# Dysregulation of cardiac signaling in disease and stress

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2024 · $384,948

## Abstract

Project Summary
G-protein coupled receptor (GPCR) kinase-2 (GRK2) is a key regulator of GPCR recycling and desensitization
that is upregulated in several cardiac pathologies, including hypertrophy and heart failure (HF). Cardiac
ischemia-reperfusion injury induces ERK-mediated phosphorylation of GRK2 at S670, which results in the
translocation of GRK2 from the cytosol to mitochondria. We discovered that in the adult cardiomyocyte
mitochondrial GRK2 regulates glucose-mediated oxidative phosphorylation by inhibiting pyruvate
dehydrogenase, the rate limiting enzyme of glucose oxidation. Although the physiological impact of mitochondrial
GRK2 was reported, it remains largely unknown how mitochondrial GRK2 regulates cardiac mitochondrial
metabolism. This proposal focuses on deciphering mechanistically how GRK2 phosphorylation and
mitochondrial translocation regulate cardiac glucose metabolism. Additionally, we propose that mitochondrial
GRK2 participates in key metabolic signaling post-myocardial infarction (MI) by acting as an amplifier of
pyroptosis- a novel lytic cell death mechanism. Thus, we hypothesize that GRK2 phosphorylation at S670 is
paramount for cardiomyocyte responses in consequence of altering metabolic availability and cardiac injury.
Using a novel GRK-S670A and two Gasdermin E mouse models, we propose to carry out two specific aims: 1.)
Determine how mitoGRK2 regulates cardiac mitochondrial metabolism; 2.) Assess whether phosphorylation of
GRK2 at S670 modulates cardiac pyroptotic signaling. Overall, our work will shed light on the role of GRK2
phosphorylation at S670 in cardiomyocytes and how this post-translational modification regulates metabolic
signaling and chronic-injury responses. The overarching goal of this research is to exploit novel mechanistic
signaling for the development and identification of new pharmaceutical drugs for HF treatment.

## Key facts

- **NIH application ID:** 11030464
- **Project number:** 7R01HL163666-03
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Priscila Sato
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $384,948
- **Award type:** 7
- **Project period:** 2022-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11030464

## Citation

> US National Institutes of Health, RePORTER application 11030464, Dysregulation of cardiac signaling in disease and stress (7R01HL163666-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11030464. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*