title: Cocaine-sensitive sigma-receptor and its interaction with steroid hormones in the human placental syncytiotrophoblast and in choriocarcinoma cells.
abstract: The expression and ligand binding characteristics of sigma-receptors in human placental syncytiotrophoblast and choriocarcinoma cells were investigated using haloperidol as a ligand. Haloperidol bound to purified placental brush border membranes with high affinity; the apparent dissociation constant for the process was about 3 nM. These binding sites were not related to dopamine (D2) and serotonin (5-HT2) receptors nor to serotonin and norepinephrine transporters. The ligands of sigma-receptors [3.g. (+)-3-(3-hydroxyphenyl)N-(1-propyl)piperidine, 1,3-di-(2-tolyl)guanidine, clorgyline, rimcazole, and dexromethorphan] were very potent in competing with haloperidol for the binding sites. The binding sites were detected not only in the brush border membrane, but also in intracellular membranes. The rank order of potency of various sigma-receptor ligands to inhibit haloperidol binding indicated that placental sigma-receptors belong to the sigma 1 subtype. Cocaine and its analog RTI-55 [2 beta-carbomethoxy-3 beta-(4-iodophenyl-) tropane] inhibited the binding of haloperidol to placental membranes with appreciable potency. The steroid hormones, progesterone and testosterone, were also potent inhibitors, and the inhibition constant for progesterone was 0.3 microM, a concentration much smaller than that found in plasma during pregnancy. The inhibition was competitive. beta-Estradiol and a number of other steroids were relatively much weaker inhibitors than progesterone and testosterone. Phenytoin and neuropeptide-Y did not interact with sigma-receptors in placenta. The choriocarcinoma cell line JAR was also found to express sigma-receptors in the plasma membrane as well as in intracellular membranes. The characteristics of the receptors in this cell were qualitatively similar to those of the receptors in normal placenta, including subtype identity and interaction with cocaine and progesterone. Interestingly, however, all sigma-receptor ligands interacted with the receptors in the JAR cell with much higher affinity than with the receptors in normal placenta. It is concluded that the placental syncytiotrophoblast and choriocarcinoma cells express cocaine-sensitive sigma-receptors and that progesterone is most likely an endogenous ligand for these receptors.
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta 30912-2100.
authors.forename: J D
authors.initials: JD
authors.lastname: Ramamoorthy
authors.forename: S
authors.initials: S
authors.lastname: Ramamoorthy
authors.forename: V B
authors.initials: VB
authors.lastname: Mahesh
authors.forename: F H
authors.initials: FH
authors.lastname: Leibach
authors.forename: V
authors.initials: V
authors.lastname: Ganapathy
mesh_terms: D002822:Choriocarcinoma / Q000378:metabolism* / Q000473:pathology; D003042:Cocaine / Q000494:pharmacology*; D005260:Female; D015726:Giant Cells / Q000378:metabolism; D012739:Gonadal Steroid Hormones / Q000378:metabolism*; D006220:Haloperidol / Q000378:metabolism; D006801:Humans; D008024:Ligands; D009478:Neuropeptide Y / Q000494:pharmacology; D010672:Phenytoin / Q000494:pharmacology; D010920:Placenta / Q000166:cytology / Q000378:metabolism*; D011247:Pregnancy; D017480:Receptors, sigma / Q000187:drug effects / Q000378:metabolism*; D014327:Trophoblasts / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014594:Uterine Neoplasms / Q000378:metabolism* / Q000473:pathology
chemical_list: D012739:Gonadal Steroid Hormones; D008024:Ligands; D009478:Neuropeptide Y; D017480:Receptors, sigma; D010672:Phenytoin; D003042:Cocaine; D006220:Haloperidol