Structures of the AMPA receptor in complex with its auxiliary subunit cornichon

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Science  06 Dec 2019:
Vol. 366, Issue 6470, pp. 1259-1263
DOI: 10.1126/science.aay2783

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Regulating synaptic signals

In the brain, AMPA-type glutamate receptors (AMPARs) are ion channels that play key roles in synaptic plasticity, cognition, learning, and memory. Two classes of subunits, the claudin family and the cornichon family, regulate AMPAR gating and trafficking. Previous structures have been presented of AMPAR bound to claudin homologs. Now, Nakagawa reports a high-resolution structure of AMPAR bound to the cornichon homolog CNIH3, determined by cryo–electron microscopy (see the Perspective by Schwenk and Fakler). In contrast to a predicted topology of three transmembrane helices and an intracellular amino terminus, CNIH3 has four transmembrane helices, and both the amino and carboxyl termini are extracellular. The structure reveals the architecture of the interaction interface between AMPAR and CNIH3 and suggests a role for lipids in regulating the assembly and function of the AMPAR-CNIH3 complex.

Science, this issue p. 1259; see also p. 1194


In the brain, AMPA-type glutamate receptors (AMPARs) form complexes with their auxiliary subunits and mediate the majority of fast excitatory neurotransmission. Signals transduced by these complexes are critical for synaptic plasticity, learning, and memory. The two major categories of AMPAR auxiliary subunits are transmembrane AMPAR regulatory proteins (TARPs) and cornichon homologs (CNIHs); these subunits share little homology and play distinct roles in controlling ion channel gating and trafficking of AMPAR. Here, I report high-resolution cryo–electron microscopy structures of AMPAR in complex with CNIH3. Contrary to its predicted membrane topology, CNIH3 lacks an extracellular domain and instead contains four membrane-spanning helices. The protein-protein interaction interface that dictates channel modulation and the lipids surrounding the complex are revealed. These structures provide insights into the molecular mechanism for ion channel modulation and assembly of AMPAR/CNIH3 complexes.

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