Endocannabinoid-Goα signalling inhibits axon regeneration in Caenorhabditis elegans by antagonizing Gqα-PKC-JNK signalling

Nat Commun. 2012:3:1136. doi: 10.1038/ncomms2136.

Abstract

The ability of neurons to regenerate their axons after injury is determined by a balance between cellular pathways that promote and those that inhibit regeneration. In Caenorhabditis elegans, axon regeneration is positively regulated by the c-Jun N-terminal kinase mitogen activated protein kinase pathway, which is activated by growth factor-receptor tyrosine kinase signalling. Here we show that fatty acid amide hydrolase-1, an enzyme involved in the degradation of the endocannabinoid anandamide (arachidonoyl ethanolamide), regulates the axon regeneration response of γ-aminobutyric acid neurons after laser axotomy. Exogenous arachidonoyl ethanolamide inhibits axon regeneration via the Goα subunit GOA-1, which antagonizes the Gqα subunit EGL-30. We further demonstrate that protein kinase C functions downstream of Gqα and activates the MLK-1-MEK-1-KGB-1 c-Jun N-terminal kinase pathway by phosphorylating MLK-1. Our results show that arachidonoyl ethanolamide induction of a G protein signal transduction pathway has a role in the inhibition of post-development axon regeneration.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amidohydrolases / metabolism
  • Amino Acid Sequence
  • Animals
  • Arachidonic Acids / metabolism
  • Axons / physiology*
  • Caenorhabditis elegans / enzymology*
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans Proteins / antagonists & inhibitors
  • Caenorhabditis elegans Proteins / metabolism*
  • Endocannabinoids / metabolism*
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism*
  • GTP-Binding Protein alpha Subunits, Gq-G11 / antagonists & inhibitors
  • GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism
  • Genes, Helminth / genetics
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • MAP Kinase Kinase Kinases / chemistry
  • MAP Kinase Kinase Kinases / metabolism
  • MAP Kinase Signaling System*
  • Models, Biological
  • Molecular Sequence Data
  • Nerve Regeneration / physiology*
  • Polyunsaturated Alkamides / metabolism
  • Protein-Tyrosine Kinases / metabolism*

Substances

  • Arachidonic Acids
  • Caenorhabditis elegans Proteins
  • Egl-30 protein, C elegans
  • Endocannabinoids
  • GOA-1 protein, C elegans
  • Polyunsaturated Alkamides
  • TPA-1 protein, C elegans
  • Protein-Tyrosine Kinases
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • Amidohydrolases
  • fatty-acid amide hydrolase
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • GTP-Binding Protein alpha Subunits, Gq-G11
  • anandamide