AMPA receptor modulation by cornichon-2 dictated by transmembrane AMPA receptor regulatory protein isoform.
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 I(KA) /I(Glu)  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.
Neuroscience Discovery Research and Clinical Investigation, Eli Lilly and Company, Indianapolis, IN 46285, USA. gill2449@yahoo.com
Martin B
MB
Gill
Akihiko S
AS
Kato
He
H
Wang
David S
DS
Bredt
D001921:Brain / Q000378:metabolism*; D004527:Egg Proteins / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D020033:Protein Isoforms / Q000378:metabolism; D018091:Receptors, AMPA / Q000378:metabolism*; D014162:Transfection
C118276:CNIH1 protein, human; D004527:Egg Proteins; D008565:Membrane Proteins; D020033:Protein Isoforms; D018091:Receptors, AMPA