Molecular mechanisms that regulate ionotropic glutamate receptor distribution during hippocampal mGluR-LTD induction and expression

Schematic model of the molecular mechanisms that regulate ionotropic glutamate receptor distribution during hippocampal mGluR-LTD induction and expression. Activation of group I mGluRs leads to dephosphorylation and activation of STEP, which transiently dephosphorylates tyrosine (Y) residues in GluA2-containing AMPARs at the PSD. This may trigger lateral diffusion of AMPARs to extrasynaptic endocytic zones from which internalization occurs. It is likely that upon internalization, AMPARs are rephosphorylated by PTKs and retained at intracellular compartments until recycled or degraded. In parallel to STEP activation, group I mGluR activation can stimulate ERK1/2 and p38 MAPK signaling pathways via G-protein release and activation of the small GTPase Rap. ERK1/2 activation could stimulate calpain proteolysis of NMDAR and AMPAR subunit C-termini, which facilitates loss of synaptic receptors. Protease involvement is also exemplified by TACE, which cleaves NPR and allows it to cluster with AMPARs and other NPs in endocytic vesicles. Activation of the p38 MAPK signaling pathway stimulates the formation of the GDI-Rab5 complex, which also mediates AMPAR endocytosis. mGluR-LTD involves regulation of gene transcription and protein translation via the activation of signaling pathways such as p38 MAPK and ERK. Protein synthesis up-regulated includes STEP, FMRP, Arc/Arg3.1, and MAP1B, which are all involved in regulation of AMPAR internalization. After synthesis, FMRP is rapidly degraded such that it can no longer inhibit translation of specific mRNAs such as Arc/Arg3.1 and can no longer down-regulate AMPAR endocytosis. Arc/Arg3.1 forms a complex with endophilin2/3 (Endo) and dynamin (Dyn), which facilitates AMPAR internalization. MAP1B also promotes receptor endocytosis by sequestering the scaffolding protein GRIP away from the PSD such that AMPAR synaptic stabilization is reduced. The dotted line corresponds to a postulated pathway involved in mGluR-LTD, solid arrows relate to confirmed molecular mechanisms that promote AMPAR internalization, and the inhibitory arrows refer to pathways that are down-regulating protein synthesis or receptor endocytosis. Figure is based on data described in and .

Publication

Metabotropic Glutamate Receptor-Mediated Long-Term Depression: Molecular Mechanisms. (2009) Clare M. Gladding, et al. Pharmacol Rev. 2009 Dec;61(4):395-412. Figure: F1. All organisms Drosophila melanogaster Homo sapiens

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