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Science 2 November 2007:
Vol. 318. no. 5851, pp. 815 - 817
DOI: 10.1126/science.1146317
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Reports

TARP Auxiliary Subunits Switch AMPA Receptor Antagonists into Partial Agonists

Karen Menuz,1,2 Robert M. Stroud,3* Roger A. Nicoll,1,4* Franklin A. Hays3

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.

1 Department of Cellular and Molecular Pharmacology, University of California at San Francisco, San Francisco, CA 94143, USA.
2 Graduate Program in Neuroscience, University of California at San Francisco, San Francisco, CA 94143, USA.
3 Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, CA 94143, USA.
4 Department of Physiology, University of California at San Francisco, San Francisco, CA 94143, USA.

* To whom correspondence should be addressed: stroud{at}msg.ucsf.edu (R.M.S.); nicoll{at}cmp.ucsf.edu (R.A.N.)

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TARP Redundancy Is Critical for Maintaining AMPA Receptor Function.
K. Menuz, J. L. O'Brien, S. Karmizadegan, D. S. Bredt, and R. A. Nicoll (2008)
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Desensitization of Chemical Activation by Auxiliary Subunits: CONVERGENCE OF MOLECULAR DETERMINANTS CRITICAL FOR AUGMENTING KCNQ1 POTASSIUM CHANNELS.
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