MOLECULAR-BIOLOGY OF GLUTAMATE-RECEPTORS IN THE CENTRAL-NERVOUS-SYSTEM AND THEIR ROLE IN EXCITOTOXICITY, OXIDATIVE STRESS AND AGING

Forty years of research into the function of L-glutamic acid as a neur otransmitter in the vertebrate central nervous system (CNS) have uncov ered a tremendous complexity in the actions of this excitatory neurotr ansmitter and an equally great complexity in the molecular structures of the receptors activated by L-glutamate. L-Glutamate is the most wid espread excitatory transmitter system in the vertebrate CNS and in add ition to its actions as a synaptic transmitter it produces long-lastin g changes in neuronal excitability, synaptic structure and function, n euronal migration during development, and neuronal viability. These ef fects are produced through the activation of two general classes of re ceptors, those that form ion channels or ''ionotropic'' and chose that are linked to G-proteins or ''metabotropic''. The pharmacological and physiological characterization of these various forms over the past t wo decades has led to the definition of three forms of ionotropic rece ptors, the kainate (KA), AMPA, and NMDA receptors, and three groups of metabotropic receptors. Twenty-seven genes are now identified for spe cific subunits of these receptors and another five proteins are likely to function as receptor subunits or receptor associated proteins. The regulation of expression of these protein subunits, their localizatio n in neuronal and glial membranes, and their role in determining the p hysiological properties oi glutamate receptors is a fertile field of c urrent investigations into the cell and molecular biology of these rec eptors. Both ionotropic and metabotropic receptors are linked io multi ple intracellular messengers, such as Ca2+, cyclic AMP, reactive oxyge n species, and initiate multiple signaling cascades that determine neu ronal growth, differentiation and survival. These cascades of complex molecular events are presented in this review. (C) 1998 Elsevier Scien ce Ltd.