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 transgeneinduced 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 DFakdependent 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.

miR-434-3p and DNA hypomethylation co-regulate eIF5A1 to increase AChRs and to improve plasticity in SCT rat skeletal muscle

“…A gene with abundant interactions is thought to make a significant contribution to functional recovery. Some of these genes, such as Myod1, Camk2d and Dmd, have been verified to benefit AChRs structure 30 31 32 . We measured the expression levels of these genes in the normal, ctrl and miR-434-3p + groups using real-time PCR.…”

“…Calcium/calmodulin-dependent protein-kinase II (Camk2d) is a ubiquitous enzyme that modulates the functions of many neuronal proteins in response to changes in intracellular calcium concentrations. Chun-Jen Lin C et al reported that Camk2d enhanced the motor axon diameter and increased the synapse numbers at the larval neuromuscular junction 32 . Moreover, myogenic differentiation (Myod) deletion resulted in major alterations in the organization of the neuromuscular junction and was linked to perturbations in the nuclear localization of β-catenin 31 .…”

The Role of Intracellular Calcium for the Development and Treatment of Neuroblastoma

“…ALK gene mutations are associated with both familial and sporadic neuroblastoma. Downstream signalling cascade of ALK signalling includes AKT, ERK1/2 and STAT3 [ 47 ].Calcium phosphorylates three kinases (AKT, ERK and FAK) that are involved in the cell survival signalling in neuroblastoma ( Figure 3 ) [ 48 , 49 ].…”

The Genetic Analysis of Functional Connectomics in Drosophila

“…Flies have two identified glutamate-gated metabotropic receptors (mGluR) (Eroglu et al ., 2003). DmGluRA acts via PI3 kinase, as an autoreceptor with a negative feedback action, at presynaptic terminals of motor neurons (Howlett et al ., 2008; Lin et al ., 2011). DmGluRA is widely expressed in the CNS but the functions of neither of the fly’s two mGluR’s in the CNS is clear (Ramaekers et al ., 2001; Devaud et al ., 2008).…”