# Dynamics of ligand gated ion channels

> **NIH NIH R35** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2020 · $602,936

## Abstract

PROJECT SUMMARY/ABSTRACT
Glutamate receptors mediate excitatory responses in the mammalian central nervous system, and ultimately
control motor and cognitive functions. Glutamate receptors are classified into three subfamilies based on
affinity profiles for several synthetic and natural agonists: N-methyl-D-aspartate (NMDA), -amino-5-methyl-3-
hydroxy-4-isoxazole propionate (AMPA) and kainate receptors. All three subtypes are broadly similar having a
dimer of dimer architecture with similar topologies. However, their gating characteristics and mechanisms are
unique resulting in unique roles in synaptic transmission. The work in my laboratory focuses on understanding
the mechanisms underlying the fine-tuning of each of these subtypes. AMPA receptors mediate fast synaptic
transmission and their gating properties are modulated by the presence of auxiliary subunits (TARPs) as well
as through post-translational modifications. Work from my laboratory has provided insight into the mechanism
of activation and desensitization in AMPA receptors using a combination of biophysical and biochemical
methods. Here, we propose to study how these mechanisms can be translated to modulation by TARPs and
post-translational modifications such as phosphorylation. For this we will use a combination of smFRET and
LRET to determine the dynamics and conformational changes, and validate these structure-dynamic changes
through functional characterization of changes elicited by biochemical manipulations of the receptor like cross
linking and mutations. The NMDA receptors, on the other hand, mediate Ca2+ permeable long depolarizing
signals and are modulated through small molecule modulators, phosphorylation and interacting partners such
as calmodulin and alpha-actinin at the intracellular carboxy terminus. smFRET and LRET investigations from
my laboratory as well as the X-ray and EM structures have provided significant insight into conformational
changes within the ordered extracellular domains. However, the communication across domains and the role
of the disordered C-terminal domain are largely unexplored. Here we propose to study the role of interactions
across domains in controlling dynamics and conformational changes in the receptor, and effects of modulators
and changes at the C-terminal domain on these interactions and conformational dynamics. These studies will
then be correlated to functional consequences thus providing insight into the structure-dynamic pathway of
activation, desensitization, and modulation in these receptors.

## Key facts

- **NIH application ID:** 9873972
- **Project number:** 5R35GM122528-04
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Vasanthi Jayaraman
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $602,936
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9873972

## Citation

> US National Institutes of Health, RePORTER application 9873972, Dynamics of ligand gated ion channels (5R35GM122528-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9873972. Licensed CC0.

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