Hypoxia regulates glutamate receptor trafficking through an HIF-independent mechanism

EMBO J. 2012 Mar 21;31(6):1379-93. doi: 10.1038/emboj.2011.499. Epub 2012 Jan 17.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Cell Hypoxia / physiology*
  • Cyclin-Dependent Kinases / metabolism
  • Membrane Proteins / metabolism
  • Mutation
  • Neurons / metabolism*
  • Oxygen / metabolism
  • Phosphorylation
  • Protein Isoforms
  • Protein Transport / genetics
  • Protein Transport / physiology
  • Receptors, AMPA / metabolism*
  • Receptors, Glutamate / metabolism*
  • Transcription Factors / metabolism*

Substances

  • Caenorhabditis elegans Proteins
  • Egl-9 protein, C elegans
  • HIF-1 protein, C elegans
  • Membrane Proteins
  • Protein Isoforms
  • Receptors, AMPA
  • Receptors, Glutamate
  • Transcription Factors
  • glr-1 protein, C elegans
  • lin-10 protein, C elegans
  • Cyclin-Dependent Kinases
  • Oxygen