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British Journal of Pharmacology
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January 1999, Volume 126, Issue 1, Pages 296 - 300 |
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| Original Article |
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Lack of interaction between nitric oxide and the redox modulatory site of the NMDA receptor
Elias Aizenman1 & William K. Potthoff Department of Neurobiology, University of Pittsburgh School of Medicine, E1456 Biomedical Science Tower, 3500 Terrace Street, Pittsburgh, Pennsylvania 15261, U.S.A.1Author for correspondence: E-mail: redox@pitt.edu |
| Keywords |
| NMDA receptor;
nitric oxide;
redox modulatory site;
cortical neurons;
recombinant expression;
patch-clamping |
| Abstract |
1 The inhibitory effects of nitric oxide (NO) on N-methyl-D-aspartate (NMDA) receptor function have been proposed to be mediated via the interaction of this gas with a redox-sensitive thiol moiety on the receptor. Here, we evaluated this suggested mechanism by examining the actions of various NO donors on native neuronal receptors as well as in wild-type and cysteine-mutated recombinant NMDA receptors expressed in Chinese hamster ovary (CHO) cells. 2 The NO donor N-ethyl-2-(1-ethyl-2-hydroxy-2-nitrosohydraxino)ethanamine (NOC-12; 100 µM) produced a rapid and readily reversible inhibition of whole-cell currents induced by NMDA (30 µM) in cultured cortical neurons. The inhibition was apparent at all holding potentials, though a more pronounced block was observed at negative voltages. The effects of NOC-12 disappeared when the donor was allowed to expire. A similar receptor block was observed with another NO-releasing agent, S-nitroso-N-acetylpenicillamine (SNAP; 1 mM). 3 The blocking effects of NO released by SNAP, 3-morpholinosydnonimine (SIN-1; 1 mM), and 3-[2-hydroxy-1-(1-methylethyl)-2-nitrosohydrazino]-1-propanamine (NOC-5; 100 µM) on currents mediated by recombinant NR1/NR2B receptors were virtually indistinguishable from those observed on native receptors. Furthermore, mutating cysteines 744 and 798 of NR1, which constitute the principal redox modulatory site of the NR1/NR2B receptor configuration, did not affect the inhibition produced by NO. 4 The NR2A subunit may contribute its own redox-sensitive site. However, the effects of NO on NR1/NR2A receptors were very similar to those seen for all other receptor configurations evaluated. Hence, we conclude that NO does not exert its inhibition of NMDA-induced responses via a modification of any of the previously described redox-sensitive sites on the receptor. |
Received 11 September 1998; Revised 5 October 1998; Accepted 14 October 1998
