Molecular Mechanism of Pregnenolone Sulfate Action at NR1/NR2B Receptors
Open Access
- 17 November 2004
- journal article
- Published by Society for Neuroscience in Journal of Neuroscience
- Vol. 24 (46), 10318-10325
- https://doi.org/10.1523/jneurosci.2099-04.2004
Abstract
NMDA receptors are highly expressed in the CNS and are involved in excitatory synaptic transmission and synaptic plasticity as well as excitotoxicity. They have several binding sites for allosteric modulators, including neurosteroids, endogenous compounds synthesized by the nervous tissue and expected to act locally. Whole-cell patch-clamp recording from human embryonic kidney 293 cells expressing NR1-1a/NR2B receptors revealed that neurosteroid pregnenolone sulfate (PS) (300 μm), when applied to resting NMDA receptors, potentiates the amplitude of subsequent responses to 1 mm glutamate fivefold and slows their deactivation twofold. The same concentration of PS, when applied during NMDA receptor activation by 1 mm glutamate, has only a small effect. The association and dissociation rate constants of PS binding and unbinding from resting NMDA receptors are estimated to be 3.3 ± 2.0 mm-1sec-1 and 0.12 ± 0.02 sec-1, respectively, corresponding to an apparent affinity Kd of 37 μm. The results of experiments indicate that the molecular mechanism of PS potentiation of NMDA receptor responses is attributable to an increase in the peak channel open probability (Po). Responses to glutamate recorded in the continuous presence of PS exhibit marked time-dependent decline. Our results indicate that the decline is induced by a change of the NMDA receptor affinity for PS after receptor activation.Keywords
This publication has 31 references indexed in Scilit:
- Activation‐Dependent Properties of Pregnenolone Sulfate Inhibition of GABAA Receptor‐Mediated CurrentThe Journal of Physiology, 2003
- Activation of NR1/NR2B NMDA receptorsNature Neuroscience, 2003
- NMDA receptor pathways as drug targetsNature Neuroscience, 2002
- Pregnenolone sulfate block of GABAA receptors: mechanism and involvement of a residue in the M2 region of the α subunitThe Journal of Physiology, 2001
- Copper Modulation of NMDA Responses in Mouse and Rat Cultured Hippocampal NeuronsEuropean Journal of Neuroscience, 1996
- GEPASI: a software package for modelling the dynamics, steady states and control of biochemical and other systemsBioinformatics, 1993
- Zinc potentiates agonist-lnduced currents at certain splice variants of the NMDA receptorNeuron, 1993
- Synthesis of the sulfates derived from 5α-cholestane-3β, 6α-diolSteroids, 1992
- High Probability Opening of NMDA Receptor Channels by L-GlutamateScience, 1992
- Activation kinetics reveal the number of glutamate and glycine binding sites on the N-methyl-d-aspartate receptorNeuron, 1991