title: The p38 MAP kinase pathway modulates the hypoxia response and glutamate receptor trafficking in aging neurons.
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.
authors.affiliation: The Waksman Institute, Rutgers The State University of New Jersey, New Jersey, United States.|Department of Genetics, Rutgers The State University of New Jersey, New Jersey, United States.
authors.forename: Eun Chan
authors.identifier: http://orcid.org/0000-0002-6147-4088
authors.initials: EC
authors.lastname: Park
authors.affiliation: The Waksman Institute, Rutgers The State University of New Jersey, New Jersey, United States.|Department of Genetics, Rutgers The State University of New Jersey, New Jersey, United States.
authors.forename: Christopher
authors.identifier: http://orcid.org/0000-0002-1361-5288
authors.initials: C
authors.lastname: Rongo
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D015687:Cell Hypoxia; D020935:MAP Kinase Signaling System; D009474:Neurons / Q000502:physiology*; D017470:Receptors, Glutamate / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; D017470:Receptors, Glutamate; D048051:p38 Mitogen-Activated Protein Kinases
keywords: <i>c. elegans</i>; cell biology; glutamate; hypoxia; membrane transport; neuroscience; signal transduction; synapse