PDZ Scaffold Protein CAL Couples with Metabotropic Glutamate Receptor 5 to Protect Against Cell Apoptosis and Is a Potential Target in the Treatment of Parkinson's Disease

Abstract

Targeting mGluR5 has been an attractive strategy to modulate glutamate excitotoxicity for neuroprotection. Although human clinical trials using mGluR5 negative allosteric modulators (NAMs) have included some disappointments, recent investigations have added several more attractive small molecules to this field, providing a promise that the identification of more additional strategies to modulate mGluR5 activity might be potentially beneficial for the advancement of PD treatment. Here, we determined the role of the interacting partner CAL (cystic fibrosis transmembrane conductance regulator-associated ligand) in mGluR5-mediated protection in vitro and in vivo. In astroglial C6 cells, CAL deficiency blocked (S)-3, 5-dihydroxyphenylglycine (DHPG)-elicited p-AKT and p-ERK1/2, subsequently prevented group I mGluRs-mediated anti-apoptotic protection, which was blocked by receptor antagonist 1-aminoindan-1, 5-dicarboxylic acid (AIDA), and PI3K or MEK inhibitor LY294002 or U0126. In rotenone-treated MN9D cells, both CAL and mGluR5 expressions were decreased in a time-and dose-dependent manner, and the correlation between these 2 proteins was confirmed by lentivirus-delivered CAL overexpression and knockdown. Moreover, CAL coupled with mGluR5 upregulated mGluR5 protein expression by inhibition of ubiquitin-proteasome-dependent degradation to suppress mGluR5-mediated p-JNK and to protect against cell apoptosis. Additionally, CAL also inhibited rotenone-induced glutamate release to modulate mGluR5 activity. Furthermore, in the rotenone-induced rat model of PD, AAV-delivered CAL overexpression attenuated behavioral deficits and dopaminergic neuronal death, while CAL deficiency aggravated rotenone toxicity. On the other hand, the protective effect of the mGluR5 antagonist MPEP was weakened by knocking down CAL. In vivo experiments also confirmed that CAL inhibited ubiquitinationproteasome-dependent degradation to modulate mGluR5 expression and JNK phosphorylation. Our findings show that CAL protects against cell apoptosis via modulating mGluR5 activity, and may be a new molecular target for an effective therapeutic strategy for PD.

Revealing the Potential Application of EC-Synthetic Retinoid Analogues in Anticancer Therapy

“…Glutamate is an essential molecule for cells, especially cancer cells due to its paracrine effect on intracellular and extracellular communications where even the small changes in its levels significantly impact the cellular transformation and cancer progression [ 99 , 100 , 101 ]. The extracellular glutamate is mainly required for intercellular communication and activation of survival pathways, like the MAPK and PI3K pathways, promoting growth and invasion [ 101 , 102 ].…”

Long noncoding RNA LINC00314 facilitates osteogenic differentiation of adipose-derived stem cells through the hsa-miR-129-5p/GRM5 axis via the Wnt signaling pathway

“…Metabotropic glutamate receptor 5, named GRM5, has been shown to activate phospholipase C and participate in multiple biological processes [16]. Many studies have shown the Wnt/β-catenin signaling pathway participant into the osteogenic differentiation of ADSCs.…”

The Golgi-Associated PDZ Domain Protein Gopc/PIST Is Required for Synaptic Targeting of mGluR5

“…In primary cultured neurons, knockdown of Gopc expression by shRNA does not affect the abundance of its associated membrane proteins (Nlgn1, NMDA receptors, and mGlu5 were tested here). Instead, for two verified interaction partners of Gopc, namely, mGlu5 [ 22 , 23 ] and Nlgn1 [ 6 , 32 ], we observed that knockdown of Gopc reduces the amount of protein that is present at the cell surface. In the second set of experiments, we used a mouse line with a conditional deletion of the Gopc gene coding for Gopc in mouse forebrain neurons.…”

“…However, which part of the sorting machinery specifically is affected by Gopc has been a subject of debate, as it may be receptor- and cell type-specific [ 18 – 20 ]. Thus, for the CFTR, it has been proposed that Gopc contributes to its degradation in lysosomes [ 8 , 10 , 21 ], whereas for mGlu5 it was reported that degradation of the receptor by the ubiquitin/proteasomal system is prevented by Gopc [ 22 , 23 ]. A more common finding has been that overexpression of Gopc leads to retention of its associated membrane proteins at the TGN [ 12 , 17 , 24 , 25 ].…”