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INTERACTION WITH NEGR1 AFFECTS MGLUR5 CELL SIGNALING AND THE NEUROPROTECTION INDUCED BY THE POSITIVE ALLOSTERIC MODULATOR VU0409551
Jennifer D. S. Guimaraesand 2 co-authors
Universidade Federal de Minas Gerais
FENS Forum 2026 (2026)
Barcelona, Spain
Board PS01-07AM-004
Presentation
Date TBA
Board: PS01-07AM-004
Event Information
Poster Board
PS01-07AM-004
Poster
View posterAbstract
The metabotropic glutamate receptor 5 (mGluR5) plays an important role in neuronal survival and synaptic plasticity. We and others have shown that mGluR5 positive allosteric modulators (PAMs) are biased agonists, triggering the activation of neuroprotective pathways and promoting neuronal survival. As mGluR5 biased pharmacology arises from drug-induced interactions with distinct protein partners, in this study we analyzed the mGluR5 interactome to identify novel binding partners capable of modulating receptor cell signaling. To identify new mGluR5 partners we employed mass spectrometry, followed by co-immunoprecipitation experiments, which confirmed the interaction between mGluR5 and the neuronal growth regulator 1 (NEGR1), a cell adhesion molecule (CAM). We next evaluated how NEGR1 affects mGluR5 cell signaling and cellular distribution using lentivirus transduction on primary neuronal cultures to knockdown NEGR1 expression. Our results demonstrate that the interaction between NEGR1 and mGluR5 is important for mGluR5 synaptic localization and for its coupling with Homer, thereby modulating the cell signaling pathways activated by the receptor. For instance, NEGR1 knockdown led to decreased mGluR5-dependent activation of ERK1/2 and reduced expression of ARC/ARG3.1 and BDNF. Importantly, NEGR1 knockdown affected mGluR5 pharmacology, as the neuroprotective effect of VU0409551 was not observed in neurons expressing low levels of NEGR1. These results indicate that NEGR1 is essential for mGluR5 biased activation of neuroprotective cell signaling pathways and for the neuroprotective effect triggered by VU0409551.
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