ReviewKainate receptors: Pharmacology, function and therapeutic potential
Introduction
The neurotransmitter (S)-glutamate (l-glutamate) activates three subtypes of ligand-gated ion channel: the N-methyl-d-aspartate (NMDA), (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) and kainate receptors (Watkins and Evans, 1981, Watkins and Jane, 2006, Lodge, 2009). Kainate receptors (KARs) are highly expressed in the central nervous system (CNS) and have been implicated in various functions in the CNS (for earlier reviews see Bleakman and Lodge, 1998, Chittajallu et al., 1999, Lerma et al., 2001, Bleakman et al., 2002, Lerma, 2003, Pinheiro and Mulle, 2006). Molecular cloning has identified 5 subtypes: GluK1, GluK2, GluK3, GluK4 and GluK5 which co-assemble in various combinations to form functional receptors (the new IUPHAR nomenclature is used in this review: Collingridge et al., 2009). Thus, the KAR subunits that were formally known as GluR5–7 (or GLUK5–7) are now named GluK1–3 and those previously called KA1 and KA2 (or GLUK1 and GLUK2) are now named GluK4 and GluK5. Therefore the subunit names mirror the corresponding gene names: GRIK1, GRIK2, GRIK3, GRIK4 and GRIK5. The existence of splice variants and editing sites on the KAR subunits increases the likelihood of pharmacological heterogeneity in the KAR family (Hollmann and Heinemann, 1994, Pinheiro and Mulle, 2006).
Compared to the other glutamate receptors, progress in the understanding of the functions of KARs has lagged behind, due mainly to the relative lack of specific pharmacological tools. A particular problem has been that KAR agonists, including the prototypic agonist kainate itself, act on both AMPA receptors (AMPARs) and KARs. An even greater problem has been the lack of selective KAR antagonists. There is therefore an urgent need for subunit specific KAR agonists and antagonists. In this review we discuss progress towards the development of selective agonists and antagonists for each KAR subunit, describe their use in understanding the physiological roles of KARs and discuss their therapeutic potential.
Section snippets
KAR pharmacology
In the following sections the activity of agonists and antagonists (for structures see Fig. 1, Fig. 2, Fig. 3, Fig. 5) discovered so far will be described on cloned KAR subtypes (see Table 1, Table 2, Table 3). This article focuses on cloned receptor data whenever possible, as characterisation of compounds on each of the cloned KAR subunits should lead to an understanding of the structural features required for the development of subunit selective agonists and antagonists. Comparison of data
The use of pharmacological agents to understand the synaptic function of KARs
The development of selective agonists and antagonists which affect KARs has enabled major breakthroughs in the understanding of the roles of these receptors in a variety of physiological functions. These studies have been aided by the availability of KAR knockouts. Each approach has its relative advantages and disadvantages but in combination are extremely powerful. The use of both pharmacology and knockout mice to understand KAR function has been the subject of several recent reviews (Lerma,
KARs and therapeutic potential
As described above, functional studies suggest that KARs mainly have a modulatory role in synaptic transmission rather than being the major postsynaptic target for synaptically released glutamate as is the case for NMDARs and AMPARs. This modulatory role makes KARs attractive as therapeutic targets. There are many studies linking KARs to therapeutic goals, including genetic analyses of human diseases and genetic manipulations in laboratory animals. These are beyond the scope of this review,
Acknowledgements
We thank the BBSRC, MRC and Eli Lilly & Company, USA for supporting our research. The authors would like to thank Dr Andy Doherty, MRC Centre for Synaptic Plasticity, University of Bristol for preparation of Fig. 6, Fig. 7, Fig. 8, Fig. 9, Fig. 10.
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