title: Distinct sites for inverse modulation of N-methyl-D-aspartate receptors by sulfated steroids.
abstract: Steroid sulfation occurs in nervous tissue and endogenous sulfated steroids can act as positive or negative modulators of N-methyl-D-aspartate (NMDA) receptor function. In the current study, structure-activity relationships for sulfated steroids were examined in voltage-clamped chick spinal cord and rat hippocampal neurons in culture and in Xenopus laevis oocytes expressing NR1(100) and NR2A subunits. The ability of pregnenolone sulfate (a positive modulator) and epipregnanolone sulfate (a negative modulator) to compete with each another, as well as with other known classes of NMDA receptor modulators, was examined. The results show that steroid positive and negative modulators act at specific, extracellularly directed sites that are distinct from one another and from the spermine, redox, glycine, Mg2+, MK-801, and arachidonic acid sites. Sulfated steroids are effective as modulators of ongoing glutamate-mediated synaptic transmission, which is consistent with their possible role as endogenous neuromodulators in the CNS.
authors.affiliation: Department of Pharmacology, Boston University School of Medicine, Massachusetts 02118, USA.
authors.forename: M
authors.initials: M
authors.lastname: Park-Chung
authors.forename: F S
authors.initials: FS
authors.lastname: Wu
authors.forename: R H
authors.initials: RH
authors.lastname: Purdy
authors.forename: A A
authors.initials: AA
authors.lastname: Malayev
authors.forename: T T
authors.initials: TT
authors.lastname: Gibbs
authors.forename: D H
authors.initials: DH
authors.lastname: Farb
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001665:Binding Sites; D001667:Binding, Competitive; D002478:Cells, Cultured; D002642:Chick Embryo; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D016202:N-Methylaspartate / Q000494:pharmacology / Q000502:physiology; D009474:Neurons / Q000648:ultrastructure; D010084:Oxidation-Reduction; D011073:Polyamines / Q000378:metabolism; D011280:Pregnanolone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D011284:Pregnenolone / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D013116:Spinal Cord / Q000648:ultrastructure; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
chemical_list: D011073:Polyamines; D016194:Receptors, N-Methyl-D-Aspartate; C018370:pregnenolone sulfate; D016718:Arachidonic Acid; D016202:N-Methylaspartate; D011284:Pregnenolone; C019427:3-hydroxypregnan-3-one 3-sulfate; D011280:Pregnanolone