One of the most profound features of AMPK as a metabolic sensor is its sensitivity to the cellular energy status, which results from its unique biochemical properties.
AMPK is a heterotrimeric protein consisting of a catalytic α and regulatory β and γ subunits (3
) (Figure ). Each α and β subunit is encoded by 2 genes (α1 and α2 or β1 and β2), whereas the γ subunit is encoded by 3 genes (γ1, γ2, and γ3). The protein is activated in response to an increase in the ratio of AMP to ATP within the cell and therefore acts as an efficient sensor for cellular energy state. Binding of AMP activates AMPK allosterically and induces phosphorylation of a threonine residue (Thr-172) within the activation domain of the α subunit by an upstream kinase, the tumor suppressor LKB1 (3
). Furthermore, binding of AMP inhibits the dephosphorylation of Thr-172 by protein phosphatase, whereas a high concentration of ATP inhibits the activation of AMPK. Recent studies identified calmodulin-dependent protein kinase kinase (CaMKK) as an additional upstream kinase of AMPK (7
). Activation of AMPK by CaMKK is triggered by a rise in intracellular calcium ions, without detectable changes in the AMP/ATP ratio (9
). CaMKK is highly expressed in the CNS, and lower levels are detected in other tissues such as liver and skeletal muscle, suggesting that the AMPK pathway is regulated by multiple mechanisms that are likely to be tissue specific (10
AMPK activity is activated by a wide array of metabolic stresses, including hypoxia, ischemia, and oxidative and hyperosmotic stresses (3
). Furthermore, exercise and glucose deprivation also activate AMPK, which suggests a role in exercise adaptations and β cell function. In general, activation of AMPK triggers catabolic pathways that produce ATP, while turning off anabolic pathways that consume ATP, to maintain cellular energy stores (4
). Metformin and thiazolidinedione, 2 widely prescribed drugs for the treatment of T2D, are also reported to increase AMPK activity (12
), underscoring the potential role of the AMPK pathway in the treatment of T2D.
Pharmacological activation of AMPK can be achieved by treatment of cells with an artificial activator, 5-aminoimidazole-4-carboxamide riboside (AICAR). AICAR is a cell-permeable adenosine analog that is taken up by the cells and phosphorylated to form 5-aminoimidazole-4-carboxamide-1-d-ribofuranosyl-5′-monophosphate (ZMP), an AMP mimetic, and confers the activating effects of AMP on the AMPK pathway (13
). However, ZMP is reported to affect other AMP-regulated enzymes (14
), and therefore caution has to be exercised in interpretation of data that involves the use of AICAR. Although elevations in the AMP/ATP ratio constitute a classical pathway of the activation of AMPK,activators of AMPK such as hyperosmotic stress do not appear to alter this ratio (12
), suggesting that other mechanisms are involved in the regulation of the AMPK pathway.