Spatiotemporal Calcium Signaling Patterns Underlying Opposing Effects of Histamine and TAS2R Agonists in Airway Smooth Muscle

Authors

Stanley Conaway, Thomas Jefferson UniversityFollow
Joshua Richard, Thomas Jefferson UniversityFollow
Deepak A. Deshpande, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

5-28-2025

Comments

This article is the author's final published version in American Journal of Physiology - Lung Cellular and Molecular Physiology, Volume 329, Issue 1, May 2025, L70 - L83.

The published version is available at https://doi.org/10.1152/ajplung.00058.2025.

Copyright © 2025 The Authors

Abstract

Intracellular calcium (Ca²⁺) release via phospholipase C (PLC) following G-protein-coupled receptor (GPCR) activation is typically linked to membrane depolarization and airway smooth muscle (ASM) contraction. However, recent findings show that bitter taste receptor agonists, such as chloroquine (CQ), induce a paradoxical and potent relaxation response despite activating the Ca²⁺ signaling pathway. This relaxation has been hypothesized to be driven by a distinct compartmentalization of calcium ions toward the cellular periphery, subsequently leading to membrane hyperpolarization, in contrast to the contractile effects of histamine. In this study, we further investigate the spatiotemporal dynamics of Ca²⁺ signaling in ASM cells using single-cell microscopy and deep learning-based segmentation, integrating the results into a comprehensive model of ASM ion channel dynamics to compare the effects of histamine, CQ, and flufenamic acid (FFA). Our results show that histamine induces a strong, synchronized calcium release, nearly twice as high as that of CQ, which produces a sustained but lower-magnitude response. Per-cell analysis reveals more variable and asynchronous Ca²⁺ signaling for CQ and FFA, with higher entropy compared with histamine. Integrating these findings into an ASM ion channel model, we observed that histamine-mediated Ca²⁺ release activates voltage-gated Ca²⁺ and Na⁺ channels (leading to depolarization). In contrast, CQ preferentially engages BKCa, SKCa, and chloride channels (promoting hyperpolarization). These findings provide insights into the unique mechanisms by which bitter taste receptor agonists can modulate ASM tone, offering potential therapeutic strategies for relaxing ASM and alleviating airway hyperresponsiveness in conditions such as asthma.

Recommended Citation

Conaway, Stanley; Richard, Joshua; and Deshpande, Deepak A., "Spatiotemporal Calcium Signaling Patterns Underlying Opposing Effects of Histamine and TAS2R Agonists in Airway Smooth Muscle" (2025). Center for Translational Medicine Faculty Papers. Paper 135.
https://jdc.jefferson.edu/transmedfp/135

Creative Commons License

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

PubMed ID

40434402

Language

English