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Comparative analysis of the pharmacology of GluR1 in complex with transmembrane AMPA receptor regulatory proteins γ2, γ3, γ4, and γ8

Authors
Journal
Neuroscience
0306-4522
Publisher
Elsevier
Publication Date
Volume
158
Issue
1
Identifiers
DOI: 10.1016/j.neuroscience.2007.12.047
Keywords
  • Stargazin
  • Ampa Receptor
  • Glutamate Receptor
  • Nasp
  • Cnqx
  • Quinoxaline
Disciplines
  • Biology
  • Pharmacology

Abstract

Abstract AMPA receptors (AMPARs) mediate the majority of fast synaptic transmission in the CNS of vertebrates. They are believed to be associated with members of the transmembrane AMPA receptor regulatory protein (TARP) family. TARPs mediate the delivery of AMPA receptors to the plasma membrane and mediate their synaptic trafficking. Moreover, TARPs modulate essential electrophysiological properties of AMPA receptors. Here, we compare the influence of rat TARPs (γ2, γ3, γ4, and γ8) on pharmacological properties of rat GluR1(Q)flip. We show that agonist potencies are increased by all TARPs, but to individually different extents. On the other hand, all TARPs increase agonist potencies at the virtually non-desensitizing mutant GluR1-L479Y almost identically. Comparison of the influence of individual TARPs on relative agonist efficacies confirmed that the TARPs can be functionally subdivided into two subgroups, one consisting of γ2 and γ3 and one consisting of γ4 and γ8. Surprisingly, we found that TARPs convert certain AMPA receptor antagonists to agonists. The potency of one of these converted antagonists is dependent on the particular TARP. Moreover, TARPs (except γ4) reduce the ion channel block by the synthetic Joro spider toxin analog 1-naphthylacetyl spermine (NASP). In addition, TARPs increase the permeability of the receptor to calcium, indicating that TARPs directly modulate important ion pore properties. In summary, the data presented herein will illustrate and help to understand the previously unexpected complexities of modulation of AMPA receptor pharmacological properties by TARPs.

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