Bioenergy sensing in the brain: the role of AMP-activated protein kinase in neuronal metabolism, development and neurological diseases

Abstract

Bioenergy homeostasis constitutes one of the most crucial foundations upon which other cellular and organismal processes may be executed. AMP-activated protein kinase (AMPK) has been shown to be the key player in the regulation of energy metabolism, and thus is becoming the focus of research on obesity, diabetes and other metabolic disorders. However, its role in the brain, the most energy-consuming organ in our body, has only recently been studied and appreciated. Widely expressed in the brain, AMPK activity is tightly coupled to the energy status at both neuronal and whole-body levels. Importantly, AMPK signaling is intimately implicated in multiple aspects of brain development and function including neuronal proliferation, migration, morphogenesis and synaptic communication, as well as in pathological conditions such as neuronal cell death, energy depletion and neurodegenerative disorders.

Figure 1

Isoforms and splice variants of mammalian AMPK. The two α subunit isoforms each contain an N-terminal catalytic domain that shares 90% homology, including a threonine residue (T172) that is phosphorylated by upstream kinases for activation. While both isoforms exist within the brain, α2 is dominantly expressed in neurons. The two β subunits contain a glycogen-binding domain that is thought to play a role in the subcellular localization of AMPK in muscle cells and a C-terminal domain required for interaction with the α and γ subunits and complex formation. Three different isoforms exist for the γ subunit (γ1, γ2 and γ3), with γ2 and γ3 each possessing two splice variants (long and short forms) that vary in the length of the N-terminal domain (NTD). γ1 is the predominant isoform within the CNS, with γ3 being restricted to skeletal muscle.