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Br J Pharmacol
2002 Feb 01;1354:901-9. doi: 10.1038/sj.bjp.0704543.
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Inhibition of the NMDA response by pregnenolone sulphate reveals subtype selective modulation of NMDA receptors by sulphated steroids.
Malayev A
,
Gibbs TT
,
Farb DH
.
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1. The neurosteroid pregnenolone sulphate (PS) potentiates N-methyl-D-aspartate (NMDA) receptor mediated responses in various neuronal preparations. The NR1 subunit can combine with NR2A, NR2B, NR2C, or NR2D subunits to form functional receptors. Differential NR2 subunit expression in brain and during development raises the question of how the NR2 subunit influences NMDA receptor modulation by neuroactive steroids. 2. We examined the effects of PS on the four diheteromeric NMDA receptor subtypes generated by co-expressing the NR1(100) subunit with each of the four NR2 subunits in Xenopus oocytes. Whereas PS potentiated NMDA-, glutamate-, and glycine-induced currents of NR1/NR2A and NR1/NR2B receptors, it was inhibitory at NR1/NR2C and NR1/NR2D receptors. 3. In contrast, pregnanolone sulphate (3alpha5betaS), a negative modulator of the NMDA receptor that acts at a distinct site from PS, inhibited all four subtypes, but was approximately 4 fold more potent at NR1/NR2C and NR1/NR2D than at NR1/NR2A and NR1/NR2B receptors. 4. These findings demonstrate that residues on the NR2 subunit are key determinants of modulation by PS and 3alpha5betaS. The modulatory effects of PS, but not 3alpha5betaS, on dose-response curves for NMDA, glutamate, and glycine are consistent with a two-state model in which PS either stabilizes or destabilizes the active state of the receptor, depending upon which NR2 subunit is present. 5. The selectivity of sulphated steroid modulators for NMDA receptors of specific subunit composition is consistent with a neuromodulatory role for endogenous sulphated steroids. The results indicate that it may be possible to develop therapeutic agents that target steroid modulatory sites of specific NMDA receptor subtypes.
,
,
Pubmed
,
,
Pubmed
,
,
Pubmed
,
,
Pubmed
,
,
Pubmed
Akazawa,
Differential expression of five N-methyl-D-aspartate receptor subunit mRNAs in the cerebellum of developing and adult rats.
1994,
Pubmed
Anson,
Identification of amino acid residues of the NR2A subunit that control glutamate potency in recombinant NR1/NR2A NMDA receptors.
1998,
Pubmed
Bowlby,
Pregnenolone sulfate potentiation of N-methyl-D-aspartate receptor channels in hippocampal neurons.
1993,
Pubmed
Corpéchot,
Pregnenolone and its sulfate ester in the rat brain.
1983,
Pubmed
DeLean,
Simultaneous analysis of families of sigmoidal curves: application to bioassay, radioligand assay, and physiological dose-response curves.
1978,
Pubmed
Dunah,
Regional and ontogenic expression of the NMDA receptor subunit NR2D protein in rat brain using a subunit-specific antibody.
1996,
Pubmed
Flood,
Evidence that cholecystokinin-enhanced retention is mediated by changes in opioid activity in the amygdala.
1992,
Pubmed
Guzikowski,
Synthesis of N-substituted 4-(4-hydroxyphenyl)piperidines, 4-(4-hydroxybenzyl)piperidines, and (+/-)-3-(4-hydroxyphenyl)pyrrolidines: selective antagonists at the 1A/2B NMDA receptor subtype.
2000,
Pubmed
,
Xenbase
Ilyin,
Subtype-selective inhibition of N-methyl-D-aspartate receptors by haloperidol.
1996,
Pubmed
,
Xenbase
Irwin,
Steroid potentiation and inhibition of N-methyl-D-aspartate receptor-mediated intracellular Ca++ responses: structure-activity studies.
1994,
Pubmed
Karlin,
On the application of "a plausible model" of allosteric proteins to the receptor for acetylcholine.
1967,
Pubmed
Kleckner,
Subtype-selective antagonism of N-methyl-D-aspartate receptors by felbamate: insights into the mechanism of action.
1999,
Pubmed
,
Xenbase
Ladurelle,
Prolonged intracerebroventricular infusion of neurosteroids affects cognitive performances in the mouse.
2000,
Pubmed
Leonard,
Apparent desensitization of NMDA responses in Xenopus oocytes involves calcium-dependent chloride current.
1990,
Pubmed
,
Xenbase
Maione,
Pregnenolone sulfate increases the convulsant potency of N-methyl-D-aspartate in mice.
1992,
Pubmed
Mathis,
The neurosteroid pregnenolone sulfate blocks deficits induced by a competitive NMDA antagonist in active avoidance and lever-press learning tasks in mice.
1996,
Pubmed
Mathis,
The neurosteroid pregnenolone sulfate blocks NMDA antagonist-induced deficits in a passive avoidance memory task.
1994,
Pubmed
McIlhinney,
Cell surface expression of the human N-methyl-D-aspartate receptor subunit 1a requires the co-expression of the NR2A subunit in transfected cells.
1996,
Pubmed
Meziane,
The neurosteroid pregnenolone sulfate reduces learning deficits induced by scopolamine and has promnestic effects in mice performing an appetitive learning task.
1996,
Pubmed
MONOD,
ON THE NATURE OF ALLOSTERIC TRANSITIONS: A PLAUSIBLE MODEL.
1965,
Pubmed
Monyer,
Developmental and regional expression in the rat brain and functional properties of four NMDA receptors.
1994,
Pubmed
Mori,
Structure and function of the NMDA receptor channel.
1995,
Pubmed
Pallarés,
The neurosteroid pregnenolone sulfate infused into the nucleus basalis increases both acetylcholine release in the frontal cortex or amygdala and spatial memory.
1998,
Pubmed
Park-Chung,
3 alpha-Hydroxy-5 beta-pregnan-20-one sulfate: a negative modulator of the NMDA-induced current in cultured neurons.
1994,
Pubmed
Park-Chung,
Distinct sites for inverse modulation of N-methyl-D-aspartate receptors by sulfated steroids.
1997,
Pubmed
,
Xenbase
Petralia,
The NMDA receptor subunits NR2A and NR2B show histological and ultrastructural localization patterns similar to those of NR1.
1994,
Pubmed
Soloviev,
Xenopus oocytes express a unitary glutamate receptor endogenously.
1997,
Pubmed
,
Xenbase
Tang,
Genetic enhancement of learning and memory in mice.
1999,
Pubmed
Vallée,
Neurosteroids: deficient cognitive performance in aged rats depends on low pregnenolone sulfate levels in the hippocampus.
1997,
Pubmed
Wafford,
Identification of amino acids in the N-methyl-D-aspartate receptor NR1 subunit that contribute to the glycine binding site.
1995,
Pubmed
,
Xenbase
Weaver,
Geometry and charge determine pharmacological effects of steroids on N-methyl-D-aspartate receptor-induced Ca(2+) accumulation and cell death.
2000,
Pubmed
Weaver,
Neuroprotective activity of a new class of steroidal inhibitors of the N-methyl-D-aspartate receptor.
1997,
Pubmed
Wenzel,
NMDA receptor heterogeneity during postnatal development of the rat brain: differential expression of the NR2A, NR2B, and NR2C subunit proteins.
1997,
Pubmed
Wenzel,
N-methyl-D-aspartate receptors containing the NR2D subunit in the retina are selectively expressed in rod bipolar cells.
1997,
Pubmed
White,
In vitro and in vivo characterization of conantokin-R, a selective NMDA receptor antagonist isolated from the venom of the fish-hunting snail Conus radiatus.
2000,
Pubmed
,
Xenbase
Williams,
Ifenprodil discriminates subtypes of the N-methyl-D-aspartate receptor: selectivity and mechanisms at recombinant heteromeric receptors.
1993,
Pubmed
,
Xenbase
Wong,
Patch-clamp analysis of direct steroidal modulation of glutamate receptor-channels.
1994,
Pubmed
Wu,
Pregnenolone sulfate: a positive allosteric modulator at the N-methyl-D-aspartate receptor.
1991,
Pubmed
Yaghoubi,
Neurosteroid modulation of recombinant ionotropic glutamate receptors.
1998,
Pubmed
,
Xenbase
Zhang,
Spermine potentiation of recombinant N-methyl-D-aspartate receptors is affected by subunit composition.
1994,
Pubmed
,
Xenbase
