FIG. 1 Regulation of smooth muscle contraction. Various agonists (neurotransmitters, hormones, etc.) bind to specific receptors to activate contraction in smooth muscle. Subsequent to this binding, the prototypical response of the cell is to increase phospholipase C activity via coupling through a G protein. Phospholipase C produces two potent second messengers from the membrane lipid phosphatidylinositol 4,5-bisphosphate: diacylglycerol (DG) and inositol 1,4,5-trisphosphate (IP3). IP3 binds to specific receptors on the sarcoplasmic reticulum, causing release of activator calcium (Ca2+). DG along with Ca2+ activates PKC, which phosphorylates specific target proteins. In most smooth muscles, PKC has contraction-promoting effects such as phosphorylation of Ca2+ channels or other proteins that regulate cross-bridge cycling. Activator Ca2+ binds to calmodulin, leading to activation of myosin light chain kinase (MLC kinase). This kinase phosphorylates the light chain of myosin, and, in conjunction with actin, cross-bridge cycling occurs, initiating shortening of the smooth muscle cell. However, the elevation in Ca2+ concentration within the cell is transient, and the contractile response is maintained by a Ca2+-sensitizing mechanism brought about by the inhibition of myosin phosphatase activity by Rho kinase. This Ca2+-sensitizing mechanism is initiated at the same time that phospholipase C is activated, and it involves the activation of the small GTP-binding protein RhoA. The precise nature of the activation of RhoA by the G protein-coupled receptor is not entirely clear but involves a guanine nucleotide exchange factor (RhoGEF) and migration of RhoA to the plasma membrane. Upon activation, RhoA increases Rho kinase activity, leading to inhibition of myosin phosphatase. This promotes the contractile state, since the light chain of myosin cannot be dephosphorylated.
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FIG. 2 Relaxation of smooth muscle. Smooth muscle relaxation occurs either as a result of removal of the contractile stimulus or by the direct action of a substance that stimulates inhibition of the contractile mechanism. Regardless, the process of relaxation requires a decreased intracellular Ca2+ concentration and increased MLC phosphatase activity. The sarcoplasmic reticulum and the plasma membrane contain Ca,Mg-ATPases that remove Ca2+ from the cytosol. Na+/Ca2+ exchangers are also located on the plasma membrane and aid in decreasing intracellular Ca2+. During relaxation, receptor- and voltage-operated Ca2+ channels in the plasma membrane close resulting in a reduced Ca2+ entry into the cell.
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