AMPA receptor

Summary

The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (also known as AMPA receptor, AMPAR, or quisqualate receptor) is an ionotropic transmembrane receptor for glutamate (iGluR) that mediates fast synaptic transmission in the central nervous system (CNS). It has been traditionally classified as a non-NMDA-type receptor, along with the kainate receptor. Its name is derived from its ability to be activated by the artificial glutamate analog AMPA. The receptor was first named the "quisqualate receptor" by Watkins and colleagues after a naturally occurring agonist quisqualate and was only later given the label "AMPA receptor" after the selective agonist developed by Tage Honore and colleagues at the Royal Danish School of Pharmacy in Copenhagen. The GRIA2-encoded AMPA receptor ligand binding core (GluA2 LBD) was the first glutamate receptor ion channel domain to be crystallized. Structure and function Subunit composition AMPARs are composed of four types

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Membrane trafficking in neurons regulated by new syntaxin 13-interacting proteins

Pascal Steiner

Recently, it has been shown that correct trafficking of neuronal plasma membrane receptors along the endosomal pathway is directly implicated in molecular mechanisms underlying synaptic plasticity and is fundamental for proper neuronal communication. To understand the molecular mechanisms that regulate neuronal trafficking through endosomes, we used syntaxin 13, an endosomal protein that we had previously characterized, as a bait to immunopurify protein complexes. Among the 5 new syntaxin 13-interacting proteins that we identified, my thesis work has focused on the characterization of 2 of them, Neuron-Enriched Endosomal Protein of 21 kDa (NEEP21) and Reticulon1-C (RTN1-C). NEEP21. Our work revealed that NEEP21 is expressed by neurons in their somatodendritic compartments, where it is mainly found in Rab4-positive subdomains of early endosomes. This domain has been implicated in the sorting of internalized surface receptors. We demonstrated that NEEP21 suppression strongly retards recycling of receptors including AMPA-type glutamate receptors. We recently identified a molecular link between NEEP21 and AMPA-receptor trafficking. NEEP21 is present in a complex with GRIP, a scaffold protein for GluR2, and GluR2, a subunit of AMPA receptors. Overexpression of the NEEP21 binding site for GRIP causes a retraction of dendrites, an effect partially compensated by GluR2 overexpression. In addition, expression of this fragment inhibits AMPA receptor recycling. Based on the recent findings of the importance of AMPA receptor trafficking between endosomes and the cell membrane during synaptic structural and functional plasticity, we postulate that NEEP21 modulates synaptic strength. RTN1-C. The second identified syntaxin 13-associated protein is RTN1-C. Reticulons constitute a family of membrane proteins localized primarily to the endoplasmic reticulum (ER). So far the cellular function of reticulons is little undertsood. We found that RTN1-C interacts with several SNARE proteins. In addition, we showed that overexpression of the RTN1-C binding site for syntaxin 1 significantly enhanced regulated secretion. Based on these findings, we hypothesized that RTN1-C could be a key actor in the regulation of SNARE-dependent membrane fusion processes. Together, our studies contribute to the elucidation of the roles of NEEP21 and RTN1-C in neurons and the molecular mechanisms of membrane protein trafficking that are at fundamental for synaptic plasticity.

EPFL2004

In this thesis, we studied two systems important for synaptic plasticity, one presynaptic and another postsynaptic. The protein complex composed of VAMP 2, SNAP-25 and syntaxin 1 (SNARE complex) is essential for docking and fusion of neurotransmitter-filled synaptic vesicles with the presynaptic membrane. In order to better understand the fusion mechanisms, we reconstituted the synaptic SNARE complex in the imaging chamber of an atomic force microscope (AFM) and measured the interaction forces between its components. Each protein was tested against the two others, taken either individually or as binary complexes. This approach allowed us to determine specific interaction forces, dissociation kinetics of the SNAREs and led us to propose a sequence of formation for the complex. A theoretical model based on our measurements suggests that a minimum of four complexes is probably necessary for fusion to occur. We also showed that the regulatory protein nSec1 injected into the AFM chamber prevented the SNARE complex formation. Finally we measured the effect of tetanus toxin protease (TeTx) on the SNARE complex and its activity by on-line registration during TeTx injection. These experiments reveal that AFM is a valuable tool to investigate complicate interactions among a protein complex containing up to four components. Trafficking of glutamate receptors AMPA is closely related to postsynaptic induction of long-term potentiation. In a second part of this thesis, we used AFM to explore the distribution of AMPA receptors on-line at the surface of living cells in correlation with cellular viscoelastic properties. First, we showed that AFM permits to detect specifically AMPA receptors at the surface of living neurons and we proved that the specificity of detection is stable during time. Moreover, we were able to visualize variations in AMPA receptor density on surface in response to different stimulations. Finally, AFM also allowed us to study local viscoelastic properties of the cell and their modifications occurring during AMPA receptor trafficking. Our measurements reveal that AMPA receptors are situated at the cell surface on local stiffness maxima. We have noticed that an excitatory stimulation removes these stiffness maxima before producing internalization of receptors. Our results suggest also that AMPA receptors may be constituted of two subpopulations depending on the cell stiffness. A "hard" subpopulation may be preferentially internalized after an excitatory stimulation whereas a "soft" one seems to remain at the cell surface.

EPFL2004

Regulation of the protein complex NEEP21 - GRIP - GluR2 implicated in AMPAR trafficking through endosomal compartments

Karina Kulangara

It is important for neurotransmission to control the number of receptors at synapses. The synaptic α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type of glutamate receptors (AMPARs) control the strength of excitatory transmission. These receptors are mobile and cycle between internal endosomal compartments and the plasma membrane. We have identified previously a protein complex between the endosomal protein NEEP21, the AMPAR subunit GluR2 and the scaffold protein GRIP necessary for correct GluR2 recycling. Here we elucidate the regulation underlying the complex formation and dissociation necessary for the trafficking through endosomal compartments. We show that a 85 kDa protein kinase, which is associated with NEEP21, phosphorylates GRIP on serine 917. Protein kinase C is activated by glutamate receptor stimulation, and leads to the activation of the NEEP21-associated kinase. The phosphorylation of GRIP leads to a reduced binding between GRIP and NEEP21, and GRIP and GluR2. Serine 917 is implicated in AMPAR cycling, since a wildtype carboxyterminal GRIP fragment expressed in hippocampal neurons interferes with GluR2 surface expression. On the contrary, a S917D mutant fragment does not interfere with GluR2 surface expression. The regulation of the formation and dissociation of the protein complex between NEEP21, GluR2 and GRIP1 may suggest a sorting mechanism between the recycling and degradation pathways for the AMPAR subunit GluR2. This is especially important in the light of the discovery of a form of plasticity which implicates GluR2-lacking AMPAR, and the fact that insertion of GluR2-lacking AMPAR are implicated in a number of neurological diseases like ALS or ischemia. Our results identify an important regulatory mechanism in the trafficking of AMPAR subunits between internal compartments and the plasma membrane.

EPFL2006