# Genetic analysis to determine the functional role of GRID1

> **NIH NIH R03** · EMORY UNIVERSITY · 2021 · $156,000

## Abstract

Summary
 The glutamate receptor gene family encodes AMPA, kainate, and NMDA receptors, which mediate
excitatory synaptic transmission in the central nervous system. Two additional gene family members, GRID1
and GRID2, encode the enigmatic delta receptor GluD1 and GluD2 subunits, which can bind D-serine but do
not appear to activate conventional signaling systems. There are four functional effects known for delta
receptors: (1) Both delta receptors (GluD1 and GluD2) are activated when certain mutations occur in the
transmembrane helices, which convert a non-gating receptor into a channel that is constitutively open,
producing a tonic inward current. In addition, chimeric receptors in which the glutamate binding domain
from a kainate or AMPA receptor replaces the analogous D-serine binding domain for GluD1 and GluD2 can
be activated by glutamate, suggesting that the highly specialized machinery needed to convert agonist binding
into pore opening is conserved in delta GluD1 receptors. (2) The binding of D-serine to GluD1 receptors
harboring a TM3 mutation that renders them constitutively active can close the channel, raising that possibility
that D-serine binding produces meaningful conformational changes with unknown physiological roles in WT
receptors. (3) Ca2+ binding to a site at the dimer interface between two adjacent D-serine binding domains
potentiates constitutive current in mutant receptors, suggesting Ca2+ could regulate GluD1 conformation and
function. (4) The distal extracellular domain serves as a ligand for presynaptic Cbln2 and neurexin, which can
alter synapse formation. Whereas Cbln2 and neurexin binding to GluD1 appears to be critical, it remains
unclear whether channel gating, D-serine binding, or Ca2+ regulation of GluD1 play important roles in brain.
 A unique power of population genetics is that it can identify key functions of a protein in an unbiased
manner. GRID1 is one of the least tolerant genes in the body, falling in the top 2 percentile for lacking
variation, suggesting it plays essential roles. Consistent with this idea, patients with neurological conditions
have been identified with missense variants in GRID1 that are absent in the general population. We will
evaluate the effects of disease-associated variants in addition to well-tolerated variants commonly observed in
the healthy population on three modalities associated with GRID1 function—constitutive activation, D-serine
binding, Ca2+ binding. If any of these functional attributes are important, then we expect to find disease-
associated variants that perturb them, while variants present in the standing population should be without
effect. Three electrophysiological experiments will answer the following questions:
Aim 1: Can missense variants produce active ion channels that are involved in neuropathology?
Aim 2: Do missense variants alter the actions of D-serine and Ca2+ on constitutively active channels?
Aim 3: Do missense variants alter the actions of glutamat...

## Key facts

- **NIH application ID:** 10217304
- **Project number:** 1R03TR003380-01A1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Stephen F Traynelis
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $156,000
- **Award type:** 1
- **Project period:** 2021-04-05 → 2022-04-04

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10217304

## Citation

> US National Institutes of Health, RePORTER application 10217304, Genetic analysis to determine the functional role of GRID1 (1R03TR003380-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10217304. Licensed CC0.

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