Trends in Pharmacological Sciences
ReviewKainate receptors: subunits, synaptic localization and function
Section snippets
Kainate receptor subunits
GluR5 was the first mammalian kainate receptor subunit to be cloned, showing ∼40% sequence homology to the AMPA receptor subunits GluR1–GluR4 (Ref. 2). To date, another four kainate receptor subumits (GluR6, GluR7, KA1 and KA2) have been identified. These subunits can be divided into two groups on the basis of their structural homology and affinity for [3H]kainate. The low-affinity subunits, GluR5–GluR7, display 75% homology while the high-affinity subunits, KA1 and KA2, are 68% homologous. The
Functional characterization of recombinant kainate receptors
For all known functional recombinant kainate receptors, kainate elicits a fast onset and rapidly desensitizing response. However, as outlined below, other pharmacological and functional properties differ depending on subunit composition.
Kainate receptor agonists, antagonists and modulators
Until recently, the antagonists of choice for non-NMDA receptors have been the quinoxalinediones cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 6-nitro-7-sulphamoylbenzo[f]quinoxaline-2,3-dione (NBQX). CNQX and NBQX display a fivefold and 30-fold selective displacement of [3H]AMPA over [3H]kainate binding, respectively31, 32. However, functional studies have shown that CNQX possesses minimal selectivity and NBQX displays only a threefold selectivity between AMPA versus kainate receptor-mediated
Kainate receptor subunit distributions
Although the exact subunit composition of native kainate receptors is still under investigation (see later discussion), in situ hybridization and immunostaining have indicated the relative distributions of the kainate receptor subunits60, 61, 62. Briefly, GluR5 mRNA is limited mainly to the subiculum, CA1 region of the hippocampus and Purkinje cell layer of the cerebellum; GluR6 mRNA is found in high levels primarily in the dentate gyrus and CA3 region of hippocampus, caudate putamen and
Peripheral nervous system (PNS)
Early evidence for pure kainate receptor-mediated responses came from observations in the PNS that kainate and l-glutamate cause fast onset and rapidly desensitizing responses in DRG neurones. These receptors displayed two predominant single-channel conductance levels of ∼4 pS and 8 pS with infrequent openings of 15–18 pS (Ref. 39). Domoate and (s)-5-iodowillardiine, also elicit rapidly desensitizing responses in DRG (48, 54). This desensitizing effect of kainate in the DRG differs from its
Presynaptic kainate receptors
In contrast to the now solid evidence for postsynaptic kainate receptors, there are contradictory results regarding presynaptic kainate receptors. Historically, the cellular localization of kainate receptors was initially investigated by lesioning studies. High-affinity [3H]kainate binding in CA3 region of hippocampus is significantly reduced following selective destruction of afferent mossy fibres, which suggests a presynaptic localization76, 77. In mice that lack cerebellar granule cells, a
Concluding remarks
The use of recently developed AMPA and kainate receptor-selective agonists and antagonists has provided compelling evidence for functional pre- and postsynaptic kainate receptors in the mammalian CNS. These advances have added new impetus to the interest in kainate receptors. It is clear that subunit composition of kainate receptors influences their pharmacological and functional profiles. Recently, a number of studies have alluded to the subunit composition of these native receptors. The
Note added in proof
The presynaptic kainate receptor-mediated inhibition of excitatory transmission in the CA1 region of the hippocampus86 has been extended to excitatory synapses in the CA3 region91. This effect can be elicited by ATPA and antagonized by LY294486 (Ref. 91). Thus, as with the postsynaptic kainate receptor-mediated currents found on CA1 pyramidal neurones74 and the presynaptic kainate receptors involved in the inhibition of inhibitory transmission in CA1 (Ref. 44), the kainate receptors involved in
Acknowledgements
We would like to thank the BBSRC, Eli Lilly, MRC and the Wellcome Trust for financial support.
Glossary
Chemical names
- GYKI52466:
- 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine
- GYKI53655; LY300168:
- 1-(4-aminophenyl)-3-methylcarbamyl-4-methyl-7,8-methylenedioxy-3,4-dihydroxy-5H-2,3-benzodiazepine
- LY293558:
- (3s, 4ar, 6r, 8ar)-6-[2-(1(2)H-tetrazol-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid
- LY294486:
- (3sr, 4ars, 6sr, 8ars)-6-((((1H-tetrazol-5-yl)methyl)oxy)methyl)-1,2,3,4,4a,5,6,7,8,8a deca-hydroisoquinoline-3-carboxylic acid
- SYM2081:
- (2s,4r)-4-methylglutamic acid
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