Format

Send to

Choose Destination
See comment in PubMed Commons below
Science. 2007 Nov 2;318(5851):815-7.

TARP auxiliary subunits switch AMPA receptor antagonists into partial agonists.

Author information

1
Department of Cellular and Molecular Pharmacology, University of California at San Francisco, San Francisco, CA 94143, USA.

Abstract

Quinoxalinedione compounds such as 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) are the most commonly used alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists. However, we find that in the presence of transmembrane AMPA receptor regulatory proteins (TARPs), which are AMPA receptor auxiliary subunits, CNQX acts as a partial agonist. CNQX induced small depolarizing currents in neurons of the central nervous system, and reconstitution of this agonist activity required coexpression of TARPs. A crystal structure of CNQX bound to the TARP-less AMPA receptor ligand-binding domain showed that, although CNQX induces partial domain closure, this movement is not transduced into linker separation, suggesting that TARPs may increase agonist efficacy by strengthening the coupling between domain closure and channel opening. Our results demonstrate that the presence of an auxiliary subunit can determine whether a compound functions as an agonist or antagonist.

PMID:
17975069
DOI:
10.1126/science.1146317
[Indexed for MEDLINE]
Free full text
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire
    Loading ...
    Support Center