Excitatory amino acid receptors coupled to phosphoinositide metabolism: Characterization and possible role in physiology and physiopathology

Abstract

It is now widely established that a large variety of neurotransmitters activate receptors linked to phospholipase C. This enzyme catalyses the hydrolysis of membrane phosphoinositides to yield two second messengers; inositol triphosphate and diacylglycerol. The former acts by mobilizing intracellular Ca2+, the latter by stimulating protein kinase C [1,2]. Since the first publications [3–5] indicating that excitatory amino acids (EAAs) stimulate the phosphoinositide cascade in rat striatal neurons, granule cells and hippocampal slices, a large number of reports have confirmed and extended these previous findings using various models [6–8]. However, until recently, the characterization of the EAAs receptor involved in the increase in inositol phosphates (IPs) production remained rather obscure. For instance, ibotenate, a rigid structural analogue of glutamate, was reported as the most active of the EAAs in stimulating IPs formation in adult rat hippocampal slices [5] while EAAs were found inactive in this same area [9]. In primary cultures of striatal neurons [3], in Xenopus oocytes injected with rat brain mRNA [10], in granule cells [4] and in rat brain synaptoneurosomes [7] quisqualate, another glutamate agonist, proved to be the most efficient EAAs agonist for inositol phospholipid hydrolysis. These apparent discrepancies may originate from various key factors which may be identified as: 1) the experimental model (slices, cells in culture or membrane vesicles), 2) the anatomical origin of the model (hippocampus, cerebellum, striatum…), 3) the age of the animal used and to a lesser extent 4) the species. In fact, in slices or cells in culture, the IPs formation induced by neuroactive substances results from several events which are: the direct effect of the substance tested on its receptor coupled to the phosphoinositide metabolism, but also indirect effects due for example to the release of other substances able to stimulate or to inhibit themselves the IPs synthesis. The choice of a given brain structure may lead to the study of a specific receptor particularly enriched in that region and linked to IPs formation. Finally, the density and the pharmacological characteristics of receptors may change during development. These considerations may explain the rather confusing situation concerning the EAAs receptors involved in IPs production.