# Targeting GRK2 in the Heart

> **NIH NIH R01** · DUKE UNIVERSITY · 2022 · $58,003

## Abstract

SUMMARY/ABSTRACT
Studies have shown that G protein-coupled receptor (GPCR) kinases (GRKs) can be important contributors to
cardiac homeostasis and pathology. Indeed, our laboratory has shown that GRK2 can contribute to heart failure
(HF) pathogenesis through its up-regulation after myocardial stress/injury. Canonical research has shown that
GRK2 contributes to -adrenergic receptor (AR) dysfunction in HF. Several studies have now shown that
inhibition of GRK2 can reverse HF. First, a peptide inhibitor of GRK2, the ARKct, which inhibits the G protein
(via G subunits) mediated membrane translocation of GRK2 to activated GPCRs, was used in HF rescue
studies and more recently, small molecule kinase inhibitors. Recent non-canonical research has shown that
GRK2 has non-GPCR effects that may be crucial to its HF pathology including effects due to its localization in
mitochondria. Although there is a basal pool of GRK2 within mitochondria, active translocation can occur after
oxidative stress. The latter is due to phosphorylation of GRK2 at Ser670 by MAP kinases causing GRK2 to bind
to mitochondrial chaperone Hsp90 where GRK2 can cause cell death and metabolic defects. We have recently
taken a non-biased proteomic approach to identify novel binding partners and potential substrates for GRK2 in
mitochondria and identified the ATP synthase where increased myocyte GRK2 does indeed lead to alterations
in ATP levels. The overall significance of this interaction following cardiac injury will be tested in this competitive
renewal application. Within past funding of this Award, we have developed an innovative GRK2-S670A knock-
in (KI) mouse model where GRK2 cannot translocate to mitochondria after stress including after ischemic injury
and these mice have less injury following myocardial infarction (MI). New data shows that despite smaller infarcts
after MI and improved function acutely, GRK2-S670A KI mice fail to have improved function chronically. We will
now study the consequences of this alteration in other cells of the heart to explain the role that GRK2-S670 has
in the heart's acute and chronic response to injury. Of note, the ARKct prevents both GRK2 activity against
GPCR desensitization by preventing G-binding as well as Hsp90 binding and mitochondrial translocation since
it contains S670. Thus, by utilizing a mutant ARKct-S670A, we can now determine the true role of canonical
versus non-canonical actions of GRK2 in HF pathology. Specifically, the Central Hypothesis of this competitive
renewal is that GRK2 plays a critical role in the pathogenesis of cardiac contractile and metabolic dysfunction
and HF via mechanisms beyond GPCR and AR desensitization. These mechanisms include the novel action
of this enzyme within mitochondria, which include novel binding partners and substrates. Specific Aims are: [1]
To determine the overall mechanistic involvement of canonical (GPCR) vs. non-canonical (mitochondrial) GRK2
inhibition for ARKct inhibition HF ...

## Key facts

- **NIH application ID:** 10931812
- **Project number:** 7R01HL061690-26
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Walter J. Koch
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $58,003
- **Award type:** 7
- **Project period:** 1998-09-30 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10931812

## Citation

> US National Institutes of Health, RePORTER application 10931812, Targeting GRK2 in the Heart (7R01HL061690-26). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10931812. Licensed CC0.

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