# G Protein-Coupled Receptor Regulation in Airway Myocytes

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2024 · $572,142

## Abstract

Summary
 The beta-2-adrenoceptor (2AR) is the most studied and best understood member of the G protein-coupled
receptor superfamily. And for good reason: it plays an important role in the regulating the function of numerous
cells types, and is the therapeutic target in the management of various diseases, including asthma. Indeed, the
last several decades have produced intensive research into how the 2AR is activated, and how it is regulated,
resulting in the development of new drugs, the majority being 2AR agonists with improved efficacy, duration of
action, and safety. Underlying these efforts have been basic science discoveries into how 2ARs are regulated,
with much of the research focused on discovering modes of receptor desensitization mediated by post-
translational modifications of the receptor. During the 25 years of HL05806, we have focused on establishing
mechanisms by which the 2AR is regulated in airway cells and in the context of lung and asthma biology, to
significantly advance our understanding of asthma pathobiology and the needs of asthma drug development.
 In this cycle of HL058506, we will explore a fascinating new mode of GPCR regulation recently discovered
to apply to 3 adrenoceptor (3AR) signaling and function in adipocytes by our co-I Tim McKinsey. In Bagchi et
al. (PNAS 2022), the McKinsey lab discovered that HDAC11 functions to de-myristoylate lysine residues on the
A kinase anchoring protein (AKAP) gravin, which localizes the 3AR to plasma membrane lipid rafts, enabling
effective coupling with transmembrane signaling partners important for signaling and protective thermogenic
gene expression. New data generated herein by the Penn and McKinsey labs suggest a similar regulation of the
2AR in airway smooth muscle (ASM) exists, prompting us to pursue a comprehensive mechanistic analysis of
this novel mode of GPCR regulation by testing the hypothesis that inhibitory targeting of HDAC11
demyristoylation of gravin augments 2AR, and possibly EP receptor, signaling in ASM by preferentially
distributing receptors to plasma membrane signaling-competent domains, resulting in increased capacity of
these receptors to regulate ASM functions. The proposal is heavily weighted in basic science
biological/biochemical/imaging approaches to understand the mechanisms underlying HDAC11
regulation of ASM GPCRs, recognizing the importance of this foundation for understanding the ultimate
physiological and clinical significance of this phenomenon. In Aim 1 we will establish mechanisms of
HDAC11 regulation of gravin in HASM using molecular, genetic, and pharmacological strategies in ASM cultures.
In Aim 2 we will employ both heterologous expression systems as well as primary HASM cells to establish how
HDAC11 regulation of gravin regulates Gs-coupled GPCRs in ASM through regulation of receptor localization,
signaling, desensitization, and resensitization. In Aim 3 we will establish how HDAC11/gravin -dependent
regulation of GPCR signaling...

## Key facts

- **NIH application ID:** 10882413
- **Project number:** 2R01HL058506-25
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** RAYMOND B. PENN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $572,142
- **Award type:** 2
- **Project period:** 1997-08-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10882413

## Citation

> US National Institutes of Health, RePORTER application 10882413, G Protein-Coupled Receptor Regulation in Airway Myocytes (2R01HL058506-25). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10882413. Licensed CC0.

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