Cellular mechanisms regulating myometrial intracellular free
calcium (Ca2+(i)) are addressed in this review, with emphasis on
G-protein-coupled receptor pathways. An increase in myometrial Ca2+(i) results in phosphorylation of
myosin light chain, an increase in
myosin adenosine monophosphatase (
ATPase) activity and contraction. Dephosphorylation of
myosin light chain and a decline in Ca2+(i) are associated with relaxation. Increases in Ca2+(i) are controlled by multiple signaling pathways, including receptor-mediated activation of
phospholipase Cbeta (PLCbeta), leading to release of Ca2+ from intracellular stores. Ca2+ also enters myometrial cells through plasma membrane Ca2+ channels. Conversely,
adenosine triphosphate (
ATP)-dependent Ca2+ pumps lower Ca2+(i) concentrations and
potassium channels promote hyperpolarization that can decrease Ca2+ entry. Receptor-coupled pathways that promote uterine relaxation primarily involve activation of cyclic
adenosine monophosphate (cAMP)- or cyclic
guanosine monophosphate (cGMP)-stimulated
protein kinases that phosphorylate
proteins regulating Ca2+ homeostasis. cAMP has inhibitory effects on myometrial contractile activity, agonist-stimulated phosphatidylinositide turnover and increases in Ca2+(i). Some of these effects require association of
protein kinase A (PKA) with a plasma membrane-associated
A-kinase-anchoring-protein (AKAP). Near term in the rat, there is a decline in the plasma membrane localization of PKA associated with this anchoring
protein. This correlates with changes in the regulation of signaling pathways controlling Ca2+(i). L-type voltage-operated Ca2+ entry is an important regulator of myometrial contraction. In addition, putative signal-regulated or capacitative Ca2+ channel
proteins, TrpCs, are expressed in myometrium, and signal-regulated Ca2+ entry is observed in human myometrial cells. This Ca2+ entry mechanism may play a significant role in the control of myometrial Ca2+(i) dynamics and myometrial contraction. The regulation of myometrial Ca2+(i) is complex. Understanding the mechanisms involved may lead to design of
tocolytics that target multiple pathways and achieve improved suppression of
premature labor.