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Oxytocin Receptors Differentially Signal via G_q and G_i Proteins in Pregnant and Nonpregnant Rat Uterine Myocytes: Implications for Myometrial Contractility

Institut für Pharmakologie für Pharmazeuten (X.-B.Z., F.S., M.K.), Universitätsklinikum Hamburg-Eppendorf, D-20246 Hamburg, Germany; and Institut für Experimentelle und Klinische Pharmakologie und Toxikologie (S.L., T.W.), Medizinische Fakultät Mannheim, Universität Heidelberg, D-68169 Mannheim, Germany

Address all correspondence and requests for reprints to: Michael Korth, Institut für Pharmakologie für Pharmazeuten, Universitätsklinikum Hamburg-Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany. E-mail: korth{at}uke.uni-hamburg.de.

Oxytocin (OT) receptors are important regulators of myometrial contractility. By using the activity of large conductance Ca²⁺-activated K⁺ (BK_Ca) channels as readout, we analyzed OT signaling in cells from nonpregnant (NPM) and pregnant (PM) rat myometrium in detail. In nystatin-perforated whole-cell patches from NPM cells, which leave the intracellular integrity intact, OT transiently increased BK_Ca-mediated outward currents (I_out). This OT-evoked I_out was caused by the Ca²⁺ transients in response to the G_q/11-mediated activation of phospholipase C and was inhibited by activation of protein kinase A (PKA). In an open-access whole-cell patch (OAP), the OT-induced transient rise in I_out was disrupted whereas the regulation of BK_Ca by the cAMP/PKA cascade remained intact. OT counteracted the isoprenaline, i.e. the ß-adrenoceptor/G_s-mediated effect in NPM cells measured in OAP. In contrast, OT further enhanced the ß-adrenoceptor/G_s-mediated effect on BK_Ca activity in PM cells. All OT effects in the OAP were mediated by pertussis toxin-sensitive G_i proteins and PKA. By quantitative real-time PCR and overexpression of the recombinant protein, we demonstrate that an up-regulation of the Gß-stimulated adenylyl cyclase II during pregnancy is most likely responsible for this switch. By studying the OT-evoked I_out in nystatin-perforated whole-cell patches of PM cells, we further detected that the OT receptor/G_iß-mediated coactivation of adenylyl cyclase II enhanced the ß-adrenoceptor/G_s-induced suppression of the OT-evoked Ca²⁺ transients and thus diminishes and self-limits OT-induced contractility. The differential regulation of the PKA-mediated suppression of OT-evoked Ca²⁺ transients and BK_Ca activity likely supports uterine quiescence during pregnancy.

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