AMP-activated protein kinase--development of the energy sensor concept

Abstract

The LKB1-->AMPK cascade is switched on by metabolic stresses that either inhibit ATP production (e.g. hypoxia, hypoglycaemia) or that accelerate ATP consumption (e.g. muscle contraction). Any decline in cellular energy status is accompanied by a rise in the cellular AMP: ATP ratio, and this activates AMPK by a complex and sensitive mechanism involving antagonistic binding of the nucleotides to two sites on the regulatory gamma subunits of AMPK. Once activated by metabolic stress, AMPK activates catabolic pathways that generate ATP, while inhibiting cell growth and biosynthesis and other processes that consume ATP. While the AMPK system probably evolved in single-celled eukaryotes to maintain energy balance at the cellular level, in multicellular organisms its role has become adapted so that it is also involved in maintaining whole body energy balance. Thus, it is regulated by hormones and cytokines, especially the adipokines leptin and adiponectin, increasing whole body energy expenditure while regulating food intake. Some hormones may activate AMPK by an LKB1-independent mechanism involving Ca2+/calmodulin dependent protein kinase kinases. Low levels of activation of AMPK are likely to play a role in the current global rise in obesity and Type 2 diabetes, and AMPK is the target for the widely used antidiabetic drug metformin.

Figure 1. Typical domain structure of the α, β and γ subunits of AMPK and its homologues in lower eukaryotes

Figure 2. Upstream regulators of AMPK

LKB1 and CaMKKs phosphorylate the same residue (Thr-172) on the α subunit of AMPK. Phosphorylation by LKB1, but not by CaMKKs, is stimulated by binding of AMP to AMPK.

Figure 3. Key processes of energy metabolism that are regulated by AMPK

A green arrow indicates activation, whereas a red line with a bar at the end indicates inhibition. Some of these processes are regulated by multiple effects of AMPK. For example, glucose uptake and fatty acid synthesis are regulated both acutely (with no change in gene expression) and chronically (via effects on gene expression).