title: mGluR and NMDAR activation internalize distinct populations of AMPARs.
abstract: Activation of metabotropic- (mGluRs) or NMDA-type glutamate receptors (NMDARs) each can induce long-term depression (LTD) of synaptic transmission in CA1 hippocampal neurons. These two forms of LTD are triggered by diverse signaling pathways yet both are expressed by the internalization of AMPA-type glutamate receptors (AMPARs). An unanswered question remains as to whether the convergence of the mGluR and NMDAR signaling pathways on AMPAR endocytosis renders these two forms of plasticity functionally equivalent, with both pathways inducing endocytosis of the same population of synaptic AMPARs. We now report evidence that these pathways couple to the endocytosis of distinct populations of AMPARs defined by their mobility in the membrane surface. NMDAR activation enhances removal of surface AMPARs that rapidly cycle into and out of the membrane surface, while activation of mGluRs with DHPG results in the internalization of a non-mobile population of AMPARs. Glutamate Receptor Interacting Proteins 1 and 2 (GRIP1/2) play a key role in defining the non-cycling receptor population. GRIP1/2 knockdown with siRNA increases the proportion of rapidly cycling surface AMPARs and inhibits mGluR- but not NMDAR-mediated AMPAR internalization. Additionally, we find that mGluR activation dissociates surface AMPARs from GRIP1/2 while stimulation of NMDARs elicits the loss of membrane receptors not bound to GRIP1/2. We propose that these two receptor pathways can drive the endocytosis of distinct populations of AMPARs: NMDARs activation induces the endocytosis of rapidly cycling surface AMPARs not directly associated with GRIP1/2 while mGluR activation induces the endocytosis of non-cycling GRIP-bound surface AMPARs.
authors.affiliation: Albert Einstein College of Medicine of Yeshiva University, Dominick P Purpura Department of Neuroscience, Rose Kennedy Center for Mental Retardation, 1410 Pelham Parkway South, Bronx, NY 10461, United States.
authors.forename: Tanya M
authors.initials: TM
authors.lastname: Casimiro
authors.forename: Kenneth G
authors.initials: KG
authors.lastname: Sossa
authors.forename: Genoveva
authors.initials: G
authors.lastname: Uzunova
authors.forename: Jennifer B
authors.initials: JB
authors.lastname: Beattie
authors.forename: Kurt C
authors.initials: KC
authors.lastname: Marsden
authors.forename: Reed C
authors.initials: RC
authors.lastname: Carroll
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004705:Endocytosis / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D036881:Long-Term Synaptic Depression / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000502:physiology; D018408:Patch-Clamp Techniques; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D002352:Carrier Proteins; C491308:Grip1 protein, rat; C118486:Grip2 protein, rat; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D018091:Receptors, AMPA; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate