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Molecular Signaling Through G-Protein-Coupled Receptors and the Control of Intracellular Calcium in Myometrium

Department of Biomedical Sciences, 102 Physiology Campus Delivery 1680, Colorado State University, Fort Collins, CO 80523 Barbara.Sanborn{at}colostate.edu

Chun-Ying Ku, PhD

Sergiy Shlykov, PhD

Lidiya Babich, PhD

Department of Biomedical Sciences, Colorado State University, Forts Collins, Colorado

Cellular mechanisms regulating myometrial intracellular free calcium (Ca²⁺) 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 incerase in myosin light chain, an increase in myosin denosine monophosphatse (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 multuiple signaling pathways, including receptor-mediated activation of phospholipase Cß (PLCß), 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 those effects require association of protein kinase A (PKA) with a plasma membraneassociated 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, Trp Cs, 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.

Key Words: Myometrium • calcium • phospholipase C • cAMP • TrpC proteins • ion channels

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