Present address: Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06511, USA.
AMPA receptor modulation by cornichon-2 dictated by transmembrane AMPA receptor regulatory protein isoform
Article first published online: 30 DEC 2011
© 2011 Eli Lilly and Company. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd
European Journal of Neuroscience
Volume 35, Issue 2, pages 182–194, January 2012
How to Cite
Gill, M. B., Kato, A. S., Wang, H. and Bredt, D. S. (2012), AMPA receptor modulation by cornichon-2 dictated by transmembrane AMPA receptor regulatory protein isoform. European Journal of Neuroscience, 35: 182–194. doi: 10.1111/j.1460-9568.2011.07948.x
- Issue published online: 17 JAN 2012
- Article first published online: 30 DEC 2011
- Received 15 August 2011, revised 12 October 2011, accepted 1 November 2011
- accessory protein;
- auxiliary subunit;
Transmembrane AMPA receptor regulatory proteins (TARPs) are auxiliary subunits that modulate AMPA receptor trafficking, gating and pharmacology throughout the brain. Why cornichon-2 (CNIH-2), another AMPA receptor-associated protein, modulates AMPA receptor gating and pharmacology in hippocampal neurons but not cerebellar granule neurons remains unresolved. Here, we report that CNIH-2 differentially impacts Type-Ia (γ-2 or γ-3) vs. Type-Ib (γ-4 or γ-8) TARP-containing AMPA receptors. Specifically, with AMPA receptors comprising γ-2, the cerebellar-enriched TARP isoform, CNIH-2 decreases IKA/IGlu ratio and decreases cyclothiazide efficacy while having minimal impact on recovery from desensitization and deactivation kinetics. By contrast, with AMPA receptors comprising γ-8, the hippocampal-enriched TARP isoform, we find that CNIH-2 slows deactivation kinetics, increases cyclothiazide potency and occludes a novel AMPA receptor kinetic phenomenon, namely resensitization. Additionally, we find that CNIH-2 differentially modulates the glutamate off-kinetics of γ-8-containing, but not γ-2-containing, AMPA receptors in a manner dependent upon the duration of agonist application. Together, these data demonstrate that the modulation of AMPA receptors by CNIH-2 depends upon the TARP isoform composition within the receptor complex.