# Regulation of sGC vascular function by the Activator of G-protein Signaling 3

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2020 · $383,698

## Abstract

Soluble guanylyl cyclase (sGC) is a highly sensitive nitric oxide (NO) receptor, which plays a key role in
neurotransmission, platelet and vascular function. Because diminished sGC function promotes coronary
artery disease, atherosclerosis, hypertension, heart attacks and vascular disorders, maintaining proper
function of sGC is an important public health issue. Understanding the mechanisms of sGC function and
regulation is essential for improving existing and developing new sGC-based therapies. While NO-dependent
activation of sGC has been extensively investigated, the process of sGC deactivation is poorly understood.
Fast deactivation is essential to properly time sGC cell signaling, but may be disadvantageous for sustaining
activated sGC for therapeutic purposes. Although published reports indicate that some proteins involved in
protein maturation and folding affect the activity of intracellular sGC 9-12, these effects are most likely not
specific to sGC. We have recently identified G-protein signaling modulator proteins GPSM1 and GPSM2 as a
new type of sGC modulators, which associate with sGC and attenuate its activation. Our preliminary studies
show a predominant expression of GPSM1 in mouse aorta and demonstrate that mice lacking GPSM1 have
increased sGC activity in aorta and a longer response to sGC activators.
 Our long-term goal is to determine how regulation of sGC can be manipulated for therapeutic purposes.
Based on preliminary studies, our central hypothesis is that GPSM1 protein is a critical factor that modulates
sGC function in normal and disease vascular smooth muscles (VSMC) and mediates the crosstalk between
NO/cGMP and Gαi-dependent signaling. The main objectives of the study are to identify the molecular
mechanism by which GPSM1 modulate sGC, to characterize the effects of this modulation in animal models,
and to determine how sGC-GPSM1 communication affects Gαi-dependent signaling in VSMC. We will test
this hypothesis by: a) determining the changes in sGC-dependent vascular function in GPSM1-/- mice; b)
establishing the fundamental step(s) in negative modulation of sGC by GPSM1, and c) elucidating the effect
of GPSM1 on communication between sGC- and Gαi-dependent signaling pathways in VSMC.
 This study is significant because it addresses the regulation of sGC, and enzyme whose function play an
important role in health and disease processes. The proposal is innovative because it establishes the basis
for the rational design of new pharmacological therapies that directly target the contact between sGC and
GPSM1 and augment the efficacy of existing sGC-based therapies.

## Key facts

- **NIH application ID:** 9848628
- **Project number:** 5R01HL139838-03
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Emil Martin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $383,698
- **Award type:** 5
- **Project period:** 2017-12-15 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9848628

## Citation

> US National Institutes of Health, RePORTER application 9848628, Regulation of sGC vascular function by the Activator of G-protein Signaling 3 (5R01HL139838-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9848628. Licensed CC0.

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