# Structure and Function of native kainate-type ionotropic glutamate receptor complexes

> **NIH NIH R35** · CASE WESTERN RESERVE UNIVERSITY · 2022 · $402,500

## Abstract

PROJECT SUMMARY/ABSTRACT
Neuronal ionotropic glutamate receptors (iGluRs) play key roles in mediating excitatory synaptic transmission in
the brain and in a wide range of brain diseases, including Alzheimer’s and Huntington’s disease, schizophrenia,
epilepsy, autism spectrum, major depression, and mood disorders. Glutamatergic signaling is pivotal for synaptic
plasticity, learning, and memory formation. Kainate-type ionotropic glutamate receptors (KARs) are distributed
throughout the brain and regulate the release of neurotransmitters and mediate excitatory synaptic transmission.
KARs form homo- or hetero-tetramers composed of five homologous subunits of GluK1–5. Each subunit exhibits
unique structural, functional, and pharmacological properties and subcellular localization. Moreover, misguided
localization and dysfunction of KARs result in neuropathologies, therefore, KARs are a promising drug target.
However, KARs are the least well understood group of iGluRs, and their molecular mechanisms remain elusive.
The activities of neuronal KARs are regulated by pH, posttranslational modifications, lipid/cholesterol, and small
molecules. Additionally, KAR function and localization are further modified by their auxiliary and accessory
proteins. Thus, such brain lipids, modifications, and protein co-factors increase the diversity of KAR functional
properties. The neuropilin and tolloid-like (NETO) auxiliary proteins, NETO1 and NETO2, are auxiliary proteins
of KARs that are distantly homologous compared with auxiliary proteins associated with other iGluRs. How do
such ligands and protein co-factors determine the gating of KARs and regulate synaptic signaling? How are the
physiological brain lipid environment and posttranslational modifications contributing to receptor activities? To
answer these questions, this proposed research will employ structural and electrophysiological approaches to
develop our mechanistic understanding of the regulation of native postsynaptic GluK2/GluK5 KARs isolated from
rat brains. The program will move forward in two major directions: In one project, I will determine high-resolution
cryo-electron microscopy (cryo-EM) structures of native GluK2/GluK5 KARs in an activated state, but also in
complex with ligands to capture multiple functional states. This will elucidate the conformational alternations of
GluK2/GluK5 KARs by their ligands, which have not been well-observed in previously determined structures.
Comparing our structures with other iGluRs will uncover how physiologically relevant heteromeric KARs are
structurally and functionally distinct from other iGluR subfamilies. In a second concurrent project, we will
elucidate the regulatory mechanisms of native KARs by NETO1 and NETO2 auxiliary proteins. Overall, our
studies will provide fundamental insights into how neuronal KAR complexes are controlled by their ligands and
auxiliary proteins, and how they mediate synaptic signaling, and thus neural activities. This informati...

## Key facts

- **NIH application ID:** 10499768
- **Project number:** 1R35GM147266-01
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** NAMI TAJIMA
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $402,500
- **Award type:** 1
- **Project period:** 2022-09-05 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10499768

## Citation

> US National Institutes of Health, RePORTER application 10499768, Structure and Function of native kainate-type ionotropic glutamate receptor complexes (1R35GM147266-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10499768. Licensed CC0.

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