Distinct Sites for Inverse Modulation ofN-Methyl-d-Aspartate Receptors by Sulfated Steroids

  1. Mijeong Park-Chung1,1,
  2. Fong-Sen Wu2,1,
  3. Robert H. Purdy2,
  4. Andrew A. Malayev1,
  5. Terrell T. Gibbs1 and
  6. David H. Farb1
  1. 1Laboratory of Molecular Neurobiology, Department of Pharmacology, Boston University School of Medicine, Boston, Massachusetts 02118 (M.P.-C., F.-S.W., A.A.M., T.T.G., D.H.F.), and 2Department of Psychiatry, University of California School of Medicine, San Diego, California 92161 (R.H.P.)

    Abstract

    Steroid sulfation occurs in nervous tissue and endogenous sulfated steroids can act as positive or negative modulators ofN-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 NR1100 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.

    Footnotes

    • Send reprint requests to: Dr. David H. Farb, Department of Pharmacology, Boston University, School of Medicine, 80 East Concord Street, Boston, MA 02118.

    • ↵1 Current affiliation: Gene Therapy Unit, Laboratory of Molecular Cell Biology, Institute of Bioscience and Biotechnology, Yasong, Taejon, Korea.

    • ↵2 Current affiliation: Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan 70101, Republic of China

    • This work was supported by National Institute of Mental Health Grant MH49469.

    • Abbreviations:
      NMDA
      N-methyl-d-aspartate
      DHEAS
      dehydroepiandrosterone sulfate
      PS
      pregnenolone sulfate
      3β5βS
      3β-hydroxy-5β-pregnan-20-one sulfate
      AMPA
      α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
      EPSC
      spontaneous excitatory postsynaptic current
      ara-C
      1-β-d-arabinofuranosylcytosine
      PHS
      pregnenolone hemisuccinate
      EGTA
      ethylene glycol bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid
      HEPES
      4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
      DTT
      dithiothreitol
      NEM
      N-ethylmaleimide
      APV
      (±)-2-amino-5-phosphonopentanoic acid
      3α5βS
      3α-hydroxy-5β-pregnan-20-one sulfate
      3β5αS
      3β-hydroxy-5α-pregnan-20-one sulfate
      3α5αS
      3α-hydroxy-5α-pregnan-20-one sulfate
      • Received March 3, 1997.
      • Accepted August 12, 1997.
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    1. Molecular Pharmacology December 1, 1997 vol. 52 no. 6 1113-1123
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