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date: 23 April 2019

Molecular Regulation of Energy Balance

This is an advance summary of a forthcoming article in the Oxford Research Encyclopedia of Neuroscience. Please check back later for the full article.

AMP-activated protein kinase (AMPK) is a sensor of energy status expressed in almost all eukaryotic cells, including neurons. It senses the levels of cellular AMP and ADP relative to ATP. If increases in AMP:ATP and/or ADP:ATP ratios are detected (indicating a reduction in cellular energy status), then AMPK is activated by a mechanism involving both allosteric activation and enhanced net phosphorylation at Thr172 on the catalytic subunit by the upstream kinase LKB1. Once activated, AMPK phosphorylates dozens of downstream targets, thus switching on catabolic pathways that generate ATP and switching off anabolic pathways and other energy-consuming processes. AMPK can also be activated by an alternate, non-canonical mechanism triggered by increases in intracellular Ca2+; this activates the calmodulin-dependent kinase CaMKK2, which can phosphorylate Thr172 in the absence of any changes in adenine nucleotide ratios. AMPK is also activated by glucose starvation by a non-canonical mechanism that is dependent upon LKB1 but is independent of changes in adenine nucleotides.

AMPK occurs in essentially all eukaryotes in the form of heterotrimeric complexes comprising a catalytic α subunit and regulatory β and γ subunits. In vertebrates, each of the three subunits is encoded by two or three genes, generating up to twelve heterotrimeric combinations displaying subtle variations in tissue distribution and regulation. The α subunits contain the kinase domain with Thr172 in the “activation loop” and regulatory regions that interact with the other two subunits. The β subunits contain a domain that, with the small lobe of the kinase domain on the α subunit, forms the “ADaM” site, the binding site for synthetic drugs that are potent allosteric activators of AMPK. It is not yet clear whether there are endogenous ligand(s) that bind to this site. The γ subunits contain three binding sites for the regulatory nucleotides, AMP, ADP, and ATP.

Consistent with its role as an ancient sensor of nutrient starvation, AMPK in specific neurons of the hypothalamus is involved in the regulation of appetite and feeding behavior, being activated by orexigenic hormones like ghrelin that act via the Ca2+-CaMKK2 pathway, and inhibited by anorexigenic hormones such as leptin, possibly via release of opioids that inhibit AMPK.

A special feature of AMPK in excitable cells is its ability to phosphorylate and modulate the function of ion channels, especially K+ channels. For example, in central neurons phosphorylation of the C-terminal tail of the delayed rectifier K+ channel Kv2.1 hyper-polarizes the plasma membrane and reduces the firing of action potentials, thus potentially conserving energy.