STIM1 is the key that unlocks airway smooth muscle remodeling and hyperresponsiveness during asthma

Abstract

Airway smooth muscle remodeling and hyperresponsiveness are critical determinants of asthma severity, but the precise mechanisms regulating these disease processes remain elusive. In their latest study published in PNAS, Trebak and colleagues demonstrate that STIM1 (stromal-interacting molecule 1) expression is upregulated in airway smooth muscle cells during asthma and facilitates Ca²⁺ influx to drive airway remodeling and hyperresponsiveness.

Keywords: Airway smooth muscle; Asthma; STIM1.

Figure 1.. STIM1 induces airway remodeling and hyperresponsiveness in airway smooth muscle cells during asthma.

(1) Agonists such as upregulated inflammatory mediators stimulate G-protein coupled receptors (GPCR) associated with phospholipase-C (PLC) produces the secondary messenger inositol-1,4,5-trisphosphate (IP₃). IP₃ binds to its receptor on the endoplasmic/sarcoplasmic reticulum (ER/SR) to facilitate Ca²⁺ release and ER store depletion. (2) As stores deplete, Ca²⁺ dissociates from the luminal EF-hand domain of STIM1 proteins, which in turn causes STIM1 to oligomerize and translocate to ER-plasma membrane junction. STIM1 oligomers activate Ca²⁺ release–activated Ca²⁺ (CRAC) channels formed by Orai proteins causing Ca²⁺ influx. Ca²⁺ associates with calmodulin to form a signaling complex. (3) Ca²⁺-calmodulin complex activates calcineurin, causing dephosphorylation of the transcription factor nuclear factor of activated T cells (NFAT). Dephosphorylated NFAT translocates to the nucleus and initiates transcription of several disease-linked genes, including those related to proliferation, migration and metabolism to induce airway remodeling. (4) Ca²⁺-calmodulin complex also activates myosin light-chain kinase (MLCK) to initiate muscle contraction and airway hyperresponsiveness. Created with BioRender.com.