# Mechanism of functional modulation of glutamate receptors by their auxiliary subunits

> **NIH NIH R56** · VANDERBILT UNIVERSITY · 2020 · $383,008

## Abstract

The AMPA type ionotropic glutamate receptors (AMPARs), a ligand gated ion channel activated by the neuro-
transmitter glutamate, mediate the majority of excitatory neurotransmission in the brain. The signals trans-
duced by these complexes are critical for synaptic plasticity, learning and memory. AMPAR auxiliary subunits
regulate trafficking and gating modulation of AMPARs. In this proposal we will investigate the mechanism of
AMPAR regulation by their auxiliary subunits. The two major AMPAR auxiliary subunits, in the hippocampus,
cortex, and striatum, are TARPs and cornichons (CNIHs). The TARPs are extensively studied and therapeutic
compounds to alleviate seizure are already available to target γ-8 TARP, a hippocampus enriched TARP. On
the other hand, our understanding on CNIHs is limited. Within the CNIH family, CNIH2/3 is known to function
as AMPAR auxiliary subunits. In humans, the N-terminus of CNIH2 that forms the interaction interface with
AMPAR is intolerant to missense mutations, indicating an essential role of CNIH2-AMPAR interaction in hu-
mans. Our hypothesis is that CNIHs play fundamental roles in regulating AMPAR gating during synaptic
transmission and plasticity. To further establish this hypothesis, we will study the functional mechanism of
complexes made of GluA2 subunit of AMPAR and CNIH3 as a model. Our lab has recently solved the cryo-EM
structure of GluA2/CNIH3 complex in GluA2:CNIH3=4:4 stoichiometry at high resolution. In Aim 1 we hypothe-
size that the GluA2/CNIH3 complex could exists in other stoichiometry, and propose to reveal the architecture
of complex in GluA2:CNIH3=4:2 stoichiometry using cryo-EM. CNIH1 is currently not categorized as AMPAR
auxiliary subunit. However the cryo-EM structure of the GluA2/CNIH3 complex tells us that CNIH1 possess
AMPAR binding motif that is present in CNIH2/3. The cryo-EM structure also revealed the presence of lipids
surrounding the complex. We hypothesize that these lipids may play important functional roles in AMPAR gat-
ing modulation. In Aim2 we will test roles of CNIH1 and lipids in gating modulation of AMPAR. Finally, we hy-
pothesize that revealing the allosteric gating modulation mechanism of CNIH3 would require obtaining snap-
shots of lipid embedded GluA2/CNIH3 complex in channel closed, open, and desensitized states. In Aim 3, we
propose to solve high resolution cryo-EM structures of GluA2/CNIH3 complex embedded in a lipid bilayer mi-
metic environment, and compare them in different functional states. The role of auxiliary subunits in tuning ion
channel gating kinetics is predicted to have significant impact on circuit dynamics. In summary, the outcomes
of this study are expected to advance our mechanistic understanding of AMPAR function and assist developing
new therapeutic compounds that can alleviate dysregulation of AMPARs seen in neurological and psychiatric
disorders, such as Alzheimer's disease, stroke, autism, Rasmussen's and limbic encephalitis, and seizure.

## Key facts

- **NIH application ID:** 10176871
- **Project number:** 1R56MH123474-01
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Terunaga Nakagawa
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $383,008
- **Award type:** 1
- **Project period:** 2020-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10176871

## Citation

> US National Institutes of Health, RePORTER application 10176871, Mechanism of functional modulation of glutamate receptors by their auxiliary subunits (1R56MH123474-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10176871. Licensed CC0.

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