Neto1 and Neto2: auxiliary subunits that determine key properties of native kainate receptors

Abstract

Kainate receptors (KARs) are a subfamily of ionotropic glutamate receptors (iGluRs) that mediate excitatory synaptic transmission, regulate neurotransmitter release, and show a remarkably selective distribution in the brain. Compared to other iGluRs, the precise contribution of KARs to brain function is less understood. Unlike recombinant KARs, native KARs exhibit characteristically slow channel kinetics. The underlying explanation for this dissimilar kinetics has remained elusive until recently. New research has identified Neto1 and Neto2 as KAR auxiliary subunits that determine unique properties of synaptic KARs, including their slow kinetics and high affinity for agonist. Whether these auxiliary subunits regulate KAR trafficking and targeting at the synapse is less clear. By regulating channel gating, Neto1 and Neto2 can increase the diversity of KAR functional properties. These auxiliary subunits may represent a starting point for a better understanding of the role played by neuronal KARs under normal and pathological conditions, but also, they may provide an alternative target for the development of new drugs regulating KARs and brain function.

Figure 1. Kainate receptor subunits and Neto auxiliary subunits

Kainate receptor subunits are classified in two classes, low- and high-affinity subunits. Low-affinity subunits, GluK1–3, can form homomeric channels, whereas high-affinity subunits GluK4/5 require low-affinity subunits to form heteromeric channels. The KAR auxiliary subunits Neto1 and Neto2 are type-1 transmembrane proteins containing two CUB domains and one LDLa domain in the extracellular domain. All three proteins have potential PDZ binding motifs at their C-terminal. NTD, N-terminal domain; LBD, ligand-binding domain.

Figure 2. Distinct kinetics of native KARs in the brain

A, in CA3 pyramidal cells of the hippocampus, mossy fibre activation elicits a fast kinetics AMPAR-EPSC and a distinct slow kinetics of KAR-EPSC. These responses have been scaled to the peak of the AMPAR-EPSC. The KAR-EPSC was recorded in the presence of the AMPAR selective antagonist GYKI53655. From Castillo et al. (1997); reprinted by permission from Macmillan Publishers Ltd: Nature©1997. B, in Neto1 knockout mice, both rise time and decay kinetics of mf-CA3 KAR-EPSCs are substantially accelerated. Normalized KAR-EPSCs from wild-type and Neto1 knockout mice are superimposed and depicted at a slow (top panel) and fast (bottom panel) time base. From Straub et al. (2011a); reprinted by permission from Macmillan Publishers Ltd: Nature Neuroscience©2011.

Figure 3. Distinct distribution of KARs in the brain

A, [³H]kainate signal shows distinct distribution of high-affinity kainate receptors in the hippocampal stratum lucidum, where mossy fibre (MF) and CA3 pyramidal cells form synapses Modified from Monaghan & Cotman (1982); by permission from Elsevier: Brain Research©1982. Neto1 mRNA is strongly expressed in CA3 pyramidal cells. Image from Allen Brain Atlas. B, [³H]kainate signal was reduced in Neto1 knockout mice (Neto1^−/−), whereas GluK2/3 localized at synapses, suggesting that Neto1 only modulates [³H]kainate affinity, but not KAR synaptic localization. Modified from Straub et al. (2011a); reprinted by permission from Macmillan Publishers Ltd: Nature Neuroscience©2011.