# Molecular Mechanisms, Modulation, and Synaptic Organization of Kainate Receptors

> **NIH NIH R35** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $423,750

## Abstract

Molecular Mechanisms, Modulation, and Synaptic Organization of Kainate Receptors
 Kainate receptors (KARs) are members of the ionotropic glutamate receptor (iGluR) family of cation
channels, which also includes AMPA and NMDA receptors. They localize to synapses where they respond to L-
glutamate (L-Glu) which is the most abundant excitatory neurotransmitter in the brain. KARs serve a canonical
role in synaptic depolarization, and non-canonical roles in modulating L-Glu and GABA release and synapse
maturation. They are involved in pain perception, epilepsy and mood disorders which has made them
important drug targets. Unfortunately, our understanding of KAR molecular mechanisms is limited without
structures for the most abundant KAR complexes in the brain. My research program aims to address
this gap by developing molecular mechanisms for KAR gating, modulation, and organization.
 KARs assemble as tetramers from a pool of five subunits (GluK1-5). After assembly and positioning at
the synapse, they respond to synaptic L-Glu by opening their ion channel and, under the sustained presence of
L-Glu, desensitize within milliseconds to close their channel. A goal of my lab is to understand how KAR
subunits are organized in the receptor, and how the subunits coordinate together to control the ion channel.
My recent cryo-electron microscopy (cryo-EM) work revealed the surprising organization, symmetries, and
domain interfaces of homo-tetrameric GluK2 (Meyerson et al. 2014 Nature; Meyerson et al. 2016 Nature).
However, these results are of limited physiological value because native KARs in the brain are hetero-tetramers
composed of GluK2 and GluK5 subunits. The GluK2/K5 hetero-tetramer has strict assembly rules and unique
kinetic properties which underpin KAR physiology, but little is known of its subunit organization, or activation
and desensitization mechanisms. Our preliminary data show successful expression, purification, and initial
structure determination of the GluK2/K5 heteromer to 3.7 Å resolution with cryo-EM. In research Area 1
we aim to determine how GluK2/K5 organizes and functions by using a combination of single
molecule fluorescence, electrophysiology, and cryo-EM.
 KARs do not function in isolation. Synaptic KAR complexes incorporate transmembrane Neto2
auxiliary proteins which shapes their characteristic kinetic profile. KARs also attach to C1ql2 proteins which
are required for proper receptor localization. Understanding how KARs interact with these proteins is essential
to bridging the gap between molecular mechanism and synapse biology and is a major research goal. Towards
this end we have developed new biochemical preparations which enable detailed mechanistic interrogation on
these systems. In Area 2 we will determine how KARs interact with and are modulated by C1ql2
and Neto2. I hypothesize that our work in research Areas 1 and 2 will give important insights into KAR
physiology.

## Key facts

- **NIH application ID:** 10417222
- **Project number:** 5R35GM142662-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Joshua Levitz
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $423,750
- **Award type:** 5
- **Project period:** 2021-06-03 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10417222

## Citation

> US National Institutes of Health, RePORTER application 10417222, Molecular Mechanisms, Modulation, and Synaptic Organization of Kainate Receptors (5R35GM142662-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10417222. Licensed CC0.

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