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Molecular signaling through G-protein-coupled receptors and the control of intracellular calcium in myometrium.

Abstract
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.
AuthorsBarbara M Sanborn, Chun-Ying Ku, Sergiy Shlykov, Lidiya Babich
JournalJournal of the Society for Gynecologic Investigation (J Soc Gynecol Investig) Vol. 12 Issue 7 Pg. 479-87 (Oct 2005) ISSN: 1556-7117 [Electronic] United States
PMID16202924 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S., Review)
Chemical References
  • Receptors, G-Protein-Coupled
  • Cyclic AMP-Dependent Protein Kinases
  • Type C Phospholipases
  • Calcium
Topics
  • Adult
  • Calcium (pharmacokinetics)
  • Cyclic AMP-Dependent Protein Kinases (metabolism)
  • Female
  • Humans
  • Myometrium (physiology)
  • Pregnancy (physiology)
  • Receptors, G-Protein-Coupled (physiology)
  • Signal Transduction
  • Tocolysis (methods)
  • Type C Phospholipases (metabolism)

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