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.