AMP-activated protein kinase regulates neuronal polarization

Question: Does the adenosine 5=monophosphate (AMP)-activated protein kinase (AMPK) signaling cascade have a role in neuronal polarization? Background: The differentiation of a single neurite into an axon, which involves increased protein and membrane synthesis as well as the intracellular trafficking of these products, is a metabolically costly process. The AMPK signaling cascade has a major role in maintaining energy homeostasis in neurons. The phosphatidylinositol 3-kinase (PI3K) family of enzymes is regulated by AMPK and is important for axonal neurite growth. This study explored the role of these kinases in initiating axon differentiation and neuronal polarization. Observations: Amato et al. found that AMPK agonists decreased the number of neurons showing normal elongated axons in slice and primary cultures of hippocampal neurons, although the length and rate of non-axonal minor neurite growth were unaffected. AMPK activation was subsequently determined to inhibit PI3K activity at the axon tip during polarization, which was found to result from a disruption between PI3K and the kinesin family motor protein 5 (Kif5). Significance: These studies suggest that energy-sensing pathways coordinated by AMPK play crucial roles in axonal initiation and neuronal differentiation and provides the mechanism that regulates the localization and activity of PI3K at the axon tip. These findings reveal a complex interplay between the bio-energy-sensing pathway, protein trafficking, and localization of specific signaling pathways in the neuronal polarization processes. Thus these results may have implications for regenerative medicine research as well as the management of neuropathy. Angiotensin II type 2 receptor signaling attenuates aortic aneurysm in mice through ERK antagonism. Habashi JP, Doyle JJ, Holm TM, Aziz H, Schoenhoff F, Bedja D, Chen Y, Modiri AN, Judge DP, Dietz HC. Science 332: 361–365, 2011.