RT Journal Article
SR Electronic
T1 Modulation of Agonist Binding to AMPA Receptors by 1-(1,4-Benzodioxan-6-ylcarbonyl)piperidine (CX546): Differential Effects across Brain Regions and GluA1–4/Transmembrane AMPA Receptor Regulatory Protein Combinations
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 965
OP 974
DO 10.1124/jpet.109.158014
VO 331
IS 3
A1 Montgomery, Kyle E.
A1 Kessler, Markus
A1 Arai, Amy C.
YR 2009
UL http://jpet.aspetjournals.org/content/331/3/965.abstract
AB Ampakines are cognitive enhancers that potentiate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor currents and synaptic responses by slowing receptor deactivation. Their efficacy varies greatly between classes of neurons and brain regions, but the factor responsible for this effect remains unclear. Ampakines also increase agonist affinity in binding tests in ways that are related to their physiological action. We therefore examined 1) whether ampakine effects on agonist binding vary across brain regions and 2) whether they differ across receptor subunits expressed alone and together with transmembrane AMPA receptor regulatory proteins (TARPs), which associate with AMPA receptors in the brain. We found that the maximal increase in agonist binding (Emax) caused by the prototypical ampakine 1-(1,4-benzodioxan-6-ylcarbonyl)piperidine (CX546) differs significantly between brain regions, with effects in hippocampus and cerebellum being nearly three times larger than that in thalamus, brainstem, and striatum, and cortex being intermediate. These differences can be explained at least in part by regional variations in receptor subunit and TARP expression because combinations prevalent in hippocampus (GluA2 with TARPs γ3 and γ8) exhibited Emax values nearly twice those of combinations abundant in thalamus (GluA4 with γ2 or γ4). TARPs seem to be critical because GluA2 and GluA4 alone had comparable Emax and also because hippocampal and thalamic receptors had similar Emax after solubilization with Triton X-100, which probably removes associated proteins. Taken together, our data suggest that variations in physiological drug efficacy, such as the 3-fold difference previously seen in recordings from hippocampus versus thalamus, may be explained by region-specific expression of GluA1–4 as well as TARPs.© 2009 by The American Society for Pharmacology and Experimental Therapeutics