [[anabolic]] energy consuming pathways (fatty acid [[synthesis]], [[protein]] synthesis, etc.) and stimulating energy producing, [[catabolic]] pathways (fatty acid oxidation, glucose transport, etc.).
A recent [[JBC]] paper on [[mouse|mice]] at [[Johns Hopkins]] has shown that when the activity of brain AMPK was pharmacologically inhibited, the mice ate less and lost weight. When AMPK activity was pharmacologically raised (AICAR see below) the mice ate more and gained weight. Research in Britain has shown that the appetite-stimulating hormone [[ghrelin]] also affects AMPK levels.
A [[2001]] study (Zhou G ''et al'') has indicated that the [[antidiabetic drug]] [[metformin]] (Glucophage) acts by stimulating peripheral AMPK, leading to reduced glucose production in the [[liver]] and reduced insulin resistance in the muscle. Metformin usually causes weight loss and reduced appetite, not weight gain and increased appetite, which is opposite of what might be expected given the John Hopkins mouse study results.
== AMPK Activation ==
Triggering the activation of AMPK can be carried out provided that two conditions are met. First, the γ subunit of AMPK must undergo a conformational change so as to expose the [[active site]] (Thr-172) on the α subunit. The conformational change of the γ subunit of AMPK can be accomplished under increased concentrations of AMP. Increased concentrations of AMP will give rise to the conformational change on the γ subunit of AMPK as two AMP bind the two Bateman domains located on that subunit. It is this conformational change brought about by increased concentrations of AMP that exposes the active site (Thr-172) on the α subunit. This critical role of AMP is further substantiated in experiments that demonstrate AMPK activation via an AMP analogue [[5-amino-4-imidazolecarboxamide ribotide]] ([[ZMP]]) which is derived from the familiar [[5-amino-4-imidazolecarboxamide riboside]] ([[AICAR]]) (14, 15, 16, 17). The second condition that must be met is the phosphorylation and consequent activation of AMPK on its activating loop at Thr-172 of the α subunit brought about by an upstream kinase (AMPKK) (19, 20). The complex formed between LKB1 (STK 11), mouse protein 25 (MO25), and the pseudokinase STE-related adaptor protein (STRAD) has of late been identified as the major upstream kinase responsible for phosphorylation of AMPK on its activating loop at Thr-172 (21, 22, 23). Although AMPK must be phosphorylated by the LKB1/MO25/STRAD complex (55), it can also be regulated by allosteric [[modulator]]s which directly increase general AMPK activity and modify AMPK to make it a better [[substrate]] for AMPKK and a worse substrate for [[phosphatase]]s (19, 20, 24). It has recently been found that [[3-phosphoglycerate]] ([[glycolysis]] [[intermediate]]) acts to further pronounce AMPK activation via AMPKK.
Muscle [[contraction]] is the main method carried out by the body that can provide the conditions mentioned above needed for AMPK activation (25). As muscles contract, ATP is hydrolyzed, forming [[ADP]]. ADP then helps to replenish cellular ATP by donating a [[phosphate]] group to another ADP, forming an ATP and an AMP. As more AMP is produced during muscle contraction, the AMP:ATP ratio dramatically increases, leading to the [[allosteric]] activation of AMPK (10, 26, 27). This fact is further authenticated with studies, such as those sited above, that used electrical stimuli as a means to contract muscle to facilitate AMPK activation (1, 6, 18, 28, 29).
For over a decade it has been known that [[calmodulin]]-dependent protein kinase kinase-beta (CaMKKbeta) can phosphorylate and thereby activate AMPK, but it was not the main AMPKK in [[liver]] (26). Richter et al (27) found that CaMKK inhibitors strongly inhibited AMPK phosphorylation in [[mouse]] [[soleus]] and EDL muscles after 2 minutes of [[contraction]], but much less as time of contraction increased. CaMKK inhibitors had no effect on 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside ([[AICAR]]) phosphorylation and activation of AMPK (27). AICAR is taken into the [[cell (biology)|cell]] and converted to ZMP, an AMP [[analog (chemistry)|analog]] that has been shown to activate AMPK (28). Recent LKB1 knockout studies have shown that without LKB1, electrical and AICAR stimulation of [[muscle]] results in very little phosphorylation of AMPK and of ACC, providing evidence that LKB1-STRAD-MO25 is the major AMPKK in muscle (29).
== AMPK and Exercise/Training ==
Many [[biochemical]] adaptations of skeletal muscle that take place during a single bout of [[exercise]] or an extended duration of [[training]], such as increased mitochondrial biogenesis and capacity (31, 32), increased muscle [[glycogen]] (37), and an increase in [[enzyme]]s which specialize in glucose uptake in cells such as GLUT4 and [[Hexokinase]] II (33, 35, 37) are thought to be mediated in part by AMPK when it is activated (2, 34). Additionally, recent discoveries can conceivably suggest a direct AMPK role in increasing [[blood supply]] to exercised/trained muscle cells by stimulating and stabilizing both [[vasculogenesis]] and [[angiogenesis]] (30). Taken together, these [[adaptation]]s most likely transpire as a result of both temporary and maintained increases in AMPK activity brought about by increases in the AMP:ATP ratio during single bouts of exercise and long-term training.
During a single [[Acute (medical)|acute]] exercise bout, AMPK takes on immediate roles to allow the contracting muscle cells adapt to the energy challenges taking place by increasing Hexokinase II expression (37), GLUT4 translocation to the [[plasma membrane]] (28, 40, 41, 42) for glucose uptake, and by stimulating glycolysis (50). If exercise bouts continue through a long-term [[training]] regimen, AMPK and other signals will facilitate contracting muscle adaptations by escorting muscle cell activity to a metabolic transition resulting in an [[oxidative]] dependent approach to [[energy]] [[metabolism]] as opposed to a [[glycolytic]] approach. AMPK accomplishes this transition to the oxidative mode of metabolism by upregulating and activating oxidative enzymes such as GLUT4, Hexokinase II, [[PPARalpha]], [[PGC-1]], [[UCP-3]], [[Cytochrome C]] and [[TFAM]], just to name a few (2, 35, 37, 38, 39, 43).
== AMPKK and Exercise/Training ==
AMPK activity increases with exercise and the LKB1/MO25/STRAD [[complex]] is considered to be the major [[upstream]] AMPKK of the 5’-AMP-activated protein kinase phosphorylating the α subunit of AMPK at Thr-172 (19, 20, 21, 22). This fact is puzzling considering that although AMPKK [[protein]] abundance has been shown to increase in skeletal [[Tissue (biology)|tissue]] with [[endurance]] training, its level of activity has been shown to decrease with endurance training in both trained and untrained tissue (18, 29, 45, 46). Currently, the activity of AMPKK immediately following a 2-hr bout of exercise of an endurance trained rat is unclear. It is possible that there exists a direct link between the observed decrease in AMPKK activity in endurance trained skeletal muscle and the apparent decrease in the AMPK response to exercise with endurance training.
== AMPK and Adipocytokine Relations ==
[[Adipokine]]s, also known as [[adipocytokine]]s, are secreted by [[adipose tissue]] to take on several different but important physiological roles in the body including the regulation of [[appetite]], metabolism, fatty acid catabolism, [[coagulation]] and systemic [[inflammation]], for example. Collectively, the adipokines are in essence [[cytokine]]s (cell-to-cell signaling proteins) which, when secreted, act on other cells, usually resulting in a [[biochemical]] and metabolic response. Two particular adipokines, [[adiponectin]] and [[leptin]], have even been demonstrated to regulate AMPK.
It has been known for some time now that among many of the metabolic roles of leptin, one of its main functions in skeletal muscle is the [[upregulation]] of fatty acid oxidation. Recently, a study revealed that leptin is able to do this by way of the AMPK signaling pathway (44). A similar study showed that much like leptin, adiponectin also
stimulates the oxidation of fatty acids via the AMPK pathway, and that it also stimulates the uptake of glucose in skeletal muscle (45). As of yet, the metabolic roles of leptin and adiponectin pertaining to biochemical adaptations to long-term [[endurance]] training remain unclear. Certainly future studies will involve an investigation of leptin and adiponectin activities and their respective relationships with the AMPK signaling pathway immediately following a high-intensity endurance training [[Protocol (natural sciences)|protocol]].
== AMPK and Maximum Life Span ==
The [[C.elegans]] homologue of AMPK, aak-2, has been shown by [[Michael Ristow]] and colleagues to be required for extension of life span in states of glucose restriction mediating a process named [[mitohormesis]].<ref name = glucose_restriction>{{cite journal |author=Schulz TJ, Zarse K, Voigt A, Urban N, Birringer M, Ristow M |title=Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress |journal=Cell Metab. |volume=6 |issue=4 |pages=280–93 |year=2007 |pmid=17908557 |doi=10.1016/j.cmet.2007.08.011}}</ref>
== AMPK and Lipid Metabolism ==
One of the effects of [[exercise]] is an increase in [[fatty acid metabolism]], which provides more [[energy]] for the cell. One of the key pathways in AMPK’s regulation of [[fatty acid oxidation]] is the phosphorylation and inactivation of [[acetyl-CoA carboxylase]] (30). Acetyl-CoA carboxylase (ACC) converts acetyl-CoA to [[malonyl-CoA]], an [[inhibitor]] of [[carnitine parmitoyltransferase]] 1 ([[CPT-1]]). CPT-1 transports [[fatty acids]] into the [[mitochondria]] for [[oxidation]]. Inactivation of ACC, therefore, results in increased fatty acid transport and subsequent oxidation. It is also thought that the decrease in malonyl-CoA occurs as a result of [[malonyl-CoA decarboxylase]] (MCD), which may be regulated by AMPK (31). MCD is an [[antagonist]] to ACC, decarboxylating malonyl-CoA to acetyl-CoA, resulting in decreased malonyl-CoA and increased CPT-1 and fatty acid oxidation.
AMPK also plays an important role in [[lipid metabolism]] in the [[liver]]. It has long been known that [[hepatic]] ACC has been regulated in the liver by [[phosphorylation]] (32). AMPK also phosphorylates and inactivates [[3-hydroxy-3-methylglutaryl-CoA reductase]] (HMGR), a key enzyme in [[cholesterol synthesis]] (28). HMGR converts 3-hydroxy-3-methylglutaryl-CoA, which is made from acetyl-CoA, into [[mevalonic acid]], which then travels down several more metabolic steps to become [[cholesterol]]. AMPK, therefore, helps regulate fatty acid oxidation and cholesterol synthesis.
== AMPK and Glucose Transport ==
[[Insulin]] is a [[hormone]] which helps regulate [[glucose]] levels in the body. When blood glucose is high, insulin is released from the [[Islets of Langerhans]]. Insulin, among other things, will then facilitate the uptake of glucose into cells via increased expression and [[translocation]] of glucose transporter [[GLUT-4]] (34). Under conditions of exercise, however, [[blood sugar]] levels are not necessarily high, and insulin is not necessarily activated, yet muscles are still able to bring in glucose. AMPK seems to be responsible in part for this [[exercise]]-induced glucose uptake. Goodyear et al. (33) observed that with exercise, the concentration of GLUT-4 was increased in the [[plasma membrane]], but decreased in the [[microsomal]] membranes, suggesting that exercise facilitates the translocation of vesicular GLUT-4 to the [[plasma membrane]]. While acute exercise increases GLUT-4 translocation, endurance training will increase the total amount of GLUT-4 protein available (35). It has been shown that both electrical contraction and AICAR treatment increase AMPK activation, glucose uptake, and GLUT-4 translocation in perfused rat [[hindlimb]] muscle, linking exercise-induced glucose uptake to AMPK (36, 37, 38). Chronic AICAR injections, simulating some of the effects of [[endurance training]], also increase the total amount of GLUT-4 [[protein]] in the [[muscle cell]] (39).
Two proteins are essential for the regulation of GLUT-4 expression at a transcriptional level – [[myocyte enhancer factor 2]] (MEF2) and [[GLUT-4 enhancer factor]] (GEF). Mutations in the [[DNA]] binding regions for either of these proteins results in [[ablation]] of [[transgene]] GLUT-4 expression (40, 41). These results prompted a study in 2005 which showed that AMPK directly phosphorylates GEF, but it doesn’t seem to directly activate MEF2 (42). AICAR treatment has been shown, however, to increase transport of both proteins into the [[Cell nucleus|nucleus]], as well as increase the binding of both to the GLUT-4 [[promoter region]] (42).
There is another protein involved in [[carbohydrate metabolism]] that is worthy of mention along with GLUT-4. The enzyme [[hexokinase]] phosphorylates a six-carbon sugar, most notably [[glucose]], which is the first step in [[glycolysis]]. When glucose is transported into the cell it is phosphorylated by hexokinase. This phosphorylation keeps glucose from leaving the [[cell (biology)|cell]], and by changing the structure of glucose through phosphorylation, it decreases the concentration of glucose molecules, allowing a gradient for more glucose to be transported into the cell. Hexokinase II [[Transcription (genetics)|transcription]] is increased in both red and white [[skeletal muscle]] upon treatment with AICAR (43). With chronic injections of AICAR, total protein content of hexokinase II increases in [[rat]] skeletal muscle (44).
== AMPK and Mitochondria ==
[[Mitochondria]] are often called the powerhouse of the [[cell (biology)|cell]]. After [[pyruvate]] is formed from [[glucose]] during [[glycolysis]] in the [[cytoplasm]], it is transported into the mitochondria, where it is oxidized to [[acetyl-CoA]] and enters the [[citric acid cycle]]. [[Oxidative phosphorylation]] is the process by which [[NADH]] and [[FADH2]] are oxidized and [[oxygen]] is reduced. This process creates a [[proton]] gradient which is used to drive [[ATP synthase]] and produce [[adenosine triphosphate|ATP]]. This process creates energy for cellular properties, and since ATP is indispensable in the contraction process, so then, are mitochondria.
Mitochondrial enzymes, such as [[cytochrome c]], [[succinate dehydrogenase]], [[malate dehydrogenase]], [[α-ketoglutarate dehydrogenase]], and [[citrate synthase]], increase in expression and activity in response to exercise (45). AICAR stimulation of AMPK increases cytochrome c and [[δ-aminolevulinate synthase]] ([[ALAS]]), a [[rate-limiting enzyme]] involved in the production of [[heme]]. [[Malate dehydrogenase]] and [[succinate dehydrogenase]] also increase, as well as citrate synthase activity, in rats treated with AICAR injections (46). Conversely, in LKB1 knockout mice, there are decreases in cytochrome c and citrate synthase activity, even if the mice are “trained” by voluntary exercise (47).
[[Peroxisome proliferator-activated receptor gamma coactivator-1α]] ([[PGC-1α]]) is a transcriptional regulator for genes involved in [[mitochondrial biogenesis]], [[fatty acid oxidation]], and [[gluconeogenesis]] (48). To do this, it enhances the activity of [[transcription factors]] like [[nuclear respiratory factor 1]] (NRF-1), [[myocyte]] enhancer factor 2 (MEF2), [[host cell]] factor (HCF), and others (49, 50). It also has a [[positive feedback loop]], enhancing its own expression (51). Both MEF2 and [[cAMP]] response element ([[CRE]]) are essential for contraction-induced PGC-1α [[promoter]] activity (50). AMPK is required for increased PGC-1α expression in skeletal muscle in response to [[creatine]] depletion (52). LKB1 knockout mice show a decrease in PGC-1α, as well as mitochondrial proteins (47).
== Thyroid Hormone and AMPK ==
AMPK and [[thyroid]] [[hormone]] regulate some similar processes. Knowing these similarities, Winder and Hardie et al designed an experiment to see if AMPK was influenced by [[thyroid hormone]] (1). They found that all of the subunits of AMPK were increased in [[skeletal muscle]], especially in the [[soleus]] and [[red quadriceps]], with thyroid hormone treatment. There was also an increase in phospho-ACC, a marker of AMPK activity.
== Controversy ==
A seemingly [[paradoxical]] role of AMPK occurs when we take a closer look at the energy-sensing [[enzyme]] in relation to exercise and long-term training. Similar to short-term acute training scale, long-term endurance training studies also reveal increases in oxidative metabolic enzymes and increases in GLUT-4, mitochondrial size and quantity, and an increased dependency on the oxidation of fatty acids; however, Winder et al. reported in [[2002]] that despite observing these increased oxidative biochemical adaptations to long-term endurance training (similar to those mentioned above), the AMPK response (activation of AMPK with the onset of exercise) to acute bouts of exercise decreased in [[red]] [[quadriceps]] (RQ) with training (3 – see Fig.1). Conversely, the study did not observe the same results in [[white]] [[quadriceps]] (WQ) and [[soleus]] (SOL) muscles that they did in RQ. The trained [[rat]]s used for that endurance [[experiment|study ran on [[treadmill]]s 5 days/wk in two 1-h sessions, [[morning]] and [[afternoon]]. The rats were also running up to 31m/min (grade 15%). Finally, following training, the rats were [[sacrifice]]d either at rest or following 10 min. of exercise.
Because the AMPK response to exercise decreases with increased training duration, many questions arise that would challenge the AMPK role with respect to [[biochemical]] [[adaptation]]s to exercise and endurance training. This is due in part to the marked increases in the [[biogenesis]] and upregulation of [[mitochondria]], [[GLUT-4]], [[UCP-3]], [[Hexokinase]] II and other metabolic and mitochondrial enzymes despite decreases in AMPK activity with training. Questions also arise because [[skeletal muscle]] [[Cell (biology)|cells]] which express these decreases in AMPK activity in response to endurance training also seem to be maintaining an oxidative dependent approach to energy metabolism, which is likewise thought to be regulated to some extent by AMPK activity (38, 39).
If the AMPK response to exercise is responsible in part for biochemical adaptations to training, how then can these adaptations to training be maintained if the AMPK response to exercise is being attenuated with training? It is hypothesized that these [[adaptive]] roles to training are maintained by AMPK activity and that the increases in AMPK activity in response to exercise in trained skeletal muscle have not yet been observed due to biochemical adaptations that the training itself stimulated in the [[muscle tissue]] to reduce the metabolic need for AMPK activation. In other words, AMPK will not become activated until it is "apparent" that the cell is in need of greater [[adaptation]] to exercise. Until energy stores (ATP) are depleted (ATP low + AMP high), AMPK will remain inactivated. Biochemical preparations for a high-intensity energy challenge must be exhausted before AMPK is to be activated in order to mediate further metabolic adaptations to exercise.
==References==
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{{refend}}
==External links==
* {{MeshName|AMP-activated+protein+kinase}}
* {{EC number|2.7.11.31}}
{{Serine/threonine-specific protein kinases}}
[[Category:Protein kinases]]