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 neurotransmitter in the vertebrate central nervous system (CNS) have uncovered a tremendous complexity in the actions of this excitatory neurotransmitter and an equally great complexity in the molecular structures of the receptors activated by L-glutamate. L-Glutamate is the most widespread excitatory transmitter system in the vertebrate CNS and in addition to its actions as a synaptic transmitter it produces long-lasting changes in neuronal excitability, synaptic structure and function, neuronal migration during development, and neuronal viability. These effects are produced through the activation of two general classes of receptors, those that form ion channels or 'ionotropic' and those that are linked to G-proteins or 'metabotropic'. The pharmacological and physiological characterization of these various forms over the past two decades has led to the definition of three forms of ionotropic receptors, the kainate (KA), AMPA, and NMDA receptors, and three groups of metabotropic receptors. Twenty-seven genes are now identified for specific 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 localization in neuronal and glial membranes, and their role in determining the physiological properties of glutamate receptors is a fertile field of current investigations into the cell and molecular biology of these receptors. Both ionotropic and metabotropic receptors are linked to multiple intracellular messengers, such as Ca, cyclic AMP, reactive oxygen species, and initiate multiple signaling cascades that determine neuronal growth, differentiation and survival. These cascades of complex molecular events are presented in this review.