# Molecular Regulation of cardiac adrenergic signaling

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2021 · $435,425

## Abstract

Summary
β adrenergic receptors (βARs) are critical for cardiac function and are linked to HF. Chronic β1AR-cAMP
signaling promotes activation of CaMKII, which is requisite for all the detrimental effects during maladaptive
remodeling in heart. However, the mechanism governing this specific signaling regulation by β1AR in HF
development is still incompletely understood. We aim to reveal a novel supercomplex of cardiac beta1
adrenergic receptor that is orchestrated by scaffold protein SAP97 and connects to L-type calcium channel
directly. Moreover, SAP97 also scaffold AKAP79/PKA and PDE4D8 in the complex to ensure rapid and
robust regulation of L-type calcium channel in local vicinity, which is essential to maintain rhythmic beat-to-
to-beat cardiac contraction during stress response. We aim to gain insight of regulation of this sophisticated
beta1 adrenergic receptor supercomplex in spatially differentiated cardiac myocytes and explore the
dissemble and dysfunction of this complex in disease development via promoting cytotoxicity in heart. We
hypothesize that GRK5 acts as a molecular switch to turn on Epac-dependent activation of CaMKII. We
have generated mice to simulate dissociation of the b1AR-SAP97 complex and to study SAP97-dependent
b1AR signaling in physiology and diseases. This study will provide new insight governing the specific b1AR
signaling involved in physiology an in HF, and offer GRK5 as a complementary therapeutic target for HF.
The hypothesis will be examined in the following aims: Aim 1. A SAP97 complex facilitates PKA-dependent
regulation of EC coupling. Aim 2. Disruption of b1AR-SAP97 interaction promotes b1AR-induced CaMKII
activity. Aim 3. GRK5 phosphorylation of b1AR at S475 controls the binding of b1AR to SAP97 to gate
cardiotoxic CaMKII in HF.

## Key facts

- **NIH application ID:** 10155584
- **Project number:** 5R01HL147263-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** YANG Kevin XIANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $435,425
- **Award type:** 5
- **Project period:** 2019-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10155584

## Citation

> US National Institutes of Health, RePORTER application 10155584, Molecular Regulation of cardiac adrenergic signaling (5R01HL147263-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10155584. Licensed CC0.

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