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.
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.