Mechanisms of Channel Block in Calcium-Permeable AMPA Receptors
Open accessAbstract
AMPA receptors mediate fast excitatory neurotransmission and are critical for CNS development and function. Calcium-permeable subsets of AMPA receptors are strongly implicated in acute and chronic neurological disorders. However, despite the clinical importance, the therapeutic landscape for specifically targeting them, and not the calcium-impermeable AMPA receptors, remains largely undeveloped. To address this problem, we used cryo-electron microscopy and electrophysiology to investigate the mechanisms by which small-molecule blockers selectively inhibit ion channel conductance in calcium-permeable AMPA receptors. We determined the structures of calcium-permeable GluA2 AMPA receptor complexes with the auxiliary subunit stargazin bound to channel blockers, including the orb weaver spider toxin AgTx-636, the spider toxin analog NASPM, and the adamantane derivative IEM-1460. Our structures provide insights into the architecture of the blocker binding site and the mechanism of trapping, which are critical for development of small molecules that specifically target calcium-permeable AMPA receptors.
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GluA2-lacking AMPARs are CP ionotropic receptors with larger single-channel conductance and can undergo voltage-dependent blockade by polyamines.
“GluA2-lacking AMPARs are CP ionotropic receptors with larger single-channel conductance and can undergo voltage-dependent blockade by polyamines (Twomey et al., 2018; Man, 2011).”
From Oxytocin neurons mediate the effect of social isolation via the VTA circuits (2022) · cites this paper as Twomey et al., 2018
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References 89 · Cited by 106
Research works printed but not linked: 2
- Bowie D, Bahring R, and Mayer ML (1999). Block of AMPA and Kainate Receptors by Polyamines and Arthropod Toxins In Ionotropic Glutamate Receptors in the CNS (Springer), pp. 251– 273.
- Nishida M, and MacKinnon R (2002). Structural basis of inward rectification: cytoplasmic pore of the G protein-gated inward rectifier GIRK1 at 1.8 A resolution. Cell 111, 957– 965. 12507423
- Authors
- Twomey, E. C., Yelshanskaya, M. V., Vassilevski, A. A., & Sobolevsky, A. I.
- Affiliations
- Columbia University (US)
- Russian Academy of Sciences (RU)
- Corresponding author
- Sobolevsky, Alexander I.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2018-09
- Volume
- 99
- Issue
- 5
- Pages
- 956-968.e4
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC6181147
- OpenAlex
- W2886834730
- Cited by
- 106
- References
- 89
- Citations by year
- 2026: 6 · 2025: 18 · 2024: 9 · 2023: 17 · 2022: 10 · 2021: 21 · 2020: 13 · 2019: 10 · 2018: 2
- FWCI
- 5.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Simons Foundation (349247)
- NYSTAR
- NIH National Institute of General Medical Sciences (GM103310)
- NIH (F31 NS093838, R01 NS083660, R01 CA206573)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Keywords
- calcium-permeable AMPA receptors, GluA2, stargazin, ion channel blockers, spider toxins, adamantane derivatives, excitatory neurotransmission
- MeSH terms
- Animals, Calcium, Humans, Spider Venoms, Protein Structure, Secondary, Protein Structure, Tertiary, Receptors, AMPA, Excitatory Amino Acid Antagonists, Rats, HEK293 Cells
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