Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 318 (5851): 815-817

Copyright © 2007 by the American Association for the Advancement of Science

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

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.

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} (R.M.S.); nicoll{at} (R.A.N.)

Expression mechanisms underlying long-term potentiation: a postsynaptic view, 10 years on.
A. J. Granger and R. A. Nicoll (2013)
Phil Trans R Soc B 369, 20130136
   Abstract »    Full Text »    PDF »
NMDA Receptor Activation and Calpain Contribute to Disruption of Dendritic Spines by the Stress Neuropeptide CRH.
A. L. Andres, L. Regev, L. Phi, R. R. Seese, Y. Chen, C. M. Gall, and T. Z. Baram (2013)
J. Neurosci. 33, 16945-16960
   Abstract »    Full Text »    PDF »
A Conserved Mechanism for Gating in an Ionotropic Glutamate Receptor.
B. S. Moore, U. L. Mirshahi, T. L. Ebersole, and T. Mirshahi (2013)
J. Biol. Chem. 288, 18842-18852
   Abstract »    Full Text »    PDF »
AMPA receptor/TARP stoichiometry visualized by single-molecule subunit counting.
P. Hastie, M. H. Ulbrich, H.-L. Wang, R. J. Arant, A. G. Lau, Z. Zhang, E. Y. Isacoff, and L. Chen (2013)
PNAS 110, 5163-5168
   Abstract »    Full Text »    PDF »
The Structure of (-)-Kaitocephalin Bound to the Ligand Binding Domain of the (S)-{alpha}-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA)/Glutamate Receptor, GluA2.
A. H. Ahmed, M. Hamada, T. Shinada, Y. Ohfune, L. Weerasinghe, P. P. Garner, and R. E. Oswald (2012)
J. Biol. Chem. 287, 41007-41013
   Abstract »    Full Text »    PDF »
Defined criteria for auxiliary subunits of glutamate receptors.
D. Yan and S. Tomita (2012)
J. Physiol. 590, 21-31
   Abstract »    Full Text »    PDF »
Stargazing from a new vantage - TARP modulation of AMPA receptor pharmacology.
A. C. Jackson and R. A. Nicoll (2011)
J. Physiol. 589, 5909-5910
   Full Text »    PDF »
Transmembrane AMPA receptor regulatory protein regulation of competitive antagonism: a problem of interpretation.
D. M. MacLean and D. Bowie (2011)
J. Physiol. 589, 5383-5390
   Abstract »    Full Text »    PDF »
Mechanism of AMPA Receptor Activation by Partial Agonists: DISULFIDE TRAPPING OF CLOSED LOBE CONFORMATIONS.
A. H. Ahmed, S. Wang, H.-H. Chuang, and R. E. Oswald (2011)
J. Biol. Chem. 286, 35257-35266
   Abstract »    Full Text »    PDF »
Probing TARP Modulation of AMPA Receptor Conductance with Polyamine Toxins.
A. C. Jackson, A. D. Milstein, D. Soto, M. Farrant, S. G. Cull-Candy, and R. A. Nicoll (2011)
J. Neurosci. 31, 7511-7520
   Abstract »    Full Text »    PDF »
Transmembrane AMPA Receptor Regulatory Proteins and Cornichon-2 Allosterically Regulate AMPA Receptor Antagonists and Potentiators.
D. A. Schober, M. B. Gill, H. Yu, D. L. Gernert, M. W. Jeffries, P. L. Ornstein, A. S. Kato, C. C. Felder, and D. S. Bredt (2011)
J. Biol. Chem. 286, 13134-13142
   Abstract »    Full Text »    PDF »
Stargazin (TARP {gamma}-2) Is Required for Compartment-Specific AMPA Receptor Trafficking and Synaptic Plasticity in Cerebellar Stellate Cells.
A. C. Jackson and R. A. Nicoll (2011)
J. Neurosci. 31, 3939-3952
   Abstract »    Full Text »    PDF »
Functional comparison of the effects of TARPs and cornichons on AMPA receptor trafficking and gating.
Y. Shi, Y. H. Suh, A. D. Milstein, K. Isozaki, S. M. Schmid, K. W. Roche, and R. A. Nicoll (2010)
PNAS 107, 16315-16319
   Abstract »    Full Text »    PDF »
Glutamate Receptor Ion Channels: Structure, Regulation, and Function.
S. F. Traynelis, L. P. Wollmuth, C. J. McBain, F. S. Menniti, K. M. Vance, K. K. Ogden, K. B. Hansen, H. Yuan, S. J. Myers, and R. Dingledine (2010)
Pharmacol. Rev. 62, 405-496
   Abstract »    Full Text »    PDF »
Desensitization and models of receptor-channel activation.
C. Shelley and S. G. Cull-Candy (2010)
J. Physiol. 588, 1395-1397
   Full Text »    PDF »
Selective Excitatory Actions of DNQX and CNQX in Rat Thalamic Neurons.
S. H. Lee, G. Govindaiah, and C. L. Cox (2010)
J Neurophysiol 103, 1728-1734
   Abstract »    Full Text »    PDF »
Regulation of Ionotropic Glutamate Receptors by Their Auxiliary Subunits.
S. Tomita (2010)
Physiology 25, 41-49
   Abstract »    Full Text »    PDF »
C-terminal Domains of Transmembrane {alpha}-Amino-3-hydroxy-5-methyl-4-isoxazole Propionate (AMPA) Receptor Regulatory Proteins Not Only Facilitate Trafficking but Are Major Modulators of AMPA Receptor Function.
C. Sager, J. Terhag, S. Kott, and M. Hollmann (2009)
J. Biol. Chem. 284, 32413-32424
   Abstract »    Full Text »    PDF »
Full Domain Closure of the Ligand-binding Core of the Ionotropic Glutamate Receptor iGluR5 Induced by the High Affinity Agonist Dysiherbaine and the Functional Antagonist 8,9-Dideoxyneodysiherbaine.
K. Frydenvang, L. L. Lash, P. Naur, P. A. Postila, D. S. Pickering, C. M. Smith, M. Gajhede, M. Sasaki, R. Sakai, O. T. Pentikainen, et al. (2009)
J. Biol. Chem. 284, 14219-14229
   Abstract »    Full Text »    PDF »
Functional Characterization and In Silico Docking of Full and Partial GluK2 Kainate Receptor Agonists.
A.-M. L. Fay, C. R. Corbeil, P. Brown, N. Moitessier, and D. Bowie (2009)
Mol. Pharmacol. 75, 1096-1107
   Abstract »    Full Text »    PDF »
Structural Insights into the Extracytoplasmic Thiamine-Binding Lipoprotein p37 of Mycoplasma hyorhinis.
K. H. Sippel, A. H. Robbins, R. Reutzel, S. K. Boehlein, K. Namiki, S. Goodison, M. Agbandje-McKenna, C. J. Rosser, and R. McKenna (2009)
J. Bacteriol. 191, 2585-2592
   Abstract »    Full Text »    PDF »
Cellular Plasticity for Group I mGluR-Mediated Epileptogenesis.
R. Bianchi, S.-C. Chuang, W. Zhao, S. R. Young, and R. K. S. Wong (2009)
J. Neurosci. 29, 3497-3507
   Abstract »    Full Text »    PDF »
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)
J. Neurosci. 28, 8740-8746
   Abstract »    Full Text »    PDF »
Z. Gao, Q. Xiong, H. Sun, and M. Li (2008)
J. Biol. Chem. 283, 22649-22658
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882