A Steroid Modulatory Domain on NR2B Controls N-Methyl-D-Aspartate Receptor Proton Sensitivity
N-methyl-D-aspartate (NMDA) receptor function is modulated by several endogenous molecules, including zinc, polyamines, protons, and sulfated neurosteroids. Zinc, polyamines, and phenylethanolamines exert their respective modulatory effects by exacerbating or relieving tonic proton inhibition. Here,...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2004-05, Vol.101 (21), p.8198-8203 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Jang, Ming-Kuei Mierke, Dale F. Russek, Shelley J. Farb, David H. Costa, Erminio |
| description | N-methyl-D-aspartate (NMDA) receptor function is modulated by several endogenous molecules, including zinc, polyamines, protons, and sulfated neurosteroids. Zinc, polyamines, and phenylethanolamines exert their respective modulatory effects by exacerbating or relieving tonic proton inhibition. Here, we report that pregnenolone sulfate (PS) uses a unique mechanism for enhancement of NMDA receptor function that is independent of the proton sensor. We identify a steroid modulatory domain, SMD1, on the NMDA receptor NR2B subunit that is critical for both PS enhancement and proton sensitivity. This domain includes the J/K helices in the S2 region of the glutamate recognition site and the fourth membrane transmembrane region (M4). A molecular model based on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor structure suggests that steroid modulatory domain 1 contributes residues to a hydrophobic pocket that is capable of accommodating PS. The results demonstrate that the J/K helices and the fourth membrane transmembrane region participate in transducing allosteric interactions induced by steroid and proton binding to their respective sites. |
| doi_str_mv | 10.1073/pnas.0401838101 |
| format | Article |
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Zinc, polyamines, and phenylethanolamines exert their respective modulatory effects by exacerbating or relieving tonic proton inhibition. Here, we report that pregnenolone sulfate (PS) uses a unique mechanism for enhancement of NMDA receptor function that is independent of the proton sensor. We identify a steroid modulatory domain, SMD1, on the NMDA receptor NR2B subunit that is critical for both PS enhancement and proton sensitivity. This domain includes the J/K helices in the S2 region of the glutamate recognition site and the fourth membrane transmembrane region (M4). A molecular model based on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor structure suggests that steroid modulatory domain 1 contributes residues to a hydrophobic pocket that is capable of accommodating PS. 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| subjects | Allosteric Regulation - drug effects Allosteric Site Amino Acid Sequence AMPA receptors Animals Biological Sciences Dimerization Dimers Glutamic Acid - metabolism Hydrophobic and Hydrophilic Interactions Models, Molecular Molecular Sequence Data Molecules N methyl D aspartate receptors Oocytes Pharmacology Physical Sciences Pregnenolone - pharmacology Protein Structure, Quaternary Protein Structure, Tertiary Protons Receptors Receptors, AMPA - chemistry Receptors, AMPA - metabolism Receptors, N-Methyl-D-Aspartate - chemistry Receptors, N-Methyl-D-Aspartate - genetics Receptors, N-Methyl-D-Aspartate - metabolism Sensors Steroids Sulfates Xenopus laevis |
| title | A Steroid Modulatory Domain on NR2B Controls N-Methyl-D-Aspartate Receptor Proton Sensitivity |
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