Neurosteroids enhance spontaneous glutamate release in hippocampal neurons -: Possible role of metabotropic σ1-like receptors

被引:110
作者
Meyer, DA
Carta, M
Partridge, LD
Covey, DF
Valenzuela, CF
机构
[1] Univ New Mexico, Dept Neurosci, Hlth Sci Ctr, Albuquerque, NM 87131 USA
[2] Washington Univ, Sch Med, Dept Mol Biol & Pharmacol, St Louis, MO 63110 USA
关键词
D O I
10.1074/jbc.M202592200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Pregnenolone sulfate (PREGS), one of the most abundantly produced neurosteroids in the mammalian brain, improves cognitive performance in rodents. The mechanism of this effect has been attributed to its allosteric modulatory actions on glutamate- and gamma-aminobutyric acid-gated ion channels. Here we report a novel effect of PREGS that could also mediate some of its actions in the nervous system. We found that PREGS induces a robust potentiation of the frequency but not the amplitude of miniature excitatory postsynaptic currents (mEPSCs) mediated by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors in cultured hippocampal neurons. PREGS also decreased paired pulse facilitation of autaptic EPSCs evoked by depolarization, indicating that it modulates glutamate release probability presynaptically. PREGS potentiation of mEPSCs was mimicked by dehydroepiandrosterone sulfate and (+)-pentazocine but not by (-)-pentazocine, the synthetic (-)-enantiomer of PREGS or the inactive steroid isopregnanolone. The a receptor antagonists, haloperidol and BD-1063, blocked the effect of PREGS on mEPSCs, as did pertussis toxin and the membrane-permeable Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (acetoxymethyl) ester. These results suggest that PREGS increases spontaneous glutamate release via activation of a presynaptic GO-coupled sigma receptor and an elevation in intracellular Ca2+ levels. We postulate that presynaptic actions of neurosteroids have a role in the maturation and/or maintenance of synaptic networks and the processing of information in the central nervous system.
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页码:28725 / 28732
页数:8
相关论文
共 60 条
[1]   The synthetic enantiomer of pregnenolone sulfate is very active on memory in rats and mice, even more so than its physiological neurosteroid counterpart: Distinct mechanisms? [J].
Akwa, Y ;
Ladurelle, N ;
Covey, DF ;
Baulieu, EE .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (24) :14033-14037
[2]   The neurosteroid pregnenolone sulphate increases dopamine release and the dopaminergic response to morphine in the rat nucleus accumbens [J].
Barrot, M ;
Vallée, M ;
Gingras, MA ;
Le Moal, M ;
Mayo, W ;
Piazza, PV .
EUROPEAN JOURNAL OF NEUROSCIENCE, 1999, 11 (10) :3757-3760
[3]   Neurosteroids: A novel function of the brain [J].
Baulieu, EE .
PSYCHONEUROENDOCRINOLOGY, 1998, 23 (08) :963-987
[4]  
BOWLBY MR, 1993, MOL PHARMACOL, V43, P813
[5]  
Brent PJ, 1997, J NEUROCHEM, V68, P2201
[6]   Intrasynaptosomal free calcium levels in rat forebrain synaptosomes: Modulation by sigma (sigma) receptor ligands [J].
Brent, PJ ;
Saunders, H ;
Dunkley, PR .
NEUROSCIENCE LETTERS, 1996, 211 (02) :138-142
[7]   Fetal alcohol exposure alters neurosteroid modulation of hippocampal N-methyl-D-aspartate receptors [J].
Costa, ET ;
Olivera, DS ;
Meyer, DA ;
Ferreira, VMM ;
Soto, EE ;
Frausto, S ;
Savage, DD ;
Browning, MD ;
Valenzuela, CF .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (49) :38268-38274
[8]  
Darnaudéry M, 1998, J NEUROCHEM, V71, P2018
[9]   Pregnenolone sulfate increases hippocampal acetylcholine release and spatial recognition [J].
Darnaudéry, M ;
Koehl, M ;
Piazza, PV ;
Le Moal, M ;
Mayo, W .
BRAIN RESEARCH, 2000, 852 (01) :173-179
[10]   Calcium stores in hippocampal synaptic boutons mediate short-term plasticity, store-operated Ca2+ entry, and spontaneous transmitter release [J].
Emptage, NJ ;
Reid, CA ;
Fine, A .
NEURON, 2001, 29 (01) :197-208