Kainate Receptors

Abstract

Kainate receptors are ionotropic glutamate receptors composed of various combinations of five subunits GluR5, GluR6, GluR7, KA1 and KA2. Kainate receptors form cationic ion channels that can flux Ca²⁺ depending on mRNA editing of a glutamine in the channel pore region. Classical glutamate receptor ligands show poor selectivity for kainate receptors over AMPA receptors, although specific antagonists directed against GluR5 containing-receptors have recently been developped, and should prove very useful for the study of kainate receptor function in synaptic physiology and pathology. At variance with AMPA and NMDA receptors which mainly operate at post-synaptic site and are the key agents of fast glutamatergic synaptic transmission, kainate receptors play a variety of functions by acting at presynaptic, postsynaptic and extrasynaptic sites. At postsynaptic sites, kainate receptors are implicated in synaptic currents of small amplitude and slow decay kinetics that display prominent summation properties in response to repetitive stimualtions. Presynaptic kainate receptors regulate the release of GABA and glutamate at many different synapses. In doing so, they can facilitate presynaptic forms of short and long term synaptic plasticity. Finally, kainate receptors regulate neuronal excitability by inhibition of Ca²⁺-dependent K⁺ channels. While kainate receptors act by the opening of a cation channels, some of the functions of kainate receptors involve a metabotropic action through the coupling to a G-protein, independent of an ionotropic action. The molecular link between kainate receptors and G-protein coupling is not yet identified. The different functions of kainate receptors result from the activation of receptors located in a variety of neuronal subdomains. This raises the question of the polarized trafficking of kainate receptors to pre- and postsynaptic sites, and their stabilization in specific functional domains. Trafficking of kainate receptors to the plasma membrane greatly depends on kainate receptors subunits and splice variants. Splice variants mainly differ in their cytoplasmic C-ter domain, which binds scaffolding proteins of the post-synaptic density as well as adhesion proteins. Kainate receptors are expressed early during development and appear to play a role in the construction of synaptic networks. Finally, kainate receptors are likely involved in many neurological disorders, including neurodegenrative diseases such as epilepsy and stroke, and in inflammatory pain. Because of their role as regulators of the maturation and function of synaptic circuits, kainate receptors appear as very promissing therapeutic targets.