Role of 5′-Adenosine Monophosphate-Activated Protein Kinase in Cell Survival and Death Responses in Neurons

Abstract

5'-Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a key sensor of cellular energy status. AMPK signaling regulates energy balance at the cellular, organ, and whole-body level. More recently, it has become apparent that AMPK plays also an important role in long-term decisions that determine cell fate, in particular cell cycle progression and apoptosis activation. Here, we describe the diverse mechanisms of AMPK activation and the role of AMPK in the regulation of cellular energy balance. We summarize recent studies implicating AMPK activation in the regulation of neuronal survival and as a key player during ischemic stroke. We also suggest that AMPK activation may have dual functions in the regulation of neuronal survival: AMPK provides a protective effect during transient energy depletion as exemplified in a model of neuronal Ca(2+) overloading, and this effect is partially mediated by the activation of neuronal glucose transporter 3. Prolonged AMPK activation, on the contrary, can lead to neuronal apoptosis via the transcriptional activation of the proapoptotic Bcl-2 family member, bim. Molecular switches that determine the protective versus cell death-inducing effects of AMPK activation are discussed.

Two-step activation of FOXO3 by AMPK generates a coherent feed-forward loop determining excitotoxic cell fate

“…Although AMPK activation has been associated with cell survival, 11,23,26 it is now evident that it is also involved in longterm cell fate decisions. AMPK activation has been shown to activate apoptosis in different cell types, 27,28 including neurons, 9,13 and this apoptosis occurs after prolonged periods of AMPK activation. 27,28 AMPK has also been shown to mediate ischemic neuronal death in vivo.…”

“…Times (h) indicate duration of AICAR treatment (continuous) or recovery times following washout of AICAR FOXO3 and AMPK D Davila et al exist to restore pAKT/pFOXO3 levels in surviving neurons. Survival responses during excitotoxicity have been associated with enhanced neuronal glucose uptake and ATP availability, as well as with growth factor signaling, 9,12 suggesting that these factors could restore pAKT/pFOXO3 levels. The persistent mTOR dephosphorylation after GLUT exposure suggests the involvement in this process of other AKT regulators besides mTOR.…”

“…8 ATP depletion activates the AMPactivated protein kinase (AMPK), which adapts the cellular response to bioenergetic stress. 9 AMPK switches off anabolic pathways, preventing ATP consumption, and switches on catabolic pathways, increasing glucose uptake and ATP production. 10 AMPK-dependent plasma membrane translocation of the glucose transporter 3, and subsequent glucose uptake mediate tolerance of neurons to excitotoxic or ischemic injury.…”

“…11,12 In contrast to these cytoprotective mechanisms, however, prolonged AMPK activation has also been shown to contribute to ischemic injury and excitotoxicity. 9,13,14 We recently demonstrated that prolonged activation of AMPK mediates excitotoxic apoptosis by inducing the expression of the pro-apoptotic Bcl-2 family protein Bim. 13 However, the mechanisms that AMPK utilizes to switch on the transcriptional activation of bim during excitotoxic apoptosis remain unknown.…”

Redox implications of AMPK-mediated signal transduction beyond energetic clues

“…Although AMPK is mainly considered to be a pro-survival kinase, its involvement in the induction of cell death has also been demonstrated, mostly in conditions of its sustained activation (Ronnett et al, 2009;Weisová et al, 2011) (Fig. 5).…”