Fig. 6

The Ca²⁺ signaling pathway and the roles of CD38, Ca²⁺ channels, and G-protein-coupled receptors. In the Ca²⁺-dependent signaling pathway, PLCb generates IP3 that binds to its receptor on the sarcoplasmic reticulum (SR) membrane and induces Ca²⁺ⁱ release. Ca²⁺ⁱ activates calmodulin and myosin light chain kinase (MLCK) to induce actin-myosin cross-bridge cycling and subsequently smooth muscle spasm. CD38 expression evokes the generation of cyclic ADP-ribose, which binds to the ryanodine receptor and stimulates the SR to release Ca²⁺ⁱ. SERCA refills the SR with cytosolic Ca²⁺ⁱ and inhibits smooth muscle spasm. The Ca²⁺-independent pathway is mediated by RhoA and ROCK, which phosphorylate and inactivate MYTP1, leading to airway smooth muscle spasm