title: Melatonin receptor signaling in pregnant and nonpregnant rat uterine myocytes as probed by large conductance Ca2+-activated K+ channel activity.
abstract: 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 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 that was blocked by the nonselective antagonist luzindole. The 2-iodomelatonin effect on channel open probability was suppressed by overexpression of the Gqalpha-inactivating protein RGS16 and the phospholipase C 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/phospholipase C/Ca2+ and the PTX-sensitive Gi/cAMP/PKA signaling pathway in rat myometrium.
authors.affiliation: Institut für Pharmakologie für Pharmazeuten, Universitätsklinikum Hamburg-Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Steffens
authors.forename: Xiao-Bo
authors.initials: XB
authors.lastname: Zhou
authors.forename: Ulrike
authors.initials: U
authors.lastname: Sausbier
authors.forename: Claudia
authors.initials: C
authors.lastname: Sailer
authors.forename: Karin
authors.initials: K
authors.lastname: Motejlek
authors.forename: Peter
authors.initials: P
authors.lastname: Ruth
authors.forename: James
authors.initials: J
authors.lastname: Olcese
authors.forename: Michael
authors.initials: M
authors.lastname: Korth
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieland
mesh_terms: D000818:Animals; D002118:Calcium / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005260:Female; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D051036:Large-Conductance Calcium-Activated Potassium Channels; D008550:Melatonin / Q000031:analogs & derivatives* / Q000494:pharmacology; D008564:Membrane Potentials; D009215:Myometrium / Q000166:cytology / Q000378:metabolism*; D037342:Pertussis Toxin / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000502:physiology*; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D044122:Receptor, Melatonin, MT1 / Q000235:genetics / Q000378:metabolism*; D044123:Receptor, Melatonin, MT2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D051036:Large-Conductance Calcium-Activated Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D044122:Receptor, Melatonin, MT1; D044123:Receptor, Melatonin, MT2; C044556:2-iodomelatonin; D000242:Cyclic AMP; D037342:Pertussis Toxin; D017868:Cyclic AMP-Dependent Protein Kinases; D010738:Type C Phospholipases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D008550:Melatonin; D007545:Isoproterenol; D002118:Calcium