Overview of the signalling pathways involved in airway smooth muscle contraction. The contractile agonist interacts with its specific G-protein-coupled receptor (GPCR) leading to the activation of phospholipase C (PLC) which hydrolyzes phosphatidylinositol bisphosphate (PIP2) leading to the formation of two-second messengers, inositol triphosphate (IP3), and diacylglycerol (DAG). IP3 interacts with its receptor () on the sarcoplasmic reticulum (SR) leading to the release of calcium ions which in turn, through forming a complex with calmodulin, activates myosin light chain kinase (MLCK). MLCK phosphorylates regulatory myosin light chain (rMLC) to form p-MLC which leads to myosin and actin crossbridging and contraction. p-MLC is deactivated by the action of myosin light chain phosphatase (MLCP). Both DAG, through its action on protein kinase C (PKC), and RhoA, through its target Rho Kinase (RhoK), have an inhibitory action on MLCP through phosphorylation. Interaction of agonist with GPCR also activates both CD38/cADPR and Rho/RhoK pathways, although the exact mechanism is not fully known. CD38/cADPR activation leads to the release of from SR through ryanodine receptors (RyR) channels. Nicotinamide adenine dinucleotide phosphate oxidase type 4 (NOX4) generates reactive oxygen species (ROS) which may affect ASM calcium homeostasis and subsequently ASM contraction through their action on the CD38/cADPR pathway. Red stars ★ indicate signalling points with abnormalities suspected of driving hypercontractility in asthmatic ASM.
