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Hippocampal AMPA receptor gating controlled by both TARP and cornichon proteins.

ABSTRACT: Transmembrane AMPA receptor regulatory proteins (TARPs) and cornichon proteins (CNIH-2/3) independently modulate AMPA receptor trafficking and gating. However, the potential for interactions of these subunits within an AMPA receptor complex is unknown. Here, we find that TARPs ?-4, ?-7, and ?-8, but not ?-2, ?-3, or ?-5, cause AMPA receptors to "resensitize" upon continued glutamate application. With ?-8, resensitization occurs with all GluA subunit combinations; however, ?-8-containing hippocampal neurons do not display resensitization. In recombinant systems, CNIH-2 abrogates ?-8-mediated resensitization and modifies AMPA receptor pharmacology and gating to match that of hippocampal neurons. In hippocampus, ?-8 and CNIH-2 associate in postsynaptic densities and CNIH-2 protein levels are markedly diminished in ?-8 knockout mice. Manipulating neuronal CNIH-2 levels modulates the electrophysiological properties of extrasynaptic and synaptic ?-8-containing AMPA receptors. Thus, ?-8 and CNIH-2 functionally interact with common hippocampal AMPA receptor complexes to modulate synergistically kinetics and pharmacology.

SUBMITTER: Kato AS

PROVIDER: S-EPMC3034222 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Hippocampal AMPA receptor gating controlled by both TARP and cornichon proteins.

Kato Akihiko S AS Gill Martin B MB Ho Michelle T MT Yu Hong H Tu Yuan Y Siuda Edward R ER Wang He H Qian Yue-Wei YW Nisenbaum Eric S ES Tomita Susumu S Bredt David S DS

Neuron 20101201 6

Transmembrane AMPA receptor regulatory proteins (TARPs) and cornichon proteins (CNIH-2/3) independently modulate AMPA receptor trafficking and gating. However, the potential for interactions of these subunits within an AMPA receptor complex is unknown. Here, we find that TARPs γ-4, γ-7, and γ-8, but not γ-2, γ-3, or γ-5, cause AMPA receptors to "resensitize" upon continued glutamate application. With γ-8, resensitization occurs with all GluA subunit combinations; however, γ-8-containing hippocam ...[more]

PMID: 21172611

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Project description:AMPA-type gultamate receptors (AMPARs) mediate excitatory signaling in the brain and are therapeutic targets for the treatment of diverse neurological disorders. The receptors interact with a variety of auxiliary subunits, including the transmembrane AMPAR regulatory proteins (TARPs). The TARPs influence AMPAR biosynthesis and trafficking and enhance receptor responses by slowing desensitization and deactivation and increasing single-channel conductance. TARP γ8 has an expression pattern that is distinct from that of other TARPs, being enriched in the hippocampus. Recently, several compounds have been identified that selectivity inhibit γ8-containing AMPARs. One such inhibitor, JNJ-55511118, has shown considerable promise for the treatment of epilepsy. However, key details of its mechanism of action are still lacking. Here, using patch-clamp electrophysiological recording from heterologously expressed AMPARs, we show that JNJ-55511118 inhibits peak currents of γ8-containing AMPARs by decreasing their single-channel conductance. The drug also modifies hallmark features of AMPAR pharmacology, including the TARP-dependent actions of intracellular polyamines and the partial agonist kainate. Moreover, we find that JNJ-55511118 reduces the influence of γ8 on all biophysical measures, aside from its effect on the recovery from desensitization. The drug is also effective when applied intracellularly, suggesting it may access its binding site from within the membrane. Additionally, we find that AMPARs incorporating TARP γ2 mutated to contain the JNJ-55511118 binding site, exhibit greater block than seen with AMPARs containing γ8, potentially reflecting differences in TARP stoichiometry. Taken together, our data provide new insight into the mechanism by which γ8-selective drugs inhibit AMPARs. SIGNIFICANCE STATEMENT: Although modulation of AMPA-type glutamate receptors shows promise for the treatment various neurological conditions, the absence of subtype-selective drugs has hindered adoption of this therapeutic strategy. We made patch-clamp recordings to characterize the actions of the γ8-selective AMPAR inhibitor JNJ-55511118 on GluA2(Q) receptors expressed in HEK cells. We report that JNJ-55511118 inhibits AMPAR-mediated currents by reducing single-channel conductance, providing clear insight into the mechanism of action of this important class of AMPAR modulators.

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Hippocampal AMPA receptor gating controlled by both TARP and cornichon proteins.

Publications

Hippocampal AMPA receptor gating controlled by both TARP and cornichon proteins.

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