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

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Abstract

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.

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Eun Chan Park

The Waksman Institute, Department of Genetics, Rutgers The State University of New Jersey, New Jersey, United States

Competing interests
The authors declare that no competing interests exist.
Christopher Rongo

The Waksman Institute, Department of Genetics, Rutgers The State University of New Jersey, New Jersey, United States

For correspondence
rongo@waksman.rutgers.edu

Competing interests
The authors declare that no competing interests exist.

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