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Comparison of the agonist binding site of homomeric, heteromeric, and chimeric GluR1 o and GluR3 o AMPA receptors
Author(s) -
Banke Tue G.,
Schousboe Arne,
Pickering Darryl S.
Publication year - 1997
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/(sici)1097-4547(19970715)49:2<176::aid-jnr6>3.0.co;2-6
Subject(s) - homomeric , ampa receptor , agonist , chemistry , receptor , xenopus , protein subunit , amino acid , biophysics , biochemistry , stereochemistry , glutamate receptor , biology , gene
A series of AMPA [(R,S)‐α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid] analogues were evaluated for activity at homomeric, heteromeric, and chimeric rat GluR1 o and GluR3 o receptors expressed in Xenopus oocytes, using the two‐electrode voltage clamp technique. The formation of heteromeric receptor complexes was demonstrated by cross‐immunoprecipitation of both subunits from solubilized oocyte membranes. The AMPA analogue ACPA [(R,S)‐2‐amino‐3‐(3‐carboxy‐5‐methyl‐4‐isoxazolyl)propionic acid] was the most potent and selective agonist tested at GluR1 o and GluR3 o , with a 10‐fold selectivity for GluR3 o . ACPA showed an intermediate potency at both the GluR1 o + 3 o heteromeric complex as well as at the homomeric chimeric receptors. These experiments suggest that for receptor activation, agonist binding occurs between the interface of the GluR1 and GluR3 subunits in the heteromeric channel complex, perhaps between the S1 region of one subunit and the S2 region of another. Also, it seems that 1) electronegative group substitutions on the isoxazole ring of AMPA and 2) decreasing the pK a of the sub stituent at position 3 play a major role in determining the degree of receptor activation under steady‐state conditions. Future studies will examine the effects of single amino acid mutations in these receptors, giving a more precise localization of the agonist binding site. J. Neurosci. Res. 49:176–185, 1997. © 1997 Wiley‐Liss, Inc.