Interactions between calcium regulatory pathways and mechanosensitive channels in airways

ABSTRACT

Introduction

Asthma is a chronic lung disease influenced by environmental and inflammatory triggers and involving complex signaling pathways across resident airway cells such as epithelium, airway smooth muscle, fibroblasts, and immune cells. While our understanding of asthma pathophysiology is continually progressing, there is a growing realization that cellular microdomains play critical roles in mediating signaling relevant to asthma in the context of contractility and remodeling. Mechanosensitive pathways are increasingly recognized as important to microdomain signaling, with Piezo and transient receptor protein (TRP) channels at the plasma membrane considered important for converting mechanical stimuli into cellular behavior. Given their ion channel properties, particularly Ca²⁺ conduction, a question becomes whether and how mechanosensitive channels contribute to Ca²⁺ microdomains in airway cells relevant to asthma.

Areas covered

Mechanosensitive TRP and Piezo channels regulate key Ca²⁺ regulatory proteins such as store operated calcium entry (SOCE) involving STIM and Orai channels, and sarcoendoplasmic (SR) mechanisms such as IP₃ receptor channels (IP₃Rs), and SR Ca²⁺ ATPase (SERCA) that are important in asthma pathophysiology including airway hyperreactivity and remodeling.

Expert opinion

Physical and/or functional interactions between Ca²⁺ regulatory proteins and mechanosensitive channels such as TRP and Piezo can toward understanding asthma pathophysiology and identifying novel therapeutic approaches.

KEYWORDS:

• STIM
• Orai
• Piezo channels
• TRPV receptor
• airway smooth muscle
• asthma

Article highlights

• In the context of diseases such as asthma, regulation of intracellular Ca²⁺ has several downstream effects toward airway contractility and even remodeling (proliferation and fibrosis).

• There is increasing recognition for the role of mechanosensitive pathways in airway cell structure and function, with particular interest in Piezo and transient receptor protein (TRP) channels that are permeant to Ca²⁺.

• A number of pathways regulate Ca²⁺ in airway cells, including Ca²⁺ release via IP₃ receptors and reuptake via Ca²⁺ ATPase in the sarcoendoplasmic reticulum, and Ca²⁺ influx pathways that respond to depletion of Ca²⁺ stores, involving STIM proteins and Orai channels. Additional pathways such as sodium-calcium exchange and caveolins provide further modulation.

• Piezo and TRP channels physically or functionally interact with Ca²⁺ regulatory pathways, typically enhancing their function.

• Crosstalk between mechanosensitive Piezo or TRP channels and Ca²⁺ regulatory pathways in the lung in the context of asthma is only now being recognized and provides an opportunity to identify novel targets to address airway hyperreactivity and remodeling.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter of materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was supported by NIH grants R01-HL142061 (CMP and YSP), R01-HL088029 and R01-HL056470 (YSP) and Foundation of Anesthesia Education and Research Mentored Research Training Grant (FAER MRTG; ERV), Science and Technology Program of Shaanxi Province (NO.2020SF-062; YY), 2023 Shaanxi University Youth Innovation Team (Prevention and Treatment of Acute Lung Injury) (79; Shengyu Wang), Science and Technology Department of Guizhou Province (ZK [2021]351; MZ).