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 maint aining neuronal function. Among these are their use as protein constit uents, as key intermediates in ammonia metabolism, and as precursors f or other neurotransmitters. Given the widespread distribution of EAA-c ontaining neurons, these transmitters are likely to be involved in vir tually all central nervous system functions, with abnormalities in neu rotransmission contributing to the symptoms of a host of neurological and psychiatric disorders. Because of the importance of EAAs in mainta ining the functional integrity of the central nervous system, efforts are underway to design agents capable of regulating the activity of th ese transmitters for therapeutic gain. Inasmuch as potential side effe cts preclude a generalized modification of this system, strategies mus t be found to alter EAA neurotransmission in selected brain regions. I n this regard, pharmacological data suggest several functionally disti nct EAA receptors, a finding confirmed by cloning studies which hint a t an even larger family of sites. Moreover, it appears that some excit atory amino acid receptor complexes are composed of interacting sites which orchestrate receptor function, and there is evidence that EAA re ceptors may influence the activity of one another. Thus, there appear to be numerous sites that can be targeted to selectively modify excita tory amino acid neurotransmission in brain. Besides the agonist recogn ition site for each receptor subtype, other targets include regulatory subunits, ion channels and components of receptor-coupled second mess enger systems.