Excitatory amino acid receptors: a gallery of new targets for pharmacological intervention

The excitatory amino acids (EAAs) L-glutamate and L-aspartate are the most abundant amino acids in brain and play a number of roles in maintaining neuronal function. Among these are their use as protein constituents, as key intermediates in ammonia metabolism, and as precursors for other neurotransmitters. Given the widespread distribution of EAA-containing neurons, these transmitters are likely to be involved in virtually all central nervous system functions, with abnormalities in neurotransmission contributing to the symptoms of a host of neurological and psychiatric disorders. Because of the importance of EAAs in maintaining the functional integrity of the central nervous system, efforts are underway to design agents capable of regulating the activity of these transmitters for therapeutic gain. Inasmuch as potential side effects preclude a generalized modification of this system, strategies must be found to alter EAA neurotransmission in selected brain regions. In this regard, pharmacological data suggest several functionally distinct EAA receptors, a finding confirmed by cloning studies which hint at an even larger family of sites. Moreover, it appears that some excitatory amino acid receptor complexes are composed of interacting sites which orchestrate receptor function, and there is evidence that EAA receptors may influence the activity of one another. Thus, there appear to be numerous sites that can be targeted to selectively modify excitatory amino acid neurotransmission in brain. Besides the agonist recognition site for each receptor subtype, other targets include regulatory subunits, ion channels and components of receptor-coupled second messenger systems.