Alterations of glutamatergic neurotransmission have been related to the neuronal damage observed after episodes of ischaemia and hypoglycaemia, as well as to the etiology of a series of neurological conditions including epilepsy, Alzheimer’s disease, Huntington’s chorea and amyotrophic lateral sclerosis. The cloning of a large number of glutamate receptor proteins and the discovery of their structural relationships have paved the way to most of our current understanding of the biophysical properties and the physiological role of each subtype in the mammalian brain. Of the glutamate receptor subtypes, NMDA, AMPA and kainate receptors, the latter is by far the less well understood. A decade ago, our understanding of the molecular properties of kainate receptors and their involvement in synaptic physiology was essentially nill, despite the observation that kainate administration in experimental animals induces seizures and patterns of neuronal damage closely resembling those observed in epileptics. For this and other reasons, it has become important to understand the physiology of these receptors in brain function. The discovery of a specific AMPA receptor antagonist, GYKI53655, has made such studies feasible. A plethora of recent studies have shown that kainate receptors are key players in the modulation of transmitter release, important mediators of the postsynaptic actions of glutamate, and possible targets for the development of antiepileptic and analgesic drugs.

Consistent with a role in epilepsy, we found that kainate depresses GABA inhibitory transmission in the rat hippocampus. GABA is the major inhibitory neurotransmitter in the brain, and its activity is crucial in maintaining neuronal excitability at normal levels. It has been also found that the effect of kainate on GABA release is sensitive to the presence of pertussis toxin, pointing to the involvement of G proteins in this regulatory process. Moreover, protein kinase C (PKC) inhibitors can also block the action of kainate, further delineating the signalling pathway involved in the modulation of inhibitory neurotransmission. The recruitment of the PKC pathway is not secondary to the depolarisation of the terminal since reducing the influx of sodium ions does not affect the action of kainate. Therefore, it has been proposed that there is a physical link between kainate receptors and the G protein involved in the process, a link that could be either direct or through an intermediary molecule. Lastly, the binding of SYM 2081 decreases after incubation of hippocampal membranes with pertussis toxin and a similar effect of the toxin has been observed on the kainate-mediated inhibition of GABA release from synaptosomes, further suggesting a direct coupling between kainate receptors and G proteins in the mammalian brain.

We have tried to find a suitable model to further delineate this non-canonical signalling by ionotropic kainate receptors and found that in cultured dorsal root ganglion (DRG) cells, kainate could increase intracellular Ca²⁺ in the absence of this extracellular cation. We also found that kainate receptor activation was able to depress K⁺-induced intracellular Ca²⁺ accumulation in a G-protein- and PKC-dependent manner. As it was the case for inhibition of GABA release in hippocampal slices, the inhibition of Ca²⁺ currents was largely independent of kainate receptor ion channel activity. Therefore, DRG neurons are a suitable model to study G protein-coupled kainate receptors and determine subunits and proteins involved.

This work was supported by grants from the DGESIC (PM99-0106) and the European Union (QLRT-2000-00929)(to J.L.). J.L.R. is the recipient of a predoctoral fellowship from the Ministry of Education and A.V.P. is a postdoctoral fellow of the Community of Madrid.