The Oxytocin-Oxytocin Receptor System and Its Antagonists as Tocolytic Agents

Figure 1

Oxytocin receptor linked signaling pathways resulting in myometrial contraction. Binding of OT to OTR activates Gα _q/11 and then PLC, which hydrolyses PIP2 to InsP3 and DAG. InsP3 causes release of Ca²⁺ from the sarcoplasmic reticulum, while DAG activates PKC. Gα _q/11 also causes activation of voltage-regulated Ca²⁺ channels and Ca²⁺ entry into the cells. Ca²⁺ binds to calmodulin, and the Ca²⁺-calmodulin complex activates MLC kinase, resulting in myometrial contraction. Both OTR and PKC activate the MAPK cascade, while OTR and MAPK result in increased cPLA2 activity. Increased cPLA2 activity and MAPK activation result in prostaglandin production, which also contributes to the contractile effect. The activation of the RhoA-ROK cascade by the OTR is another pathway that results in increased MLC phosphorylation and myometrial contraction. OT: oxytocin, OTR: oxytocin receptor, PLC: phospholipase, PIP2: phosphatidylinositol 4,5-bisphosphate, InsP3: inositol 1,4,5- triphosphate, DAG: diacylglycerol, PKC: protein kinases type C, MLC: myosin light-chain, MAPK: mitogen-activated protein kinase, cPLA2: cytosolic phospholipase A2, ROK: RhoA associated protein kinase.