Kainate receptors function

Antagonists selective for kainate receptors are not available yet. The non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) blocks AMPA as well as kainate receptors. Nevertheless, compounds like GYKI53655, which acts as a noncompetitive antagonist of AMPA receptors and completely blocks AMPA receptor function at certain concentrations at which no antagonistic effect on kainate receptors is discernible, has been used to demonstrate the kainate receptor-mediated currents in neurons. 

Kainate receptors may be formed by homomeric combination of GluRS, GluR6 or GluR7 or by heteromeric combination of any of GluRS 7 with the kainate binding proteins, KAl or KA2. KAl and KA2 do not form functional homomeiic receptors. 

The role of the kainate receptor system in the brain is at an early stage since there are as yet few pharmacological tools to study its function. However, mutations in the kainate receptor genes have been made in mice and there is a GluR6 kainate receptor knock-out mouse. Kainate binding is absent in areas of the brain which normally have high levels such as the hippocampus. Here, in normal animals kainate receptors mediate a postsynaptic current which is absent in the GluR6 knock-out mouse. The mice have... 

The kainate receptors are composed of subunits from the GluR5-GluR7 class and the KA1-KA2 class of subunits. Homomeric receptors of the former class generate functional receptors and bind kainate with an affinity of 50 to 100 nM. KA1 or KA2 do not generate functional channels, but the receptors bind kainate with an affinity of 5 to 10 nM. Homomeric GluR6 and KA2 receptors are neither activated by AMPA, nor do they bind AMPA. Interestingly, when they are co-expressed, heteromeric receptors respond to AMPA. 

Subunits of the GluR5-GluR7 family, on the other hand, coassemble with KA1 or KA2 into functional kainate receptors when studied in heterologous expression systems. Results of experiments with radioligands demonstrate that homomeric GluR5 and GluR7 receptors... 

The quinoxalinedione derivatives 6-cyano-7-nitroquinoxaline (CNQX), 6,7-dinitro-quinoxaline-2,3-dione (DNQX), and 2,3-dioxo-6-nitro-l,2,3,4-tetrahydrobenzo[f]quinox-aline-7-sulphonamide (NBQX) are potent competitive antagonists of AMPA and kainate receptors. Of these, NBQX shows the most functional selectivity (approximately threefold) for AMPA over KA receptors (45), and has been used in low concentrations (1 pM) to isolate kainate currents in hippocampal interneurons (46). 

The recently developed GLUK5 selective compound LY382884 (47) is the first antagonist that is selective enough for kainate receptors over AMPA receptors to be used to study the functions of native KA receptors in the presence of intact AMPA receptor-mediated transmission. The use of LY382884 has uncovered a role for kainate receptors in the regulation of short- and long-term synaptic plasticity in the mossy-fiber pathway (49,77) as well as at thalamocortical synapses (87) (Fig. 3)... 

Schiffer, H. H., Swanson, G. T., and Heinemann, S. F. (1997) Rat GluR7 and a carboxy-terminal splice variant, GluR7b, are functional kainate receptor subunits with a low sensitivity to glutamate. Neuron 19,1141-1146. 

Patemain, A. V., Herrera, M. T Nieto, M. A., and Lerma, J. (2000) GluR5 and GluR6 kainate receptor subunits coexist in hippocampal neurons and coassemble to form functional receptors../. Neurosci. 20, 196-205. 

Rodrtguez-Moreno, A. and Lerma, J. (1998) Kainate receptor modulation of GABA release involves a metabotropic function. Neuron 20,1211-1218. 

Anandamide has dual effects on NMDA receptor function. It reduces NMDA Ca2-i- currents, which is mediated by cannabinoid receptors and G-protein mechanisms (Hampson et al. 1998). However, anandamide potentiates NMDA currents due to a direct effect on the NMDA receptor itself. THC did not have the same effect. So anandamide appears to have at least one other CNS effect that is not through the cannabinoid receptors. THC also reduces AMPA/kainate activity, which is mediated by CBl receptors (Shen and Thayer 1999) (table 10.5). THC may in-... 

Durand GM, Kovalchuk Y, Konnerth A (1996) Long-term potentiation and fimctional synapse induction in developing hippocampus. Nature 381 71-75 Eder M, Becker K, Rammes G, et al (2003) Distribution and properties of functional postsy-naptic kainate receptors on neocortical layer V pyramidal neurons. J Nemosci 23 6660-... 

Recently, it has been shown that spinal neurons express functional kainate receptors which contribute to synaptic transmission between primary afferent fibers and dorsal horn neurons (Li et al., 1999). Administration of the AMPA/kainate antagonist CNQX to the spinal cord... 

Chittajallu R., Braithwaite S. P., Clarke V. R. J., and Henley J. M. (1999). Kainate receptors subunits, synaptic localization and function. Trends Pharmacol. Sci. 20 26-35. 

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