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The Journal of Neuroscience, November 17, 2004, 24(46):10318-10325; doi:10.1523/JNEUROSCI.2099-04.2004

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Cellular/Molecular
Molecular Mechanism of Pregnenolone Sulfate Action at NR1/NR2B Receptors

Martin Horak,¹ Kamil Vlcek,¹ Milos Petrovic,¹ Hana Chodounska,² and Ladislav Vyklicky, Jr¹

¹Institute of Physiology, Academy of Sciences of the Czech Republic, 142 20 Prague 4, Czech Republic, and ²Institute of Organic Chemistry and Biochemistry, 166 10 Prague 2, Czech Republic

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 K_d 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 (P_o). 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.

These results suggest that the PS is a modulator of NMDA receptor P_o, the effectiveness of which is lowered by glutamate binding. This modulation may have important consequences for the neuronal excitability.

Key words: neurosteroids; NMDA receptor; open probability; patch-clamp recording; recombinant receptors; glutamate

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Received Feb 18, 2004; revised October 5, 2004; accepted October 5, 2004.

This article has been cited by other articles:

				M. L. Blanke and A. M. J. VanDongen The NR1 M3 Domain Mediates Allosteric Coupling in the N-Methyl-D-aspartate Receptor Mol. Pharmacol., August 1, 2008; 74(2): 454 - 465. [Abstract] [Full Text] [PDF]

				T. Johansson, P.-A. Frandberg, F. Nyberg, and P. Le Greves Molecular Mechanisms for Nanomolar Concentrations of Neurosteroids at NR1/NR2B Receptors J. Pharmacol. Exp. Ther., February 1, 2008; 324(2): 759 - 768. [Abstract] [Full Text] [PDF]

				M. Petrovic, M. Sedlacek, M. Horak, H. Chodounska, and L. Vyklicky Jr 20-Oxo-5{beta}-Pregnan-3{alpha}-yl Sulfate Is a Use-Dependent NMDA Receptor Inhibitor J. Neurosci., September 14, 2005; 25(37): 8439 - 8450. [Abstract] [Full Text] [PDF]

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