scholarly journals The action of Con-ikot-ikot toxin on single AMPA-type glutamate receptors

2021 ◽  
Author(s):  
Jelena Baranovic ◽  
Sebastian Braunbeck ◽  
Nikolai Zaki ◽  
Sonja Minniberger ◽  
Miriam Chebli ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Glutamate Receptors ◽  
Ampa Receptor ◽  
Ampa Receptors ◽  
Single Channel ◽  
Basic Research ◽  
High Specificity ◽  
Direct Consequence ◽  
Binding Mode ◽  
Binding Domains

SummaryConotoxins are a large group of naturally occurring toxic peptides produced by the predatory sea snails of the genus Conus. Many of these toxins target ion channels, often with high specificity and affinity. As such, they have proven to be invaluable for basic research as well as acting as leads for therapeutic strategies. Con-ikot-ikot is the only conotoxin so far identified that targets AMPA-type glutamate receptors, the main mediators of excitatory neurotransmission in the vertebrate brain. Here, we describe how the toxin modifies the activity of AMPA receptors at the single-channel level. The toxin binds to the AMPA receptor with high affinity (EC50 = 5 nM) and once bound, takes minutes to wash out. As shown previously, it effectively blocks desensitization of AMPA receptors, however, compared to other desensitisation blockers, it is a poor stabiliser of the open channel because toxin-bound AMPA receptors undergo frequent, brief closures. We propose this is a direct consequence of its unique binding mode to the ligand binding domains. Unlike other blockers of desensitization, which stabilise individual dimers within an AMPA receptor tetramer, the toxin immobilizes all four ligand binding domains of the tetramer. This result further emphasises that quaternary reorganization of independent LBD dimers is essential for the full activity of AMPA receptors.

scholarly journals Noncompetitive antagonists induce cooperative AMPA receptor channel gating

2019 ◽  
Vol 151 (2) ◽  
pp. 156-173 ◽  
Author(s):  
Edward Y. Shi ◽  
Christine L. Yuan ◽  
Matthew T. Sipple ◽  
Jayasri Srinivasan ◽  
Christopher P. Ptak ◽  
...  
Keyword(s):  
Ampa Receptor ◽  
Ampa Receptors ◽  
Single Channel ◽  
Channel Gating ◽  
Binding Domains ◽  
Low Concentrations ◽  
The Central Nervous System ◽  
Presynaptic Nerve Terminals ◽  
Pore Domain ◽  
Receptor Channel

Glutamate is released from presynaptic nerve terminals in the central nervous system (CNS) and spreads excitation by binding to and activating postsynaptic iGluRs. Of the potential glutamate targets, tetrameric AMPA receptors mediate fast, transient CNS signaling. Each of the four AMPA subunits in the receptor channel complex is capable of binding glutamate at its ligand-binding domains and transmitting the energy of activation to the pore domain. Homotetrameric AMPA receptor channels open in a stepwise manner, consistent with independent activation of individual subunits, and they exhibit complex kinetic behavior that manifests as temporal shifts between four different conductance levels. Here, we investigate how two AMPA receptor-selective noncompetitive antagonists, GYKI-52466 and GYKI-53655, disrupt the intrinsic step-like gating patterns of maximally activated homotetrameric GluA3 receptors using single-channel recordings from cell-attached patches. Interactions of these 2,3-benzodiazepines with residues in the boundary between the extracellular linkers and transmembrane helical domains reorganize the gating behavior of channels. Low concentrations of modulators stabilize open and closed states to different degrees and coordinate the activation of subunits so that channels open directly from closed to higher conductance levels. Using kinetic and structural models, we provide insight into how the altered gating patterns might arise from molecular contacts within the extracellular linker-channel boundary. Our results suggest that this region may be a tunable locus for AMPA receptor channel gating.

AMPA Receptor Antagonist CFM-2 Decreases Survivin Expression in Cancer Cells

2018 ◽  
Vol 18 (4) ◽  
pp. 591-596 ◽  
Author(s):  
Domingo Sanchez Ruiz ◽  
Hella Luksch ◽  
Marco Sifringer ◽  
Achim Temme ◽  
Christian Staufner ◽  
...  
Keyword(s):  
Cell Survival ◽  
Receptor Antagonist ◽  
Cancer Cells ◽  
Glutamate Receptors ◽  
Cancer Cell ◽  
Ampa Receptor ◽  
Ampa Receptors ◽  
Survivin Expression ◽  
Ampa Receptor Antagonist ◽  
Cancer Cell Survival

Background: Glutamate receptors are widely expressed in different types of cancer cells. α-Amino-3- hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors are ionotropic glutamate receptors which are coupled to intracellular signaling pathways that influence cancer cell survival, proliferation, and migration. Blockade of AMPA receptors by pharmacologic compounds may potentially constitute an effective tool in anticancer treatment strategies. Method: Here we investigated the impact of the AMPA receptor antagonist CFM-2 on the expression of the protein survivin, which is known to promote cancer cell survival and proliferation. We show that CFM-2 inhibits survivin expression at mRNA and protein levels and decreases the viability of cancer cells. Using a stably transfected cell line which overexpresses survivin, we demonstrate that over-expression of survivin enhances cancer cell viability and attenuates CFM-2–mediated inhibition of cancer cell growth. Result: These findings point towards suppression of survivin expression as a new mechanism contributing to anticancer effects of AMPA antagonists.

scholarly journals IQSEC2-Associated Intellectual Disability and Autism

2019 ◽  
Vol 20 (12) ◽  
pp. 3038 ◽  
Author(s):  
Nina S. Levy ◽  
George K. E. Umanah ◽  
Eli J. Rogers ◽  
Reem Jada ◽  
Orit Lache ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Nmda Receptors ◽  
Glutamate Receptors ◽  
Ampa Receptor ◽  
Ampa Receptors ◽  
Neuronal Development ◽  
Catalytic Domain ◽  
Excitatory Synapses ◽  
Ampa Receptor Subunit ◽  
Ion Influx

Mutations in IQSEC2 cause intellectual disability (ID), which is often accompanied by seizures and autism. A number of studies have shown that IQSEC2 is an abundant protein in excitatory synapses and plays an important role in neuronal development as well as synaptic plasticity. Here, we review neuronal IQSEC2 signaling with emphasis on those aspects likely to be involved in autism. IQSEC2 is normally bound to N-methyl-D-aspartate (NMDA)-type glutamate receptors via post synaptic density protein 95 (PSD-95). Activation of NMDA receptors results in calcium ion influx and binding to calmodulin present on the IQSEC2 IQ domain. Calcium/calmodulin induces a conformational change in IQSEC2 leading to activation of the SEC7 catalytic domain. GTP is exchanged for GDP on ADP ribosylation factor 6 (ARF6). Activated ARF6 promotes downregulation of surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors through a c-jun N terminal kinase (JNK)-mediated pathway. NMDA receptors, AMPA receptors, and PSD-95 are all known to be adversely affected in autism. An IQSEC2 transgenic mouse carrying a constitutively active mutation (A350V) shows autistic features and reduced levels of surface AMPA receptor subunit GluA2. Sec7 activity and AMPA receptor recycling are presented as two targets, which may respond to drug treatment in IQSEC2-associated ID and autism.

Comparison of the Effects of Convulsant and Depressant Barbiturate Stereoisomers on AMPA-type Glutamate Receptors

1999 ◽  
Vol 90 (6) ◽  
pp. 1704-1713. ◽  
Author(s):  
Yoshinori Kamiya ◽  
Tomio Andoh ◽  
Ryosuke Furuya ◽  
Satoshi Hattori ◽  
Itaru Watanabe ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Glutamate Receptors ◽  
Ampa Receptor ◽  
Ampa Receptors ◽  
Dependent Manner ◽  
Induced Current ◽  
Gaba A ◽  
The Central Nervous System

Background Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors mediate fast excitatory synaptic transmission in the central nervous system. Although barbiturates have been shown to suppress the AMPA receptor-mediated responses, it is unclear whether this effect contributes to the anesthetic action of barbiturates. The authors compared the effects of depressant [R(-)] and convulsant [S(+)] stereoisomers of 1-methyl-5-phenyl-5-propyl barbituric acid (MPPB) on the AMPA and gamma-aminobutyric acid type A (GABA(A)) receptor-mediated currents to determine if the inhibitory effects on AMPA receptors correlate to the in vivo effects of the isomers. Method The authors measured whole-cell currents in the rat cultured cortical neuron at holding potential of -60 mV. Kainate 500 microM was applied as the agonist for AMPA receptors. Thiopental (3-300 microM), R(-)-MPPB or S(+)-MPPB (100-1,000 microM) was coapplied with kainate under the condition in which the GABA(A) receptor-mediated current was blocked. Effects of MPPB isomers on the current elicited by GABA 1 microM were studied in the separate experiments. Results Thiopental inhibited the kainate-induced current reversibly and in a dose-dependent manner, with a concentration for 50% inhibition of 49.3 microM. Both R(-)-MPPB and S(+)-MPPB inhibited the kainate-induced current with a little stereoselectivity. R(-)-MPPB was slightly but significantly more potent than S(+)-MPPB. In contrast, R(-)-MPPB enhanced but S(+)-MPPB reduced the GABA-induced current. Conclusions Both convulsant and depressant stereoisomers of the barbiturate inhibited the AMPA receptor-mediated current despite of their opposite effects on the central nervous system in vivo. Although thiopental exhibited a considerable inhibition of AMPA receptors, the results suggest that the inhibition of AMPA receptors contributes little to the hypnotic action of the barbiturates.

scholarly journals Architecture and subunit arrangement of native AMPA receptors elucidated by cryo-EM

Science ◽  
2019 ◽  
Vol 364 (6438) ◽  
pp. 355-362 ◽  
Author(s):  
Yan Zhao ◽  
Shanshuang Chen ◽  
Adam C. Swensen ◽  
Wei-Jun Qian ◽  
Eric Gouaux
Keyword(s):  
Molecular Structure ◽  
Electron Microscopy ◽  
Signal Transduction ◽  
Ligand Binding ◽  
Ampa Receptor ◽  
Ampa Receptors ◽  
Mammalian Brain ◽  
Receptor Complexes ◽  
Cryo Electron Microscopy ◽  
Chemical Synapses

Glutamate-gated AMPA receptors mediate the fast component of excitatory signal transduction at chemical synapses throughout all regions of the mammalian brain. AMPA receptors are tetrameric assemblies composed of four subunits, GluA1–GluA4. Despite decades of study, the subunit composition, subunit arrangement, and molecular structure of native AMPA receptors remain unknown. Here we elucidate the structures of 10 distinct native AMPA receptor complexes by single-particle cryo–electron microscopy (cryo-EM). We find that receptor subunits are arranged nonstochastically, with the GluA2 subunit preferentially occupying the B and D positions of the tetramer and with triheteromeric assemblies comprising a major population of native AMPA receptors. Cryo-EM maps define the structure for S2-M4 linkers between the ligand-binding and transmembrane domains, suggesting how neurotransmitter binding is coupled to ion channel gating.

scholarly journals NMDA and AMPA Receptor Ligand-Binding Domains Exhibit Subtype-Specific Conformational Propensities

2014 ◽  
Vol 106 (2) ◽  
pp. 29a
Author(s):  
John Belcher ◽  
Yongneng Yao ◽  
Anthony Berger ◽  
Mark L. Mayer ◽  
Albert Y. Lau
Keyword(s):  
Ligand Binding ◽  
Ampa Receptor ◽  
Receptor Ligand ◽  
Binding Domains

scholarly journals α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Channels Lacking the N-terminal Domain

2002 ◽  
Vol 277 (51) ◽  
pp. 49662-49667 ◽  
Author(s):  
Arja Pasternack ◽  
Sarah K. Coleman ◽  
Annukka Jouppila ◽  
David G. Mottershead ◽  
Maria Lindfors ◽  
...  
Keyword(s):  
Cell Surface ◽  
Ligand Binding ◽  
Ampa Receptor ◽  
Protein Interactions ◽  
Ampa Receptors ◽  
Terminal Domain ◽  
Gated Channel ◽  
Surface Ligand ◽  
Amino Acid Binding ◽  
G Protein Coupled

Ionotropic glutamate receptor (iGluR) subunits contain a ∼400-residue extracellular N-terminal domain (“X domain”), which is sequence-related to bacterial amino acid-binding proteins and to class C G-protein-coupled receptors. The X domain has been implicated in the assembly, transport to the cell surface, allosteric ligand binding, and desensitization in various members of the iGluR family, but its actual role in these events is poorly characterized. We have studied the properties of homomeric α-amino-3-hydroxy-5-methylisoxazolepropionate (AMPA)-selective GluR-D glutamate receptors carrying N-terminal deletions. Our analysis indicates that, surprisingly, transport to the cell surface, ligand binding properties, agonist-triggered channel activation, rapid desensitization, and allosteric potentiation by cyclothiazide can occur normally in the complete absence of the X domain (residues 22–402). The relatively intact ligand-gated channel function of a homomeric AMPA receptor in the absence of the X domain indirectly suggests more subtle roles for this domain in AMPA receptors,e.g.in the assembly of heteromeric receptors and in synaptic protein interactions.

scholarly journals Amyloid-β-Induced Dysregulation of AMPA Receptor Trafficking

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Sumasri Guntupalli ◽  
Jocelyn Widagdo ◽  
Victor Anggono
Keyword(s):  
Glutamate Receptors ◽  
Ampa Receptor ◽  
Ampa Receptors ◽  
Molecular Mechanisms ◽  
Metabotropic Glutamate Receptor ◽  
Amyloid Β ◽  
Neuronal Loss ◽  
Brain Regions ◽  
Receptor Trafficking ◽  
Ampa Receptor Trafficking

Evidence from neuropathological, genetic, animal model, and biochemical studies has indicated that the accumulation of amyloid-beta (Aβ) is associated with, and probably induces, profound neuronal changes in brain regions critical for memory and cognition in the development of Alzheimer’s disease (AD). There is considerable evidence that synapses are particularly vulnerable to AD, establishing synaptic dysfunction as one of the earliest events in pathogenesis, prior to neuronal loss. It is clear that excessive Aβlevels can disrupt excitatory synaptic transmission and plasticity, mainly due to dysregulation of the AMPA and NMDA glutamate receptors in the brain. Importantly, AMPA receptors are the principal glutamate receptors that mediate fast excitatory neurotransmission. This is essential for synaptic plasticity, a cellular correlate of learning and memory, which are the cognitive functions that are most disrupted in AD. Here we review recent advances in the field and provide insights into the molecular mechanisms that underlie Aβ-induced dysfunction of AMPA receptor trafficking. This review focuses primarily on NMDA receptor- and metabotropic glutamate receptor-mediated signaling. In particular, we highlight several mechanisms that underlie synaptic long-term depression as common signaling pathways that are hijacked by the neurotoxic effects of Aβ.

Sign in / Sign up

Export Citation Format

Share Document