Molecular Physiology of Kainate Receptors

Abstract

A decade ago, our understanding of the molecular properties of kainate receptors and their involvement in synaptic physiology was essentially null. A plethora of recent studies has altered this situation profoundly such that kainate receptors are now regarded as key players in the modulation of transmitter release, as important mediators of the postsynaptic actions of glutamate, and as possible targets for the development of antiepileptic and analgesic drugs. In this review, we summarize our current knowledge of the properties of kainate receptors focusing on four key issues: 1) their structural and biophysical features, 2) the important progress in their pharmacological characterization, 3) their pre- and postsynaptic mechanisms of action, and 4) their involvement in a series of physiological and pathological processes. Finally, although significant progress has been made toward the elucidation of their importance for brain function, kainate receptors remain largely an enigma and, therefore, we propose some new roads that should be explored to obtain a deeper understanding of this young, but intriguing, class of proteins.

Effect of age on kainate-induced seizure severity and cell death

“…Several studies have recognized age-related changes in the density and function of the different ionotropic glutamate receptors (Gonzales et al, 1991;Pittaluga et al, 1993;Nicoletti et al, 1995;Magnusson, 1998;Mitchell and Anderson, 1998;Wenk and Barnes, 2000). Although still somewhat controversial, many studies have shown that the expression of AMPA-, KA-and NMDA-sensitive receptors as well as the GABA A receptor is either constant or variably diminished in many different brain regions including the hippocampus during aging (Gonzales et al, 1991;Pittaluga et al, 1993;Le Jeune et al, 1996;Nicolle et al, 1996;EcklesSmith et al, 2000;Kuehl-Kovarik et al, 2000;Magnusson, 2000;Sonntag et al, 2000;Wenk and Barnes, 2000;Adams et al, 2001;Clayton and Browning, 2001;Clayton et al, 2002;Lerma et al, 2001). Differences in a variety of other factors, including voltage-gated calcium channels (Vigues et al, 1999;Kelly et al, 2003), androgen levels (Mejias-Aponte et al, 2002;Ramsden et al, 2003;Ciriza et al, 2004), and GABA receptor function (MacGregor et al, 1997;Ma et al, 2001) which have been shown to modulate kainate-induced seizure activity in young animals, may modulate susceptibility in aged animals as well.…”

Calcium release via activation of presynaptic IP3 receptors contributes to kainate-induced IPSC facilitation in rat neocortex

“…This decrease was associated with an increase in synaptic failures, indicating a presynaptic action possibly involving direct coupling between KARs and G proteins (Rodriguez-Moreno et al, 1997;Rodriguez-Moreno and Lerma, 1998;Lerma et al, 2001). An indirect mechanism of KA inhibition, involving an increase in action potential firing which produces enhanced GABA release, has also been postulated (Frerking et al, 1999).…”

Differential contribution of kainate receptors to excitatory postsynaptic currents in superficial layer neurons of the rat medial entorhinal cortex

“…In addition to being resistant to GYKI, KAR-mediated EPSCs have decay kinetics slower than their AMPA receptor mediated counterparts, and are inhibited by CNQX (For reviews, see (Chittajallu et al, 1999, Frerking and Nicoll, 2000, Lerma et al, 2001, Lerma, 2003, Lerma, 2006). Thus, we used these additional criteria to establish that the GYKI-resistant EPSCs in mEC neurons were indeed mediated by postsynaptic KARs.…”

“…These receptors have been shown to both mediate and modulate synaptic transmission in both the central and peripheral nervous system (for reviews see (Chittajallu et al, 1999, Frerking and Nicoll, 2000, Lerma et al, 2001, Lerma, 2003, Lerma, 2006, Pinheiro and Mulle, 2006). Regarding the mediation of synaptic transmission, functional postsynaptic KARs have been demonstrated in a variety of cell types (Castillo et al, 1997, Vignes and Collingridge, 1997, Cossart et al, 1998, Frerking et al, 1998, DeVries and Schwartz, 1999, Kidd and Isaac, 1999, Li et al, 1999, Bureau et al, 2000, Cossart et al, 2002, Ali, 2003, Eder et al, 2003, Vitten et al, 2004, Wu et al, 2005, Jin et al, 2006 and may impose unique integrative properties to neurons (Frerking and Ohliger-Frerking, 2002).…”

“…Furthermore, the expression of postsynaptic KARs has been shown to be restricted in a cellular and subcellular manner. For instance, CA3 pyramidal neurons of the hippocampus have been shown to have postsynaptic KARs that mediate a substantial portion of the synaptic response, specifically at their mossy fiber synapse, while CA1 neurons do not have postsynaptic KAR mediated EPSCs (Castillo et al, 1997, Frerking et al, 1998, Bureau et al, 1999, Lerma et al, 2001. Additionally, KARs in hippocampal CA3 neurons have been shown to underlie the kainate-induced gamma oscillations observed in these neurons (Fisahn et al, 2004).…”