Molecular signaling through G-protein-coupled receptors and the control of intracellular calcium in myometrium.
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.
Sanborn
Barbara M
BM
Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado 80523, USA. Barbara.Sanborn@colostate.edu
Ku
Chun-Ying
CY
Shlykov
Sergiy
S
Babich
Lidiya
L
D000328:Adult; D002118:Calcium / Q000493:pharmacokinetics*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D009215:Myometrium / Q000502:physiology*; D011247:Pregnancy / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D015398:Signal Transduction; D015145:Tocolysis / Q000379:methods; D010738:Type C Phospholipases / Q000378:metabolism
D043562:Receptors, G-Protein-Coupled; D017868:Cyclic AMP-Dependent Protein Kinases; D010738:Type C Phospholipases; D002118:Calcium