Effects of AMP-activated protein kinase in cerebral ischemia

Abstract

AMP-activated protein kinase (AMPK) is a serine threonine kinase that is highly conserved through evolution. AMPK is found in most mammalian tissues including the brain. As a key metabolic and stress sensor/effector, AMPK is activated under conditions of nutrient deprivation, vigorous exercise, or heat shock. However, it is becoming increasingly recognized that changes in AMPK activation not only signal unmet metabolic needs, but also are involved in sensing and responding to 'cell stress', including ischemia. The downstream effect of AMPK activation is dependent on many factors, including the severity of the stressor as well as the tissue examined. This review discusses recent in vitro and in vivo studies performed in the brain/neuronal cells and vasculature that have contributed to our understanding of AMPK in stroke. Recent data on the potential role of AMPK in angiogenesis and neurogenesis and the interaction of AMPK with 3-hydroxy-3-methy-glutaryl-CoA reductase inhibitors (statins) agents are highlighted. The interaction between AMPK and nitric oxide signaling is also discussed.

Figure 1

AMPK signaling when energy balance is unmet. Green arrow: activation; red arrow: inhibition. AMPK is activated when the energy demand is higher than the supply and inhibited when the supply is higher than demand. CaMKK β, Ca2⁺/calmodulin-dependent protein kinase β; TAK1, TGF β-activated kinase 1; PP2Cα, protein phosphatase-2Cα; GS, glycogen synthase; HMG-CoAR, 3-hydroxy-3-methy-glutaryl-CoA reductase; PFK-2, phosphofructokinase-2; TF, transcription factors; P53, tumor protein 53; mTOR, mammalian target of rapamicin; eEF2K, eukaryotic elongation factor-2 kinase; GLUT-3,4, glucose transporter 3 and 4. (The color reproduction of this figure is available on the html full text version of the manuscript.)

Figure 2

Regulation of AMPK phosphorylation. Green arrow: activation; red arrow: inhibition. CaMKK β, Ca2⁺/calmodulin-dependent protein kinase β; TAK1, TGF β-activated kinase 1; PP2C, protein phosphatase 2C. (The color reproduction of this figure is available on the html full text version of the manuscript.)

Figure 3

The differential effects of AMPK in regulating glycolysis in neurons and astrocytes. Ischemia/hypoxia-induced AMPK phosphorylation activates phosphofructokinase 2 (PFK2) in astrocytes, leading to enhanced glycolysis and increased glycolytic products (pyruvate, lactate, and ATP). In neurons where there is minimal PFK-2 activity, the ability to produce ATP through glycolysis is limited. F6P, fructose-6-phosphate; F2, 6P, fructose-2,6-bisphosphate. Green arrow: activation; red arrow: inhibition. (The color reproduction of this figure is available on the html full text version of the manuscript.)

Figure 4

Statins regulate neurogenesis, angiogenesis, and vascular protection through AMPK, eNOS, and NO pathways. HMG-CoAR, 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Green arrow: activation; red arrow: inhibition. (The color reproduction of this figure is available on the html full text version of the manuscript.)