Intracellular Ca²⁺ is critical for regulating airway smooth muscle (ASM) tension. A rapid rise in the intracellular Ca²⁺ concentration ([Ca²⁺]_i) of ASM cells is crucial for modulating the intensity and length of the ASM contraction. Because this rapid increase in [Ca²⁺]_i largely depends on the balance between Ca²⁺ released from intracellular Ca²⁺ stores and extracellular Ca²⁺ entry, exploring the mechanisms mediating Ca²⁺ transport is critical for understanding ASM contractility and the pathogenesis of bronchial contraction disorders. Transient receptor potential vanilloid 4 (TRPV4) is a highly Ca²⁺-permeable non-selective cation channel that mediates Ca²⁺ influx to increase [Ca²⁺]_i, which then directly or indirectly regulates the contraction and relaxation of ASM. The [Ca²⁺]_i returns to basal levels through several uptake and extrusion pumps, such as the sarco(endo)plasmic reticulum Ca²⁺ ATPase and inositol 1,4,5-trisphosphate receptors (IP₃Rs), the plasmalemmal Ca²⁺ ATPase, and the plasma membrane Na⁺/Ca²⁺ exchanger (NCX). Thus, to further understand ASM tension regulation in normal and diseased tissue, the present study examined whether an interaction exists among TRPV4, IP₃Rs, and NCX. The TRPV4-specific and potent agonist GSK1016790A increased [Ca²⁺]_i in mouse ASM cells, an effect that was completely blocked by the TRPV4-specific antagonist HC067047. However, GSK1016790A induced relaxation in mouse tracheal rings precontracted with carbachol in vitro. To determine the mechanism underlying this TRPV4-induced relaxation of ASM, we blocked specific downstream molecules. We found that the GSK1016790A-induced relaxation was abolished by the NCX inhibitors KB-R7943 and LiCl but not by specific inhibitors of the Ca²⁺-activated large-, intermediate-, or small-conductance K⁺ channels (BK_Ca, IK, and SK₃, respectively). The results of co-immunoprecipitation (co-IP) assays showed an interaction of TRPV4 and IP₃R₁ with NCX_s. Taken together, these findings support a physical and functional interaction of TRPV4 and IP₃R₁ with NCXs as a novel TRPV4-mediated Ca²⁺ signaling mechanism and suggest a potential target for regulation of ASM tension and treatment of respiratory diseases, especially tracheal spasm.

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