# Structure and Function of AMPA subtype ionotropic glutamate receptors

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $501,283

## Abstract

AMPA receptors mediate fast excitatory neurotransmission, contribute to high cognitive processes such as
learning and memory and are implicated in numerous psychiatric and neurodegenerative diseases. In
particular, AMPA receptors play a key role in epileptogenesis and seizure spread and, thus, have recently
emerged as one of the most promising targets for epilepsy therapy. However, development of drugs targeting
AMPA receptors has been stalled because of the lack of knowledge about AMPA receptor structure and
function. For example, only structures of homotetrameric intact AMPA receptors have been determined, while
the overwhelming majority of AMPA receptors in the central nervous system are heterotetramers. A number of
noncompetitive inhibitors and ion channel blockers have been identified as promising candidates for drug
development but structural mechanisms of their action on AMPA receptors remain largely unexplored. This
missing information is absolutely critical for the future structure-based rational drug design. We plan to study
structure and function of AMPA receptors using a combination of biophysical and biochemical approaches,
including modern crystallographic and cryo-electron microscopy (cryo-EM) techniques, fluorescence-based
methods, electrophysiology, kinetic and molecular modeling. Our specific aims are to (1) obtain structures of
heteromeric AMPA receptors, (2) establish the molecular mechanism of noncompetitive inhibition, and (3) build
a structural model of ion channel block. To reach our goals, we will optimize AMPA receptor constructs for
crystallization and cryo-EM experiments, develop protocols of their expression and purification and solve
structures of heterotetrameric AMPA receptors and AMPA receptors in complex with noncompetitive inhibitors
and ion channel blockers. To improve our structural models, we will use new methods of structural refinement
combined with molecular dynamics (MD) simulations. We will also test our models using a combination of
experimental and in silico mutagenesis, whole-cell patch-clamp recordings and MD simulations. To understand
the molecular mechanisms of AMPA receptor heteromeric assembly, noncompetitive inhibition and ion channel
block, we will perform extensive MD simulations of homo- and heteromeric AMPA receptors in different
activation states and in the presence or absence of noncompetitive inhibitors and ion channel blockers. We will
combine the results of structural, computational, functional and mutagenesis experiments to propose molecular
models of AMPA receptor heteromeric assembly, noncompetitive inhibition and ion channel block. Reaching
our research goals will provide molecular level knowledge essential to greatly facilitate design of new
molecules that will have a potential to become safe and more efficacious drugs to treat epilepsy and other
disorders related to excitatory neurotransmission.

## Key facts

- **NIH application ID:** 10197227
- **Project number:** 5R01NS083660-09
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** MARIA G KURNIKOVA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $501,283
- **Award type:** 5
- **Project period:** 2013-09-30 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10197227

## Citation

> US National Institutes of Health, RePORTER application 10197227, Structure and Function of AMPA subtype ionotropic glutamate receptors (5R01NS083660-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10197227. Licensed CC0.

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