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Pre‐TM4 residues of GluN2 subunits modulate the function of recombinant N‐methyl‐D‐aspartate (NMDA) receptors
Author(s) -
Hughes Benjamin,
Woodward John
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.lb519
Subject(s) - nmda receptor , chemistry , glutamate receptor , transmembrane domain , receptor , ionotropic effect , protein subunit , ligand (biochemistry) , glycine , gating , agonist , biophysics , amino acid , stereochemistry , biochemistry , biology , gene
The N‐methyl‐D‐aspartate (NMDA) receptor is a ligand‐gated ionotropic receptor activated by the neurostransmitter glutamate and is essential to fast excitatory neurotransmission. NMDARs are heteromeric tetramers composed of obligate GluN1 subunits as well as GluN2 or GluN3 subunits. Four distinct types of GluN2 subunits (GluN2A‐D) are known and impart divergent receptor properties including changes in agonist affinity and channel gating. In the present study, we identified a sequence of amino acids in the pre‐TM4 region of GluN2B that affects ligand affinity and the effectiveness of ethanol to inhibit the channel. This sequence, that immediately precedes the fourth transmembrane domain, is highly conserved amongst GluN2 subunits. Glycine substitutions at discrete locations within this sequence produce a significant leftward shift of the glutamate concentration‐response curve and currents display a significantly longer decay constant. Furthermore, glycine substitutions in this region also increase the sensitivity of the receptor to ethanol inhibition. Ongoing studies are focused on determining how this region, distinct from the S1 and S2 ligand‐binding domain, affects the sensitivity of the receptor to agonists and antagonists. Supported by grants T32 AA007474 (B.A.H) and R37 AA009986 (J.J.W.).