Core signaling pathways responsible for airway smooth muscle contraction. Airway smooth muscle contractile force is generated by cyclic cross-bridging of actin and smooth muscle myosin, which depends on myosin phosphorylation. Myosin phosphorylation is regulated by cyclic increases in cytosolic calcium (Ca²⁺) that activate calmodulin (CaM) to phosphorylate myosin light chain kinase (MLCK), which directly phosphorylates myosin. In parallel, the small GTPase, RhoA, is activated by both calcium-dependent and -independent pathways. Rho directly activates Rho-associated coiled-coil protein kinase (ROCK) which, in turn, phosphorylates and thereby inactivates myosin light chain phosphatase (MLCP), which normally dephosphorylates myosin. The most important physiological pathway for increasing cytosolic calcium in airway smooth muscle involves activation of Gαq by G protein–coupled receptors that respond to extracellular contractile agonists, such as methacholine (Mch), serotonin (5-HT), and histamine. Gαq activates phospholipase C β (PLCβ), which generates IP3 to bind to IP3 receptors on the sarcoplasmic reticulum and release sequestered Ca²⁺.