标题AMPK信号通路图

AMPK signaling pathway, a fuel sensor ａnd regulator, promotes ATP-producing ａnd inhibits ATP-consuming pathways in various tissues. AMPK is a heterotrimer composed of alpha-catalytic ａnd beta ａnd gamma-regulatory subunits. Humans ａnd rodents have two alpha ａnd beta ａnd three gamma isoforms; some genes are subject to alternative splicing increasing the range of possible heterotrimer combinations. Cellular stresses that inhibit ATP production or increase its consumption change the AMP:ATP ratio ａnd activate the pathway. AMPK activation by AMP is not completely understood; the current model states that binding of AMP to the gamma subunit leads to conformational changes that allosterically activate AMPK ａnd render phosphorylated-Thr172 unavailable for inhibitory dephosphorylation. ATP antagonizes the effect of AMP; both AMP ａnd ATP bind in a mutually exclusive manner to the Bateman （CBS） domains of the gamma subunit. The upstream kinase, known as Lkb1, is a complex of one catalytic ａnd two regulatory subunits; Lkb1 is believed to be ‘constitutively active’. In certain cell types, Thr172 can be phosphorylated by calmodulin-dependent protein kinase kinases （CAmKK）, in turn activated by calcium. A well known role of AMPK is in the regulation of lipid metabolism; it stimulates fatty acids oxidation ａnd inhibits their synthesis. Phosphorylation by AMPK inhibits acetyl-CoA carboxylase （ACC） ａnd results in reduced levels of malonyl-CoA product. Malonyl CoA is a substrate in the de novo synthesis of fatty acids ａnd fatty acids elongation. Importantly, it is also an inhibitor of the carnitine palmitoyl transferase I, required for the transfer of primed cytosolic fatty acids into the mitochondrion where they can undergo degradative beta-oxidation. AMPK inhibits mTOR signaling pathway by activating Tsc2 ａnd downstream of Tsc2 by inhibiting Raptor component of mTOR complex 1 [note that this effect is opposite to Tsc2 phosphorylation ａnd inactivation by PI3K-Akt signaling downstream of insulin]. AMPK is also involved in promoting glucose uptake ａnd utilization ａnd integrates adipokynes ａnd hormonal signals in both the hypothalamus ａnd the periphery with potential impact on energy expenditure ａnd uptake by molecular mechanisms that remain to be established. Due to its roles in fuel regulation, the AMPK pathway is regarded as a potential therapeutic target for diabetes type II, obesity ａnd metabolic syndrome. As a note, drugs used in the treatment of insulin resistance ａnd diabetes can activate AMPK.AMP-activated protein kinase （AMPK） plays a key role as a ｍaster regulator of cellular energy homeostasis. The kinase is activated in response to stresses that deplete cellular ATP supplies such as low glucose, hypoxia, ischemia ａnd heat shock. It exists as a heterotrimeric complex composed of a catalytic α subunit ａnd regulatory β ａnd γ subunits. Binding of AMP to the γ subunit allosterically activates the complex, making it a more attractive substrate for its major upstream AMPK kinase, LKB1. Several studies indicate that signaling through adiponectin, leptin ａnd CAMKKβ may also be important in activating AMPK.

As a cellular energy sensor responding to low ATP levels, AMPK activation positively regulates signaling pathways that replenish cellular ATP supplies. For example, activation of AMPK enhances both the transcription ａnd translocation of GLUT4, resulting in an increase in insulin-stimulated glucose uptake. In addition, it also stimulates catabolic processes such as fatty acid oxidation ａnd glycolysis via inhibition of ACC ａnd activation of PFK2. AMPK negatively regulates several proteins central to ATP consuming processes such as TORC2, glycogen synthase, SREBP-1 ａnd TSC2, resulting in the downregulation or inhibition of gluconeogenesis, glycogen, lipid ａnd protein synthesis. Due to its role as a central regulator of both lipid ａnd glucose metabolism, AMPK is considered to be a key therapeutic target for the treatment of obesity, type II diabetes mellitus, ａnd cancer.

（来源：Scimall科学在线）

本信号转导涉及的信号分子主要包括：
Glut4，Adiponectin Receptor，Leptin，α-Adrenergic Receptor，Insulin Receptor，PLCβ，Gαq，CaMKK，LKB1，STRAD，MO25α，PKA，Sestrin，AMPKα，AMP，ATP，AMPKβ，AMPKγ，PI3K，Akt，mTOR，p70S6K，PI3 Kinase ClassIII，eEF2K，TSC1，TSC2，GβL，4E-BP1，p53，HuR，eEF2，GEF，MEF2，GS，PFK2，Torc2，PGC-1α，ACC，CPT1，HMG-CoA Reductase，HNF4α，SREBP-1，Fatty Acid Synthasa，HSL，SirT1，eNOS，Cyclin A，Cyclin B1，P21，Waf1，Cip1等。

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