The AMPA receptors are ligand-gated ion channels belonging to the family of ionotropic glutamate receptors. They play an essential role in fast excitatory synaptic transmission in the CNS of vertebrates. Their activity-dependent directed transport and fast turnover at the plasma membrane contribute to synaptic plasticity and require numerous trafficking and scaffolding proteins. Participating in the delivery and synaptic localization of AMPA receptors is a recently discovered protein family named transmembrane AMPA receptor regulatory proteins (TARPs). In addition to their function in trafficking, TARPs alter the biophysical properties of AMPA receptors in remarkable ways and thus contribute significantly to the functional plasticity of the synapse. The study of TARP-mediated functional plasticity of AMPA receptors, which has emerged only recently as a hot new field, promises to yield valuable insight into the regulation of neuronal communication.

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.

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.