The primary signal for smooth-muscle contraction is an increase in sarcoplasmic free Ca2+ concentration ([Ca2+]i). This triggers activation of calmodulin-dependent myosin light-chain kinase, which catalyses myosin phosphorylation, thereby activating crossbridge cycling and the development of force or contraction of the muscle cell. Restoration of resting [Ca2+]i deactivates the kinase; myosin is dephosphorylated by myosin light-chain phosphatase and the muscle relaxes. Recent evidence suggests that other signal-transduction pathways can modulate the contractile state of a smooth-muscle cell by affecting specific steps in the myosin phosphorylation-dephosphorylation mechanism.