The Response of Neurons to Low Oxygen Levels (Hypoxia and Anoxia)

Environment can impact nervous system function, and neurons can respond to accommodate a changing environment. Specifically, oxygen influences behavior in many organisms, and low oxygen levels (hypoxia) can have devastating consequences for neuron survival due to excitotoxicity from overactivated neurotransmitter receptors and impaired mitochondrial function. We have shown that hypoxia blocks the membrane recycling of glutamate-gated ion channels to synapses, thereby depressing glutamatergic signaling. Surprisingly, HIF-1, which is the canonical transcription factor that mediates most cellular hypoxia responses, does not mediate this effect. Instead, a specific isoform of the prolyl hydroxylase EGL-9, a key sensor for oxygen, recruits LIN-10, a known PDZ scaffolding protein, to endosomes, where together the two proteins promote glutamate receptor recycling. This is a novel way by which animals can sense and respond to oxygen levels, and it suggests that the protective mechanisms are more diverse than originally appreciated.  A complete understanding of the hypoxia response pathway (i.e., EGL-9 and HIF-1) is important for understanding ischemic stroke. In addition, this pathway has become a target of interest for new chemotherapeutics, as HIF-1 is activated and plays a key role in cancer progression and metastasis. Therefore, we have broadened our studies of this pathway, and we are now conducting RNA-seq and ChIP-seq experiments to identify both HIF-1-dependent and HIF-1-independent targets of hypoxia-induced gene regulation.  We have also identified over 400 unique metabolites that are regulated by this pathway and correlate with the changes in gene expression.  

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The p38 MAP kinase pathway modulates the hypoxia response and glutamate receptor trafficking in aging neurons.

Park EC, Rongo C. Elife. 2016 Jan 5;5. pii: e12010. doi: 10.7554/eLife.12010. PMID:26731517

Neurons are sensitive to low oxygen (hypoxia) and employ a conserved pathway to combat its effects. Here, we show that p38 MAP Kinase (MAPK) modulates this hypoxia response pathway in C. elegans. Mutants lacking p38 MAPK components pmk-1 or sek-1 resemble mutants lacking the hypoxia response component and prolyl hydroxylase egl-9, with impaired subcellular localization of Mint orthologue LIN-10, internalization of glutamate receptor GLR-1, and depression of GLR-1-mediated behaviors. Loss of p38 MAPK impairs EGL-9 protein localization in neurons and activates the hypoxia-inducible transcription factor HIF-1, suggesting that p38 MAPK inhibits the hypoxia response pathway through EGL-9. As animals age, p38 MAPK levels decrease, resulting in GLR-1 internalization; this age-dependent downregulation can be prevented through either p38 MAPK overexpression or removal of CDK-5, an antagonizing kinase. Our findings demonstrate that p38 MAPK inhibits the hypoxia response pathway and determines how aging neurons respond to hypoxia through a novel mechanism.

Hypoxia regulates glutamate receptor trafficking through an HIF-independent mechanism.

Park EC, Ghose P, Shao Z, Ye Q, Kang L, Xu XZ, Powell-Coffman JA, Rongo C. EMBO J. 2012 Mar 21;31(6):1379-93. doi: 10.1038/emboj.2011.499. Epub 2012 Jan 17. Erratum in: EMBO J. 2012 Mar 21;31(6):1618-9. PMID:22252129

Oxygen influences behaviour in many organisms, with low levels (hypoxia) having devastating consequences for neuron survival. How neurons respond physiologically to counter the effects of hypoxia is not fully understood. Here, we show that hypoxia regulates the trafficking of the glutamate receptor GLR-1 in C. elegans neurons. Either hypoxia or mutations in egl-9, a prolyl hydroxylase cellular oxygen sensor, result in the internalization of GLR-1, the reduction of glutamate-activated currents, and the depression of GLR-1-mediated behaviours. Surprisingly, hypoxia-inducible factor (HIF)-1, the canonical substrate of EGL-9, is not required for this effect. Instead, EGL-9 interacts with the Mint orthologue LIN-10, a mediator of GLR-1 membrane recycling, to promote LIN-10 subcellular localization in an oxygen-dependent manner. The observed effects of hypoxia and egl-9 mutations require the activity of the proline-directed CDK-5 kinase and the CDK-5 phosphorylation sites on LIN-10, suggesting that EGL-9 and CDK-5 compete in an oxygen-dependent manner to regulate LIN-10 activity and thus GLR-1 trafficking. Our findings demonstrate a novel mechanism by which neurons sense and respond to hypoxia.