# Dopamine D2 Receptor Mutations and Hyperkinetic Movement Disorders

> **NIH VA I01** · PORTLAND VA MEDICAL CENTER · 2022 · —

## Abstract

Project Summary
Dopamine receptors are the primary therapeutic targets for a variety of neurological and psychiatric disorders,
including schizophrenia, Parkinson’s disease, and many other movement disorders. The five subtypes of
dopamine receptors (D1-D5) are members of the superfamily of G protein-coupled receptors. This proposal is
focused on the D2 receptor and, in particular, on two novel DRD2 allelic variants that are linked to hyperkinetic
movement disorders. An important distinction between the two variants is that subjects with the mutation
M374R have more severe dysfunction with an earlier onset than those with the mutation I212F. The three aims
will use a variety of approaches to compare and contrast the effects of the two mutations on D2 receptor
function. Our overall goal is to determine which changes to receptor function are pathogenic, and which are
benign or even potentially neuroprotective. D2-I212F exhibits increased constitutive activation of G proteins,
increased sensitivity to low concentrations of agonist, decreased arrestin binding, slow kinetics for regulation of
potassium channels, and inefficient expression. We will determine if the more severe clinical outcome caused
by the M374R mutation is explained by qualitatively similar changes that differ only in magnitude, or if there are
qualitative differences with I212F. In Aim 1 we will assess arrestin binding and G protein activation by the two
novel variants, expanding our characterization to all D2 receptor-activated Gα subtypes and exploring the role
of receptor phosphorylation. In Aim 2 we will carry out in silico studies of receptor activation. In Aim 3 we will
create a knock-in mouse model of heterozygous expression of D2-M374R. We will evaluate the functional
properties of D2-M374R in midbrain dopamine neurons by slice electrophysiology, using first viral expression
of D2-M374R, and then the knock-in mice as they become available. We will also evaluate gait abnormalities in
the knock-in mice, and quantify D2 receptor expression in midbrain and neostriatum. The aims proposed here
will quantify the effect of these novel polymorphisms on the function and expression of the D2 receptor in cells
and in mouse brain and should provide a biological explanation for manifestation of neurological dysfunction in
humans with these variants.

## Key facts

- **NIH application ID:** 10486365
- **Project number:** 1I01BX005986-01
- **Recipient organization:** PORTLAND VA MEDICAL CENTER
- **Principal Investigator:** KIM Arthur NEVE
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2022-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10486365

## Citation

> US National Institutes of Health, RePORTER application 10486365, Dopamine D2 Receptor Mutations and Hyperkinetic Movement Disorders (1I01BX005986-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10486365. Licensed CC0.

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