# A novel molecular determinant of the cardiac beta1-adrenergic receptor response

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $584,907

## Abstract

PROJECT SUMMARY/ABSTRACT
β1-adrenergic receptors (β1ARs) are the principle mediators of catecholamine actions in cardiomyocytes.
β1ARs rapidly adjust cardiac output by activating a Gs-adenylyl cyclase pathway that increases cAMP,
activates protein kinase A, and phosphorylates substrates involved in excitation-contraction coupling.
However, chronic β1AR activation in the setting of heart failure leads to a spectrum of changes that contribute
to adverse cardiac remodeling. This has been attributed to β1AR activation of signaling pathways that induce
cell death. While β1ARs also activate signaling pathway that promote cell survival, this is not sufficient to afford
cardioprotection in the setting of heart failure. The notion that β1AR might contain specific molecular
determinants that influence their signaling phenotype in cardiomyocytes (and influence the balance of signaling
between pro-apoptotic vs. anti-apoptotic pathways) has never been considered. This application implicates the
β1AR extracellular N-terminus (which typically is dismissed as playing a negligible role in receptor
activation/regulation mechanisms) as a heretofore-unrecognized structural determinant of β1AR activation. We
show that the β1AR N-terminus is a target for O-glycosylation at two specific sites (S37/S41) adjacent to an N-
terminal cleavage site, that O-glycosylation at these sites prevents β1AR N-terminal cleavage, and that
cleavage influences β1AR signaling bias to cAMP/PKA vs. ERK pathways in cardiomyocytes. Studies in aim #1
of the application will take advantage of mutagenesis approaches (generating O-glycosylation-defective,
truncated, and cleavage-resistant forms of the β1AR) and a range of state-of-the-art cell-based approaches in
cardiomyocytes (including studies with fluorescent sensors) to define the molecular basis for the altered
signaling properties of O-glycosylation-defective/truncated β1ARs in cardiomyocytes. The studies will focus on
whether the N-terminus exerts its function as an inherent modifier of the β1AR structure itself or whether the
altered signaling phenotype of N-terminally truncated β1ARs is due to changes in its subcellular
trafficking/compartmentation pattern and/or coupling to signaling partners and downstream effectors. Aim #2
will use mouse models engineered to express mutant glycosylation defective/truncated or cleavage-resistant
β1ARs in place of the WT-β1AR, to determine the role of β1AR N-terminal processing as regulator of cardiac
function and catecholamine responsiveness. The overarching goal of these studies is to examine the role of
the N-terminus as a novel structural determinant of the β1AR that influences signaling to the proarrhythmic
cAMP/PKA pathway, contributes to the pathologic cardiac remodeling, and can be pharmacologically targeted
to prevent or mitigate the evolution of catecholamine-induced pathologic cardiac remodeling during heart
failure.

## Key facts

- **NIH application ID:** 9869034
- **Project number:** 5R01HL138468-03
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Susan F Steinberg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $584,907
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9869034

## Citation

> US National Institutes of Health, RePORTER application 9869034, A novel molecular determinant of the cardiac beta1-adrenergic receptor response (5R01HL138468-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9869034. Licensed CC0.

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