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Vol. 52, Issue 6, 1113-1123, 1997
Laboratory 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
Department of
Psychiatry, University of California School of Medicine, San Diego,
California 92161 (R.H.P.)
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 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.
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