title: The metabotropic glutamate receptor activates the lipid kinase PI3K in Drosophila motor neurons through the calcium/calmodulin-dependent protein kinase II and the nonreceptor tyrosine protein kinase DFak.
abstract: Ligand activation of the metabotropic glutamate receptor (mGluR) activates the lipid kinase PI3K in both the mammalian central nervous system and Drosophila motor nerve terminal. In several subregions of the mammalian brain, mGluR-mediated PI3K activation is essential for a form of synaptic plasticity termed long-term depression (LTD), which is implicated in neurological diseases such as fragile X and autism. In Drosophila larval motor neurons, ligand activation of DmGluRA, the sole Drosophila mGluR, similarly mediates a PI3K-dependent downregulation of neuronal activity. The mechanism by which mGluR activates PI3K remains incompletely understood in either mammals or Drosophila. Here we identify CaMKII and the nonreceptor tyrosine kinase DFak as critical intermediates in the DmGluRA-dependent activation of PI3K at Drosophila motor nerve terminals. We find that transgene-induced CaMKII inhibition or the DFak(CG1) null mutation each block the ability of glutamate application to activate PI3K in larval motor nerve terminals, whereas transgene-induced CaMKII activation increases PI3K activity in motor nerve terminals in a DFak-dependent manner, even in the absence of glutamate application. We also find that CaMKII activation induces other PI3K-dependent effects, such as increased motor axon diameter and increased synapse number at the larval neuromuscular junction. CaMKII, but not PI3K, requires DFak activity for these increases. We conclude that the activation of PI3K by DmGluRA is mediated by CaMKII and DFak.
authors.affiliation: Department of Biochemistry and Cell Biology, Rice University, Houston, Texas 77005, USA.
authors.forename: Curtis
authors.initials: C
authors.lastname: Chun-Jen Lin
authors.forename: James B
authors.initials: JB
authors.lastname: Summerville
authors.forename: Eric
authors.initials: E
authors.lastname: Howlett
authors.forename: Michael
authors.initials: M
authors.lastname: Stern
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D015536:Down-Regulation; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism / Q000494:pharmacology*; D007150:Immunohistochemistry; D007814:Larva / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D046529:Microscopy, Electron, Transmission; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009469:Neuromuscular Junction / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D019076:Transgenes; D015854:Up-Regulation
chemical_list: D029721:Drosophila Proteins; D018094:Receptors, Metabotropic Glutamate; C494781:mGluR protein, Drosophila; D018698:Glutamic Acid; D019869:Phosphatidylinositol 3-Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2