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The Journal of Neuroscience, September 14, 2005, 25(37):8439-8450; doi:10.1523/JNEUROSCI.1407-05.2005

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Cellular/Molecular
20-Oxo-5-Pregnan-3-yl Sulfate Is a Use-Dependent NMDA Receptor Inhibitor

Milos Petrovic,¹ Miloslav Sedlacek,¹ Martin Horak,¹ Hana Chodounska,² and Ladislav Vyklick, 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 ligand-gated ion channels permeable to calcium and play a critical role in excitatory synaptic transmission, synaptic plasticity, and excitotoxicity. They are heteromeric complexes of NR1 combined with NR2A-D and/or NR3A-B subunits that are activated by glutamate and glycine and whose activity is modulated by allosteric modulators. In this study, patch-clamp recordings from human embryonic kidney 293 cells expressing NR1/NR2 receptors were used to study the molecular mechanism of the endogenous neurosteroid 20-oxo-5-pregnan-3-yl sulfate (35S) action at NMDA receptors. 35S was a twofold more potent inhibitor of responses mediated by NR1/NR2C-D receptors than those mediated by NR1/NR2A-B receptors. The structure of the extracellular loop between the third and fourth transmembrane domains of the NR2 subunit was found to be critical for the neurosteroid inhibitory effect. The degree of 35S-induced inhibition of responses to glutamate was voltage independent, with recovery lasting several seconds. In contrast, application of 35S in the absence of agonist had no effect on the subsequent response to glutamate made in the absence of the neurosteroid. A kinetic model was developed to explain the use-dependent action of 35S at NMDA receptors. In accordance with the model, 35S was a less potent inhibitor of NMDA receptor-mediated EPSCs and responses induced by a short application of 1 mM glutamate than of those induced by a long application of glutamate.

These results suggest that 35S is a use-dependent but voltage-independent inhibitor of NMDA receptors, with more potent action at tonically than at phasically activated receptors. This may be important in the treatment of excitotoxicity-induced neurodegeneration.

Key words: neurosteroids; NMDA receptor; inhibition; patch-clamp recording; recombinant receptors; culture

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Received April 11, 2005; revised July 26, 2005; accepted July 28, 2005.

This article has been cited by other articles:

				C. L. Kussius, N. Kaur, and G. K. Popescu Pregnanolone Sulfate Promotes Desensitization of Activated NMDA Receptors J. Neurosci., May 27, 2009; 29(21): 6819 - 6827. [Abstract] [Full Text] [PDF]

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