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This version published online on July 17, 2003
Molecular Endocrinology, doi:10.1210/me.2003-0047
A more recent version of this article appeared on October 1, 2003
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Submitted on February 10, 2003
Accepted on July 7, 2003

Melatonin Receptor Signaling in Pregnant and Non-Pregnant Rat Uterine Myocytes as Probed by BKCa Channel Activity

Frank Steffens1, Xiao-Bo Zhou1, Ulrike Sausbier1, Claudia Sailer1, Karin Motejlek1, Peter Ruth1, James Olcese1, Michael Korth1*, and Thomas Wieland1

1 Institut für Pharmakologie für Pharmazeuten, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Pharmazeutisches Institut, Pharmakologie und Toxikologie Universität Tübingen, Auf der Morgenstelle 8, D-72076 Tübingen, Institut für Biochemische Pharmakologie, Universität Innsbruck, Peter-Mayr-Stra{beta}e 1, A-6020 Innsbruck Institut für Hormon- und Fortpflanzungsforschung, Grandweg 64, D-22529 Hamburg, Institut für Pharmakologie und Toxikologie, Fakultät für Klinische Medizin Mannheim, Universität Heidelberg, Maybachstr. 14-16, D-68169 Mannheim

* To whom correspondence should be addressed.

The mRNAs of MT1 and MT2 melatonin receptors are present in cells from non-pregnant (NPM) and pregnant (PM) rat myometrium. To investigate the coupling of melatonin receptors to Gq and Gi-type of heterotrimeric G proteins we analyzed the activity of large conductance Ca2+-activated K+ (BKCa) 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 (NPo) that was blocked by the non-selective antagonist luzindole. The 2-iodomelatonin effect on NPo was suppressed by overexpression of the Gq{alpha} inactivating protein RGS16 and the PLC inhibitor U-73122. The activity of BKCa channels is differentially regulated by protein kinase A (PKA) in NPM and PM cells. Thus, the {beta}-adrenoceptor agonist isoprenaline inhibited the BKCa channel conducted whole-cell outward current (Iout) in NPM cells and enhanced Iout in PM cells. Additional application of 2-iodomelatonin antagonized the isoprenaline effect on Iout in NPM cells but enhanced Iout in PM cells. All 2-iodomelatonin effects on Iout were sensitive to PTX treatment and the PKA inhibitor H-89. We therefore conclude that melatonin activates both the PTX-insensitive Gq/PLC/Ca2+ and the PTX-sensitive Gi/cAMP/PKA signaling pathway in the rat myometrium.
Key words: melatonin receptors • rat uterine myocytes • G-proteins • signal transduction • BKCa channels • K+ current • patch-clamp recording




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