Store-operated calcium entry is required for sustained contraction and Ca2+ oscillations of airway smooth muscle

Abstract

Asthma is characterized by airway hyper-responsiveness – the excessive contraction of airway smooth muscle. The extent of this airway contraction is proportional to the frequency of Ca²⁺ oscillations within airway smooth muscle cells (ASMCs). Sustained Ca²⁺ oscillations require a Ca²⁺ influx to replenish Ca²⁺ losses across the plasma membrane. Our previous studies implied store-operated calcium entry (SOCE) as the major pathway for this Ca²⁺ influx. Here, we explore this hypothesis, by examining the effects of SOCE inhibitors (GSK7975A and GSK5498A) as well as L-type voltage-gated Ca²⁺ channel (VGCC) inhibitors (nifedipine and nimodipine) on airway contraction and Ca²⁺ oscillations and SOCE-mediated Ca²⁺ influx in ASMCs within mouse precision-cut lung slices (PCLS). We found that both GSK7975A and GSK5498A were able to fully relax methacholine (MCh)-induced airway contraction by abolishing the Ca²⁺ oscillations, in a manner similar to that observed in zero extracellular Ca²⁺ ([Ca²⁺]_e). In addition, GSK7975A and GSK5498A inhibited increases in intracellular Ca²⁺ ([Ca²⁺]_i) in ASMCs with depleted Ca²⁺-stores in response to increased [Ca²⁺]_e, a response consistent with an inhibition of SOCE. However, GSK7975A and GSK5498A did not reduce Ca²⁺ release via IP₃ receptors stimulated with IP₃ released from caged-IP₃. By contrast, nifedipine and nimodipine only partially reduced airway contraction, Ca²⁺ oscillation frequency and SOCE-mediated Ca²⁺ influx. These data implicate that SOCE is the major Ca²⁺ influx pathway for ASMCs to sustain agonist-induced airway contraction and the underlying Ca²⁺ oscillations. The mechanisms of SOCE may therefore form novel targets for new bronchodilators.

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