AMPK Signaling

AMP activated protein kinase (AMPK) is a master metabolic regulator which inhibits key enzymes of ATP consuming pathways and induces pathways that generate ATP. AMPK is activated by stimuli like muscle contraction, inflammation, sepsis, metabolic poisoning, exercise, hypoxia, ischemia, heat shock and neuronal necrosis. It controls metabolic processes that include glucose uptake, fatty acid oxidation, glycogen, cholesterol and protein synthesis and induction of mitochondrial biogenesis. Activation of AMPK requires the phosphorylation of its catalytic α-subunit by upstream kinases, namely AMPKKs. AMPK consists of a catalytic α-subunit and regulatory β and γ-subunits. It is regulated by the cellular AMP/ATP ratio. AMPKKs activating AMPK include LKB1/STK11, MO25/CAB39 and STRAD. The AMPKK complex phosphorylates AMPK under stress conditions and in turn is activated by AMP, ZMP and PKA. High levels of AMP under stress conditions activate PKA. The AMPK system is allosterically inhibited by creatine phosphate. Creatine phosphate is converted back to creatine by the action of intracellular CPK in order to stimulate muscle contraction.AMPK stimulates fatty acid oxidation by inactivating ACC and decreasing the concentration of malonyl-CoA, which inhibits the entry and subsequent oxidation of long-chain fatty acids into the mitochondria. ACC localizes to mitochondria and the malonyl-CoA it produces is presented directly to CPT1. CPT1 converts carnitine and palmitoyl-CoA to palmitoylcarnitine, which is converted back to carnitine and palmitoyl-CoA by CPT2 that in turn forms an intermediate during β-oxidation. Acetyl-CoA acts as a substrate for ACC and is made available for ACC by CRAT. Activity of GPAT/GPAM catalyzes the first reaction in triacylglycerol synthesis and is phosphorylated and inhibited by AMPK. Another target for AMPK is MCD.AMPK activation causes the phosphorylation of AICAR. The non-phosphorylated AICAR is taken up by cells and is phosphorylated by cellular adenylate kinase to form ZMP. Iodotubercidin facilitates AICAR activation of AMPK by enhancing the production of ZMP. MCD is also activated by contraction or by AICAR through AMPK. Upon AICAR activation, AMPK increases glucose transport independent of insulin action.AMP inhibits the dephosphorylation and inactivation of AMPK by PP2A and PP2C. AMPK also inactivates the muscle isoform of GYS in order to prevent glycogen synthesis. AMPK inhibits CFTR, a Chloride channel involved in trans-epithelial ion transport and fluid secretion. AICAR stimulated activation of AMPK also inhibits protein synthesis by preventing the activation and phosphorylation of p70S6K and eIF4EBP1. AMPK activates TSC that in turn inhibits mTOR and Raptor activity and ultimately phosphorylates p70S6K and eIF4EBP1.iNOS derived nitric oxide, through its mitochondrial effect at COX, decreases the cellular energy charge, a necessary factor for activating AMPK. Once active, AMPK activates PFK2 which synthesizes F(2,6)P2 and F(1,6)P2 from fructose-6-phosphate resulting in the rapid activation of glycolysis. Nitric oxide, peroxynitrite and superoxide anions activate AMPK via an Src mediated, PI3K dependent pathway. This in turn promotes mitogen stimulated AKT activation and angiogenesis. AKT phosphorylates eNOS in hypoxic cells. Also, AMPK regulates the coordination of SWI/SNF complex and PCAF/GCN5 in order to combat stress conditions. AMPK has been the subject of intense investigation because of its potential as a therapeutic target for anti-diabetic and anti-cancer drugs.