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Melatonin Receptor Signaling in Pregnant and Nonpregnant Rat Uterine Myocytes as Probed by Large Conductance Ca²⁺-Activated K⁺ Channel Activity

Institut für Pharmakologie für Pharmazeuten (F.S., X.-B.Z., K.M., M.K.), Universitätsklinikum Hamburg-Eppendorf; Pharmazeutisches Institut (U.S., P.R.), Pharmakologie und Toxikologie Universität Tübingen, D-72076 Tübingen, Germany; Institut für Biochemische Pharmakologie (C.S.), Universität Innsbruck, A-6020 Innsbruck, Austria; Institut für Hormon-und Fortpflanzungsforschung (J.O.), D-22529 Hamburg, Germany; and Institut für Pharmakologie und Toxikologie (T.W.), Fakultät für Klinische Medizin Mannheim, Universität Heidelberg, D-68169 Mannheim, Germany

Address all correspondence and requests for reprints to: Michael Korth, M.D., Institut für Pharmakologie für Pharmazeuten, Universitätsklinikum Hamburg-Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany.

The mRNAs of MT₁ and MT₂ melatonin receptors are present in cells from nonpregnant (NPM) and pregnant (PM) rat myometrium. To investigate the coupling of melatonin receptors to G_q- and G_i-type of heterotrimeric G proteins, we analyzed the activity of large-conductance Ca²⁺-activated K⁺ (BK_Ca) channels, the expression of which in the uterus is confined to smooth muscle cells. The melatonin receptor agonist 2-iodomelatonin induced a pertussis toxin (PTX)-insensitive increase in channel open probability that was blocked by the nonselective antagonist luzindole. The 2-iodomelatonin effect on channel open probability was suppressed by overexpression of the G_q-inactivating protein RGS16 and the phospholipase C inhibitor U-73122. The activity of BK_Ca channels is differentially regulated by protein kinase A (PKA) in NPM and PM cells. Thus, the ß-adrenoceptor agonist isoprenaline inhibited the BK_Ca channel conducted whole-cell outward current (I_out) in NPM cells and enhanced I_out in PM cells. Additional application of 2-iodomelatonin antagonized the isoprenaline effect on I_out in NPM cells but enhanced I_out in PM cells. All 2-iodomelatonin effects on I_out were sensitive to PTX treatment and the PKA inhibitor H-89. We therefore conclude that melatonin activates both the PTX-insensitive Gq/phospholipase C/Ca²⁺ and the PTX-sensitive G_i/cAMP/PKA signaling pathway in rat myometrium.

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