Calcium Signaling in Airway Smooth Muscle Physiology

Calcium ions orchestrate contraction and relaxation in airway smooth muscle by regulating excitation–contraction coupling. In quiescent cells, basal cytosolic Ca2+ is maintained at nanomolar levels by the coordinated activity of sarcoplasmic reticulum Ca2+ stores, plasma-membrane pumps and exchangers. Upon exposure to contractile agonists such as acetylcholine or histamine, G-protein-coupled receptor activation stimulates phospholipase C, generating inositol trisphosphate which binds to its receptor on the sarcoplasmic reticulum, triggering the release of Ca2+ into the cytosol. The ensuing rise in intracellular Ca2+ concentration evokes periodic Ca2+ oscillations, the frequency of which dictates the degree of muscle contraction. Concurrently, depletion of internal stores activates store-operated calcium entry through specialised channels in the plasma membrane, reinforcing the contractile response. Voltage-dependent Ca2+ channels open upon membrane depolarisation and contribute to sustained Ca2+ influx, while nonselective cation channels and members of the transient receptor potential family provide additional entry pathways. The precise spatio-temporal patterning of Ca2+ signals is further modulated by kinases, phosphatases and the tension of the cytoskeleton. Dysregulation of these processes underlies the airway hyperresponsiveness characteristic of asthma, chronic obstructive pulmonary disease and other obstructive airway conditions. Recent advances have elucidated novel regulatory proteins, defined cross-talk between epithelial and smooth muscle compartments, and identified new therapeutic targets to normalise calcium handling and restore airway tone.

Research from Nature Portfolio

Recent studies have identified an epithelium-derived factor that directly modulates calcium influx in airway smooth muscle. This secreted protein binds to and inhibits the Orai1 channel, a key conduit for store-operated calcium entry, thereby attenuating agonist-induced intracellular Ca2+ elevation and muscle contraction. In models lacking this regulator, airway tissues exhibit heightened contractility, which can be reversed by the addition of the recombinant factor. These findings reveal a critical cross-talk mechanism between airway epithelium and smooth muscle and suggest that restoration of this regulatory pathway holds promise for the treatment of asthma and related disorders.

Calcium Signaling in Airway Smooth Muscle Physiology publication trend

The graph below shows the total number of articles in calcium signaling in airway smooth muscle physiology across all publications each year (not limited to Nature Index journals).

Technical terms

Sarcoplasmic reticulum (SR): Intracellular organelle in muscle cells that stores and releases calcium ions during excitation–contraction coupling.

Store-operated calcium entry (SOCE): Mechanism by which depletion of SR calcium stores triggers influx of extracellular calcium through specialised plasma-membrane channels.

L-type voltage-dependent Ca2+ channel (L-VDCC): Membrane channel that mediates calcium entry in response to membrane depolarisation, contributing to sustained intracellular calcium elevation.

Nonselective cation channel (NSCC): Membrane channel permeable to multiple cations, including calcium, which contributes to calcium influx during smooth muscle activation.

Orai1 channel: Pore-forming subunit of store-operated calcium entry channels that facilitates calcium influx following store depletion.

Transient receptor potential vanilloid 4 (TRPV4): Mechanosensitive and chemically gated channel that mediates calcium and sodium influx in response to physical and chemical stimuli.

References

1. Airway smooth muscle relaxation results from a reduction in the frequency of Ca2+ oscillations induced by a cAMP-mediated inhibition of the IP3 receptor. Respiratory Research (2006).
2. Identification of BPIFA1/SPLUNC1 as an epithelium-derived smooth muscle relaxing factor. Nature Communications (2017).
3. Vandetanib as a prospective anti-inflammatory and anti-contractile agent in asthma. Frontiers in Pharmacology (2024).
4. TRPV4 Activation during Guinea Pig Airway Smooth Muscle Contraction Promotes Ca2+ and Na+ Influx. Pharmaceuticals (2024).
5. Estrogenic Modulation of Ionic Channels, Pumps and Exchangers in Airway Smooth Muscle. International Journal of Molecular Sciences (2023).