Kainate/AMPA receptors

Pellegrini-Giampietro DE, Bennett MVL, Zukin RS (1992) Are Ca-2-i--permeable kainate/ AMPA receptors more abundant in immature brain. Neurosci Lett 144 65-69 Persson J, Hasselstrom J, Wiklund B, et al (1998) The analgesic effect of racemic ketamine in patients with chronic ischemic pain due to lower extremity arteriosclerosis obliterans. Acta Anaesthesiol Scand 42 750-758... 

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. 

FIGURE 3.8 Kainate and AMPA activate different current responses in the different classes of kainate and AMPA receptors (a) the AMPA receptor, GluRl (b) and (c) kainate receptors (d) glutamate + glycine activation of the NMDA receptor. The current response is characterized by a slow onset and offset compared to the kainate and AMPA receptors. 

TABLE 3.2 Subunits of the 3TM NMDA Receptors Superfamily AMPA Receptors Kainate Receptors Orphan Receptors... 

AMPA and kainate receptors are both blocked by quinoxalinediones but have different desensitization pharmacologies. AMPAreceptors are widespread throughout the CNS they serve as receptors for fast excitatory synaptic transmission mediated by glutamate. AMPA receptor subunits are GluRl-GluR4, kainate receptor... 

AMPA receptors desensitize within milliseconds upon exposure to AMPA, and kainate receptors likewise upon exposure to kainate. AMPA and kainate receptors can be securely distinguished from one another by their response to two drugs, cyclothiazide and the lectin concanavalin A [10], Cyclothiazide relieves AMPA receptor desensitization without affecting kainate receptors. 

Conversely, concanavalin A relieves desensitization of kainate receptors, presumably via interaction with surface sugar chains, but has insignificant effects on AMPA receptors. 

An important class of noncompetitive antagonists selective for AMPA receptors is represented by the 2,3-benzodiazepines such as GYKI 53655. These compounds act at sites different from those acted on by cyclothiazide and are useful tools for isolating synaptic responses mediated by kainate receptors. These compounds also show some promise as neuroprotective drugs for treating ischemic neuronal injury. 

In vitro studies on excitotoxicity suggest that while both NMDA and a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainate (KA) receptors can mediate excitotoxicity (see Ch. 15), these classes of glutamate receptors do not do so equally. Experiments with cortical or hippocampal cell cultures suggest that much of the neuronal death associated with brief, intense glutamate exposure is mediated by NMDA receptor activation, probably because this can induce lethal amounts of Ca2+ influx more rapidly than can AMPA/KA receptor stimulation. 

The focus of the present chapter is on the AMPA receptor subunits iGluRl-4, but examples taken from studies of the low-affinity kainate receptor subunits iGluR5-7 are also included. 

Ionotropic glutamate receptors mediate fast excitatory neurotransmission in practically all areas of the central nervous system (CNS). They are also critical for both the induction and expression of synaptic plasticity, and have been implicated in diverse pathological conditions, such as epilepsy, ischemic brain damage, anxiety, and addiction. There are three subtypes of ionotropic glutamate receptors that are named after their high-affinity agonists as a-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), N-1nethyl-D-aspartate (NMDA), and kainate (KA) receptors (1). 

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