Microdomain elements of airway smooth muscle in calcium regulation and cell proliferation

Airway remodeling manifested by hyperplasia of airway smooth muscle cells (ASMCs) and other structural and functional changes is a pathological condition in asthma not addressed by current treatment. Ca²⁺ signaling is crucial for ASMC proliferation. Inositol-1,4,5-trisphosphate receptor (IP3R) and ryanodine receptor (RyR) mediate Ca²⁺ release from endoplasmic reticulum/sarcoplasmic reticulum (ER/SR). Upon sensing the depletion of Ca²⁺ in ER/SR, stromal interaction molecule 1 (STIM1) aggregates and redistributes at the microdomain of ER/SR-plasma membrane (PM) and activates Orai1, a component of the store-operated Ca²⁺ (SOC) channels, to initiate Ca²⁺ influx. The STIM1/Orai1-mediated SOC entry is the main cause of a sustained intracellular calcium ([Ca²⁺]_i) elevation, which is different from a transient rise of [Ca²⁺]_i mediated by IP₃R and RyR. Extended-synaptotagmin 1 (E-Syt1) is recruited to the ER/SR-PM junction and anchors to the PM lipid phosphatidylinositol-4,5-bisphosphate (PI(_4,5)P₂) in a SOC-dependent manner. The subsequent strengthening of the ER/SR-PM connection by E-Syt1 facilitates the phosphatidylinositol (PI) transfer protein, Nir2, to supplement PI, a PI(_4,5)P₂ substrate, for the generation of IP3 and the propagation of Ca²⁺ signaling. Calcineurin and nuclear factor of activated T cells are the downstream signaling factors of elevated [Ca²⁺]_i contributing to ASMC proliferation. Mitochondrial Ca²⁺ uptake/efflux, mitochondrial fission/fusion and mitochondrial-ER/SR coupling also play important roles in modulating [Ca²⁺]_i and ASMC proliferation. Together, these pathways and mechanisms represent new therapeutic targets for airway remodeling. The present review provides an overview of our current understanding of the mechanisms of ASMC proliferation involving Ca²⁺ and highlights potential directions to control airway remodeling in asthma.