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, 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 alpha-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.
Jang
Ming-Kuei
MK
Laboratory of Molecular Neurobiology, Department of Pharmacology, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118; and Department of Molecular Pharmacology, Division of Biology and Medicine, and Department of Chemistry, Brown University, Providence, RI 02912.
Mierke
Dale F
DF
Russek
Shelley J
SJ
Farb
David H
DH
D000494:Allosteric Regulation / Q000187:drug effects; D000495:Allosteric Site; D000595:Amino Acid Sequence; D000818:Animals; D019281:Dimerization; D018698:Glutamic Acid / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011284:Pregnenolone / Q000494:pharmacology*; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D011522:Protons; D018091:Receptors, AMPA / Q000737:chemistry / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis
C121001:NR2B NMDA receptor; D011522:Protons; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C018370:pregnenolone sulfate; D018698:Glutamic Acid; D011284:Pregnenolone