Functional Proteomics Identify Cornichon Proteins as Auxiliary Subunits of AMPA Receptors

Abstract

Glutamate receptors of the AMPA-subtype (AMPARs), together with the transmembrane AMPAR regulatory proteins (TARPs), mediate fast excitatory synaptic transmission in the mammalian brain. Here, we show by proteomic analysis that the majority of AMPARs in the rat brain are coassembled with two members of the cornichon family of transmembrane proteins, rather than with the TARPs. Coassembly with cornichon homologs 2 and 3 affects AMPARs in two ways: Cornichons increase surface expression of AMPARs, and they alter channel gating by markedly slowing deactivation and desensitization kinetics. These results demonstrate that cornichons are intrinsic auxiliary subunits of native AMPARs and provide previously unknown molecular determinants for glutamatergic neurotransmission in the central nervous system.

Neurobeachin regulates neurotransmitter receptor trafficking to synapses

“…Several key regulators of synaptic glutamate receptor localization and function have been characterized (Malinow and Malenka, 2002;Bredt and Nicoll, 2003), such as CaMKII (Pettit et al, 1994), transmembrane AMPA receptor regulatory proteins (Tomita et al, 2005), Cornichon (Schwenk et al, 2009), or CKAMP44 (von Engelhardt et al, 2010. Upon synaptic activity, AMPA receptor GluA1 and GluA2/3 subunits are differentially trafficked to synapses (Wenthold et al, 1996;Hayashi et al, 2000;Shi et al, 2001).…”

Transmembrane AMPA Receptor Regulatory Proteins and Cornichon-2 Allosterically Regulate AMPA Receptor Antagonists and Potentiators

“…Binding by Non-competitive Antagonists-Recent proteomic analyses have identified several additional AMPA receptor accessory proteins that modulate channel kinetics and/or pharmacology (11,14). In particular, CNIH (cornichon) proteins modulate surface trafficking of AMPA receptors and channel gating (11)(12)(13).…”

“…In particular, CNIH (cornichon) proteins modulate surface trafficking of AMPA receptors and channel gating (11)(12)(13). CNIH-2 is present in multiple brain regions with high levels of expression occurring in the hippocampus and low levels of expression in the cerebellum, particularly within the Purkinje neuron population (12,13).…”

“…In addition to the principal GluA subunits, neuronal AMPA receptors typically contain auxiliary transmembrane AMPA receptor regulatory protein (TARPs) 2 subunits (4,5), which enhance receptor trafficking (6) and modulate channel gating (7)(8)(9)(10). Neuronal AMPA receptors may also associate with other transmembrane proteins, including CNIH (cornichon) proteins and CKAMP44, which can further modulate receptor trafficking and channel function (11)(12)(13)(14). AMPA receptors play fundamental roles in controlling behavior, learning, and memory; dysfunction of these receptors likely underlies a variety of neuropsychiatric disorders (15)(16)(17)(18)(19)(20)(21).…”

Control of AMPA Receptor Activity by the Extracellular Loops of Auxiliary Proteins

“…Since the identification of the protein Stargazin, also known as g2, as the prototype transmembrane AMPA receptor regulatory protein (TARP) (Chen et al, 2000), several families of auxiliary proteins for the AMPA receptor have been described that include TARPs (Schwenk et al, 2012;Tomita et al, 2003), cornichons (Schwenk et al, 2009), GSG1L (Shanks et al, 2012) and CKAMPs (von Engelhardt et al, 2010;Klaassen et al, 2016). These proteins play an essential role in tethering AMPA-type glutamate receptors at the synapse, and also exert complex control over surface expression of functional receptors (Dakoji et al, 2003;Yamazaki et al, 2010).…”