# Project 2 - Airway Smooth Muscle Bitter Taste Receptors as Targets for Novel Bronchodilators

> **NIH NIH P01** · RUTGERS BIOMEDICAL/HEALTH SCIENCES-RBHS · 2020 · $388,947

## Abstract

Project Summary
Bitter taste receptors (TAS2Rs) are expressed on human airway smooth muscle (HASM) and when activated
markedly relax the muscle and dilate the airway. Utilization of this pathway, which is distinct from that of β-
agonists acting at β2-adrenergic receptors (β2ARs), will provide a new class of direct bronchodilators for treating
or preventing bronchospasm in asthma. The TAS2R14 subtype is highly expressed in HASM and is a prime
target for developing a novel therapeutic agent. However, there are gaps in our knowledge about the
molecular/cellular biology and physiology of HASM TAS2Rs, including how they couple to relaxation, the
potential for tachyphylaxis due to short-term (receptor phosphorylation) and long-term (downregulation of
receptor expression) events, and the potential to bias receptor signaling towards favorable signaling for asthma
treatment. The broad, long-term objective of the Project is to improve our understanding of HASM TAS2R
biology relevant to treating airway contraction in asthma. To fill these gaps in our knowledge, in Aim 1 we will
define the mechanism by which TAS2Rs evoke relaxation, which we hypothesize is via inhibiting
phosphorylation of the actin severing protein cofilin. Studies will be performed in cultured HASM cells derived
from nonasthmatic as well as asthmatic donor lungs, the latter being important because of the potential for the
disease to modify receptor function. Studies will include siRNA-based knockouts of cofilin, and the upstream
components of the proposed pathway that link the receptor:G-protein:effector complex to cofilin. In Aim 2,
agonist-prompted phosphorylation of TAS2R14 by GRKs will be studied using whole cell phosphorylation and
receptor purification experiments. To define the precise residues phosphorylated by GRKs, TAS2R14 will be
mutated to substitute potential Ser/Thr phospho-acceptor sites with Ala, thus defining a bar-code for βarrestin
binding. The consequences of phosphorylation on βarrestin conformation and intracellular receptor
signaling, and HASM relaxation, will then be determined. In Aim 3, a panel of TAS2R14 agonists will be
utilized to determine the mechanisms by which a TAS2R agonist can be biased away from deleterious
outcomes and towards advantageous outcomes in regards to asthma therapy. This endeavor will provide the
basis for agonist-based “tuning” of the receptor to be highly efficacious in bronchodilating and inhibiting HASM
proliferation, but display little short- or long-term agonist-promoted desensitization or downregulation, such that
clinical tachyphylaxis is not apparent. All three aims will utilize parallel physiological measurements of
contraction and relaxation using nonasthmatic and asthmatic HASM cells, and an inflammatory precision-cut
human lung slice model, in order to link biochemical events to clinically relevant physiological responses.
Collectively, these studies will provide the basis for development of a novel class of direct bronchodila...

## Key facts

- **NIH application ID:** 9998005
- **Project number:** 5P01HL114471-07
- **Recipient organization:** RUTGERS BIOMEDICAL/HEALTH SCIENCES-RBHS
- **Principal Investigator:** Stephen B Liggett
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $388,947
- **Award type:** 5
- **Project period:** 2013-07-15 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9998005

## Citation

> US National Institutes of Health, RePORTER application 9998005, Project 2 - Airway Smooth Muscle Bitter Taste Receptors as Targets for Novel Bronchodilators (5P01HL114471-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9998005. Licensed CC0.

---

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