Gating motions underlie AMPA receptor secretion from the endoplasmic reticulum

Penn, Andrew C.; Williams, Stephen R.; Greger, Ingo H.

doi:10.1038/emboj.2008.222

Cited by 87 publications

(113 citation statements)

References 63 publications

Supporting

Mentioning

105

Contrasting

Order By: Relevance

“…This analysis suggested that the magnitude of ΔF was reduced by a substantial background signal (60-80%). This level of intracellular fluorescence is consistent with measurements of fluorescent or radioactively labeled GluA2, which suggests that at least half is immature and resident in the endoplasmic reticulum in HEK cells during overexpression (36,37).…”

Section: Voltage-dependent Quenching Of Yfp In the Intracellular Regisupporting

confidence: 71%

Structural rearrangement of the intracellular domains during AMPA receptor activation

Zachariassen

Katchan

Jensen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are ligand-gated ion channels that mediate the majority of fast excitatory neurotransmission in the central nervous system. Despite recent advances in structural studies of AMPARs, information about the specific conformational changes that underlie receptor function is lacking. Here, we used single and dual insertion of GFP variants at various positions in AMPAR subunits to enable measurements of conformational changes using fluorescence resonance energy transfer (FRET) in live cells. We produced dual CFP/ YFP-tagged GluA2 subunit constructs that had normal activity and displayed intrareceptor FRET. We used fluorescence lifetime imaging microscopy (FLIM) in live HEK293 cells to determine distinct steady-state FRET efficiencies in the presence of different ligands, suggesting a dynamic picture of the resting state. Patch-clamp fluorometry of the double-and single-insert constructs showed that both the intracellular C-terminal domain (CTD) and the loop region between the M1 and M2 helices move during activation and the CTD is detached from the membrane. Our time-resolved measurements revealed unexpectedly complex fluorescence changes within these intracellular domains, providing clues as to how posttranslational modifications and receptor function interact.T he α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type ionotropic glutamate receptors (iGluRs) reside in postsynaptic membranes in the central nervous system (1). Like the other major iGluR subtypes, the N-methyl-Daspartate receptors (NMDARs) and kainate receptors, AMPARs are ligand-gated cation channels formed by hetero-or homotetrameric assembly of the GluA1 to GluA4 subunits into a membranespanning receptor with an integral ion channel. The energy from binding of the excitatory neurotransmitter glutamate at extracellular sites triggers AMPARs to passage through functional states that can include ion channel activation, deactivation, and desensitization. The timing and interplay between the necessarily distinct conformations of these states determine both basal transmission and short-term plasticity of the postsynapse (2-4).Structures of AMPARs captured in various functional states using X-ray crystallography and cryoelectron microscopy have recently become available (5-9). Overall, the structures confirm three distinct structural layers (Fig. 1). The amino-terminal domain (ATD) and the ligand-binding domain (LBD), both distal to the membrane, and the transmembrane ion channel are each formed from four copies of the respective domain from each subunit. However, a fourth region of the receptor extends from the intracellular side of the membrane. This part of the receptor includes intracellular loops between the transmembrane helices and the variable C-terminal domain (CTD), and remains entirely unresolved in the presently available AMPAR structures.The GluA2 structures and previous results from biochemical, biophysical, and crystallographic studies of isolated subunits and fu...

show abstract

Section: Voltage-dependent Quenching Of Yfp In the Intracellular Regisupporting

confidence: 71%

Structural rearrangement of the intracellular domains during AMPA receptor activation

Zachariassen

Katchan

Jensen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Recent work on the biosynthesis of AMPARs may provide some insight into the second question. It has been proposed that during AMPAR biosynthesis, glutamate-induced conformational changes in the ER serve as early trafficking checkpoints to ensure that only functional receptors are exported to the cell surface (23)(24)(25)(26)(27). It may be a common function of CNIHs and TARPs to participate in glutamate-induced conformational changes by immature AMPARs, which then disengage from CNIHs but remain bound to TARPs as they are delivered to the plasma membrane and then targeted to synapses.…”

Section: Discussionmentioning

confidence: 99%

Functional comparison of the effects of TARPs and cornichons on AMPA receptor trafficking and gating

Shi¹,

Suh

Milstein

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

107

159

View full text Add to dashboard Cite

Glutamate receptors of the AMPA subtype (AMPARs) mediate fast synaptic transmission in the brain. These ionotropic receptors rely on auxiliary subunits known as transmembrane AMPAR regulatory proteins (TARPs) for both trafficking and gating. Recently, a second family of AMPAR binding proteins, referred to as cornichons, were identified and also proposed to function as auxiliary subunits. Cornichons are transmembrane proteins that modulate AMPAR function in expression systems much like TARPs. In the present study we compare the role of cornichons in controlling AMPA receptor function in neurons and HEK cells to that of TARPs. Cornichons mimic some, but not all, of the actions of TARPs in HEK cells; their role in neurons, however, is more limited. Although expressed cornichons can affect the trafficking of AMPARs, they were not detected on the surface of neurons and failed to alter the kinetics of endogenous AMPARs. This neuronal role is more consistent with that of an endoplasmic reticulum (ER) chaperone rather than a bona fide auxiliary subunit.stargazin | synapse | auxiliary subunit | hippocampus

show abstract

“…An intact and functional LBD capable of gating motions is essential for the maturation and forward trafficking of fulllength AMPARs (52,53). Surprisingly, the HA-GluA1-⌬ECD construct, which lacks the LBD and is therefore incapable of agonist-induced gating motions, was expressed to the cell surface instead of being trapped in the ER (Fig.…”

Section: Discussionmentioning

confidence: 99%

The Transmembrane Domain Mediates Tetramerization of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors

Gan¹,

Dai

Zhou

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

AMPA receptors (AMPARs) mediate fast excitatory neurotransmission in the central nervous system. Functional AMPARs are tetrameric complexes with a highly modular structure, consisting of four evolutionarily distinct structural domains: an amino-terminal domain (ATD), a ligand-binding domain (LBD), a channel-forming transmembrane domain (TMD), and a carboxyl-terminal domain (CTD). Here we show that the isolated TMD of the GluA1 AMPAR is fully capable of tetramerization. Additionally, removal of the extracellular domains from the receptor did not affect membrane topology or surface delivery. Furthermore, whereas the ATD and CTD contribute positively to tetramerization, the LBD presents a barrier to the process by reducing the stability of the receptor complex. These experiments pinpoint the TMD as the "tetramerization domain" for AMPARs, with other domains playing modulatory roles. They also raise intriguing questions about the evolution of iGluRs as well as the mechanisms regulating the biogenesis of AMPAR complexes.

show abstract

Gating motions underlie AMPA receptor secretion from the endoplasmic reticulum

Cited by 87 publications

References 63 publications

Structural rearrangement of the intracellular domains during AMPA receptor activation

Structural rearrangement of the intracellular domains during AMPA receptor activation

Functional comparison of the effects of TARPs and cornichons on AMPA receptor trafficking and gating

The Transmembrane Domain Mediates Tetramerization of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors

Contact Info

Product

Resources

About