Kainate receptors coming of age: milestones of two decades of research

Abstract

Two decades have passed since the first report of the cloning of a kainate-type glutamate receptor (KAR) subunit. The intervening years have seen a rapid growth in our understanding of the biophysical properties and function of KARs in the brain. This research has led to an appreciation that KARs play very distinct roles at synapses relative to other members of the glutamate-gated ion channel receptor family, despite structural and functional commonalities. The surprisingly diverse and complex nature of KAR signaling underlies their unique impact upon neuronal networks through their direct and indirect effects on synaptic transmission, and their prominent role in regulating cell excitability. This review pieces together highlights from the two decades of research subsequent to the cloning of the first subunit, and provides an overview of our current understanding of the role of KARs in the CNS and their potential importance to neurological and neuropsychiatric disorders.

Figure 1. Timeline for two decades of discoveries in KAR neurobiology

Cloning of the KARs, beginning with the first subunit (GluR5/GluK1) in 1990, led to a large effort to characterize the biophysical and physiological properties of KARs. Development of knockout mice and selective ligands began to uncover diverse roles for KARs in the brain. Resolution of the crystal structure of the ligand binding domain increased our understanding of KAR biophysics and accelerated the potential development of selective ligands. Post-translational modifications and important accessory proteins were found to contribute to the diversity of neuronal KAR function. Additionally, genetic association studies have identified several potential linkages between neurological disorders and KARs.

Figure 2. KAR subunit diversity and structure

(A) KAR subunits (GluK1-5) and splice variants. Black boxes represent membrane domains (M1-M4). Triangles depict sites of RNA editing, including the “Q/R” site within both GluK1 and GluK2, which controls ion permeability of the channel. The primary subunits (GluK1-3) have high sequence homology and are required for the formation of a functional heteromeric receptor complex. The high affinity subunits (GluK4-5) are incorporated into heteromeric receptors and modulate receptor properties. (B) KAR subunit topology depicting the three transmembrane domains (M1, M3,M4) and the re-entrant pore loop (M2), the extracellular N-terminus and the intracellular C-terminal loop. D1 and D2 refer to modular lobes within the ligand binding domain (LBD). R1 and R2 refer to component lobes of the N-terminal domain (NTD). Crystalstructure of the NTD [39] and the LBD [38] are shown.

Figure 3. Cartoon representations of examples of diverse physiological actions of KARs

Presynaptic kainate receptors can (A) depress [142] (at synapses between thalamic neurons and layer IV (LIV) neurons), or (C) facilitate [90] (at synapses between dentate gyrus (DG) neurons and CA3 pyramidal cells (PC)) glutamate release. Similarly both a (B) depression (between Stratum Radiatum interneurons (St Rad IN) and CA1 PCs) [105], and (D) facilitation (between St Rad INs) [110] of GABA release have been reported. In addition, non-synaptic KARs can mediate modulation of excitability of different cellular compartments, including the (E) somatodendritic compartment of PCs in the CA1 region of the hippocampus and (F) the axon of DG granule cells [116, 143]. These effects are mediated through diverse signaling pathways and are specific to particular cell-types and brain regions.