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