Flip and Flop: A Molecular Determinant for AMPA Receptor Channel Opening

Pei, Weimin; Huang, Zhen; Wang, Congzhou; Yao, Han; Park, Jae-Seon; Niu, Li

doi:10.1021/bi8015907

Cited by 51 publications

(85 citation statements)

References 57 publications

(176 reference statements)

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“…15,16,33,34 Apparently, these compounds cannot be used to control the difference in various functional properties between the flip and flop isoforms of GluA2, such as desensitization 35−39 and channel opening reaction. 40 Together, these data show that the single stereoisomeric difference at the C-4 position gives rise to the difference in biological activity of BDZ-d and BDZ-e in that the S configuration significantly diminishes the activity of the enantiomer on the same receptor.…”

Section: ■ Results and Discussionmentioning

confidence: 69%

Mechanism of Inhibition of the GluA2 AMPA Receptor Channel Opening by Talampanel and Its Enantiomer: The Stereochemistry of the 4-Methyl Group on the Diazepine Ring of 2,3-Benzodiazepine Derivatives

Wang

Niu

2013

ACS Chem. Neurosci.

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Stereoselectivity of 2,3-benzodiazepine compounds provides a unique way for the design of stereoisomers as more selective and more potent inhibitors as drug candidates for treatment of the neurological diseases involving excessive activity of AMPA receptors. Here we investigate a pair of enantiomers known as Talampanel and its (+) counterpart about their mechanism of inhibition and selectivity toward four AMPA receptor subunits or GluA1−4. We show that Talampanel is the eutomer with the endismic ratio being 14 for the closed-channel and 10 for the open-channel state of GluA2. Kinetic evidence supports that Talampanel is a noncompetitive inhibitor and it binds to the same site for those 2,3-benzodiazepine compounds with the C-4 methyl group on the diazepine ring. This site, which we term as the "M" site, recognizes preferentially those 2,3-benzodiazepine compounds with the C-4 methyl group being in the R configuration, as in the chemical structure of Talampanel. Given that Talampanel inhibits GluA1 and GluA2, but is virtually ineffective on the GluA3 and GluA4 AMPA receptor subunits, we hypothesize that the "M" site(s) on GluA1 and GluA2 to which Talampanel binds is different from that on GluA3 and GluA4. If the molecular properties of the AMPA receptors and Talampanel are used for selecting an inhibitor as a single drug candidate for controlling the activity of all AMPA receptors in vivo, Talampanel is not ideal. Our results further suggest that addition of longer acyl groups to the N-3 position should produce more potent 2,3-benzodiazepine inhibitors for the "M" site.

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Section: ■ Results and Discussionmentioning

confidence: 69%

Mechanism of Inhibition of the GluA2 AMPA Receptor Channel Opening by Talampanel and Its Enantiomer: The Stereochemistry of the 4-Methyl Group on the Diazepine Ring of 2,3-Benzodiazepine Derivatives

Wang

Niu

2013

ACS Chem. Neurosci.

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“…Cartridges were prepared by coating 10 mg gold particles (1 m; BioRad) with 10 g endotoxin-free plasmid encoding enhanced green fluorescent protein (pEGFP-N1; Clontech, Heidelberg, Germany) as reporter alone, or in combination with 10 g pcDNA3.0 plasmid encoding one of the following AMPAR variants: GluA1(Q)-flip, GluA1(Q)-flop, the dominant-negative mutant GluA1(R)-flip (Pei et al, 2009)…”

Section: Expression Plasmids and Biolistic Transfectionmentioning

confidence: 99%

“…AMPAR flip subunitcontaining receptors are more efficiently activated by glutamate and they desensitize with slower kinetics (Mosbacher et al, 1994;Sommer et al, 1990). GluA3(Q)-flip receptors, for example, recover more quickly from desensitization and display 4-fold longer channel open times than GluA3(Q)-flop (Pei et al, 2007;Pei et al, 2009).…”

Section: The Importance Of Flip and (Q) Variantsmentioning

confidence: 99%

Cell class-specific regulation of neocortical dendrite and spine growth by AMPA receptor splice and editing variants

et al. 2011

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SUMMARYGlutamatergic transmission converging on calcium signaling plays a key role in dendritic differentiation. In early development, AMPA receptor (AMPAR) transcripts are extensively spliced and edited to generate subunits that differ in their biophysical properties. Whether these subunits have specific roles in the context of structural differentiation is unclear. We have investigated the role of nine GluA variants and revealed a correlation between the expression of flip variants and the period of major dendritic growth. In interneurons, only GluA1(Q)-flip increased dendritic length and branching. In pyramidal cells, GluA2(Q)-flop, GluA2(Q)-flip, GluA3(Q)-flip and calcium-impermeable GluA2(R)-flip promoted dendritic growth, suggesting that flip variants with slower desensitization kinetics are more important than receptors with elevated calcium permeability. Imaging revealed significantly higher calcium signals in pyramidal cells transfected with GluA2(R)-flip as compared with GluA2(R)-flop, suggesting a contribution of voltage-activated calcium channels. Indeed, dendritic growth induced by GluA2(R)-flip in pyramidal cells was prevented by blocking NMDA receptors (NMDARs) or voltage-gated calcium channels (VGCCs), suggesting that they act downstream of AMPARs. Intriguingly, the action of GluA1(Q)-flip in interneurons was also dependent on NMDARs and VGCCs. Cell class-specific effects were not observed for spine formation, as GluA2(Q)-flip and GluA2(Q)-flop increased spine density in pyramidal cells as well as in interneurons. The results suggest that AMPAR variants expressed early in development are important determinants for activity-dependent dendritic growth in a cell type-specific and cell compartment-specific manner.

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“…Alternative splicing of GluA1-4 generates 2 different variants of each subunit (flip or flop), forming AMPA receptors with distinct kinetic properties. [7][8][9] In addition, AMPA and KA receptor transcripts can be modified by RNA editing. 10 The most frequent RNA editing process in eukaryotes involves conversion of adenosine to inosine catalyzed by the adenosine deaminases acting on RNA (ADAR) enzymes.…”

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

Ionotropic glutamate receptor mRNA editing in the prefrontal cortex: no alterations in schizophrenia or bipolar disorder

Lyddon

Navarrett²,

Dracheva³

2012

jpn

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IntroductionGlutamate is the main neurotransmitter responsible for excitatory neurotransmission throughout the brain. Glutamate serves as a ligand for G-protein coupled metabotropic and ionotropic (iGluRs) receptors. The latter consists of N-methyl-D-aspartate, α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) and kainate (KA) subtypes. Glutamate dysfunction has been linked to numerous diseases, including schizophrenia, bipolar disorder and major depressive disorder. 1-6The AMPA and KA receptors are ligand-gated nonselective cation channels that mediate fast excitatory neurotransmission. Each receptor is a tetramer composed of a combination of subunits encoded by separate genes, GluA1-4 for AMPA, and GluK1-3 and KA1-2 for KA receptors. Individual subunit transcripts undergo posttranscriptional modifications that substantially alter the structure and function of the resulting receptors. Alternative splicing of GluA1-4 generates 2 different variants of each subunit (flip or flop), forming AMPA receptors with distinct kinetic properties. [7][8][9] In addition, AMPA and KA receptor transcripts can be modified by RNA editing. 10The most frequent RNA editing process in eukaryotes involves conversion of adenosine to inosine catalyzed by the adenosine deaminases acting on RNA (ADAR) enzymes.11 As inosine is interpreted as a guanosine during splicing and translation, the editing event can result in recoding. A total of Background: Dysfunction of glutamate neurotransmission has been implicated in the pathology of schizophrenia and bipolar disorder, and one mechanism by which glutamate signalling can be altered is through RNA editing of ionotropic glutamate receptors (iGluRs). The objectives of the present study were to evaluate the editing status of iGluRs in the human prefrontal cortex, determine whether iGluR editing is associated with psychiatric disease or suicide and evaluate a potential association between editing and alternative splicing in the α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) iGluR subunits' pre-mRNA. Methods: We studied specimens derived from patients with antemortem diagnoses of bipolar disorder (n = 31) or schizophrenia (n = 34) who died by suicide or other causes, and from psychiatrically healthy controls (n = 34) who died from causes other than suicide. The RNA editing at all 8 editing sites within AMPA (GluA2-4 subunits) and kainate (GluK1-2 subunits) iGluRs was analyzed using a novel real-time quantitative polymerase chain reaction assay. Results: No differences in editing were detected among schizophrenia, bipolar or control groups or between suicide completers and patients who died from causes other than suicide. The editing efficiency was significantly higher in the flop than in the flip splicoforms of GluA3-4 AMPA subunits (all p < 0.001). Limitations: The study is limited by the near absence of specimens from medicationnaive psychiatric patients and considerable variation in medication regimens among individuals, both of which introduce considerable uncertainty into the ana...

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Flip and Flop: A Molecular Determinant for AMPA Receptor Channel Opening

Cited by 51 publications

References 57 publications

Mechanism of Inhibition of the GluA2 AMPA Receptor Channel Opening by Talampanel and Its Enantiomer: The Stereochemistry of the 4-Methyl Group on the Diazepine Ring of 2,3-Benzodiazepine Derivatives

Mechanism of Inhibition of the GluA2 AMPA Receptor Channel Opening by Talampanel and Its Enantiomer: The Stereochemistry of the 4-Methyl Group on the Diazepine Ring of 2,3-Benzodiazepine Derivatives

Cell class-specific regulation of neocortical dendrite and spine growth by AMPA receptor splice and editing variants

Ionotropic glutamate receptor mRNA editing in the prefrontal cortex: no alterations in schizophrenia or bipolar disorder

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