# Imaging G protein-coupled receptor macromolecular complexeswith the Keyence VHX-7000

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2020 · $160,000

## Abstract

α1D-adrenergic receptors (ARs) are essential G protein-coupled receptors (GPCRs) of the sympathetic nervous
system, and are a promising therapeutic target for an array of diseases. In the central nervous system, the α1D-
AR tightly regulates stimulus-induced locomotor activity, and is 1 of 13 hypermethylated genes associated with
decreased brain volume in schizophrenic patients. The α1D-AR is critical for blood pressure regulation and
stenosis of damaged blood vessels; and negatively impacts urine flow by contracting the prostate in patients
suffering from benign prostatic hypertrophy (BPH). Thus, α1-AR antagonists (“α-blockers”) are often used to
treat hypertension, urinary incontinence, and most recently with promising success, to prevent reoccurring
nightmares in combat veterans afflicted with Post-Traumatic Stress Disorder. Unfortunately, major toxicities
can often occur in patients taking α-blockers. During the ALLHAT trial, α-blocker therapy was discontinued due
to increased patient morbidity. Accordingly, a clearer picture of how the α1D-AR engages with its cellular
environment will provide critical insights towards the further development of small molecule α1D-AR modulators
beneficial for the treatment of PTSD, BPH, and cardiovascular disease. Surprisingly, our basic knowledge of
α1D-AR biochemical processes is lacking within human contexts, primarily because no human cell lines have
been identified that express endogenous α1D-ARs. Without adequate cell culture models and human model cell
systems to examine their discrete biochemical interactions, it will continue to be challenging to develop new
small molecules targeting α1D-ARs and to understand their essential molecular and cellular functions. We have
made significant progress towards solving some of these mysteries. First, we discovered that α1D-ARs interact
with multiple PSD95/DLG1/Zo-1 (PDZ) domain-containing proteins. Second, we found these interactions are
essential for α1D-ARs to be expressed as functional receptors at the plasma membrane. Remarkably, we found
that α1D-ARs interact with two PDZ-proteins, syntrophin and scribble, in all human cell lines we examined. This
novel discovery provides an opportunity to develop small molecule allosteric ligands targeting α1D-AR:PDZ-
protein interaction-interfaces. However, this first requires a thorough characterization of α1D-AR:PDZ-protein
architecture and function. The initial aims we that were proposed were the following:
Aim 1: Determine whether scribble organizes α1D-ARs into signaling clusters.
Aim 2: Identify α1D-AR:PDZ-protein complex(es) in human cells.

## Key facts

- **NIH application ID:** 10132165
- **Project number:** 3R01GM100893-09S1
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Chris S Hague
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $160,000
- **Award type:** 3
- **Project period:** 2012-06-07 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10132165

## Citation

> US National Institutes of Health, RePORTER application 10132165, Imaging G protein-coupled receptor macromolecular complexeswith the Keyence VHX-7000 (3R01GM100893-09S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10132165. Licensed CC0.

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