title: Comparative analysis of the pharmacology of GluR1 in complex with transmembrane AMPA receptor regulatory proteins gamma2, gamma3, gamma4, and gamma8.
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 (gamma2, gamma3, gamma4, and gamma8) 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 gamma2 and gamma3 and one consisting of gamma4 and gamma8. 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 gamma4) 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.
authors.affiliation: Department of Biochemistry I-Receptor Biochemistry, Building NC, Room 6/171, Ruhr University Bochum, Universitätsstr. 150, D-44780 Bochum, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Kott
authors.forename: C
authors.initials: C
authors.lastname: Sager
authors.forename: D
authors.initials: D
authors.lastname: Tapken
authors.forename: M
authors.initials: M
authors.lastname: Werner
authors.forename: M
authors.initials: M
authors.lastname: Hollmann
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects* / Q000502:physiology; D007473:Ion Channels / Q000187:drug effects* / Q000378:metabolism; D046911:Macromolecular Substances / Q000378:metabolism*; D008565:Membrane Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000187:drug effects / Q000235:genetics; D009865:Oocytes; D020033:Protein Isoforms / Q000187:drug effects / Q000378:metabolism; D018091:Receptors, AMPA / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013111:Spider Venoms / Q000819:agonists; D014982:Xenopus laevis
chemical_list: D015220:Calcium Channels; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018698:Glutamic Acid; D007473:Ion Channels; D046911:Macromolecular Substances; D008565:Membrane Proteins; D020033:Protein Isoforms; D018091:Receptors, AMPA; D013111:Spider Venoms; C113940:Cacng2 protein, mouse; C044936:JSTX spider toxin; C532482:TARP gamma-4 protein, mouse; C515550:TARP gamma-8 protein, mouse