The biochemistry and pharmacology of excitatory sulphur-containing amino acids.

1,-Glutamate is now well established as the predominant transmitter at fast-acting excitatory synapses in the mammalian central nervous system. Other amino acids such as L-aspartate and several acidic sulphur-containing amino acids (SAAs) which exhibit potent depolarizing actions similar to that of Lglutamate [I-31 are known to exist in the brain and/or are present in the brain under pathological conditions. The putative SAA transmitters (see Figure 1) comprise the L-aspartate analogues, Lcysteine sulphinate (CSA) and L-cysteate (CA), and the L-glutamate analogues, L-homocysteine sulphinate (HCSA), L-homocysteate (HCA) and S-sulphoL-cysteine (SSC). Of these, evidence to support a neurotransmitter/neuromodulator role is most complete for CSA and HCA [4, 51. The SAAs or a disturbance in the metabolism of their precursors have been implicated in the pathogenesis of various neurological and neurodegenerative disorders (e.g. [6-91) and they also appear to reproduce a similar range of excitotoxic properties to that of r>-glutamate-induced cell damage [ 10, 1 I], possibly mediated by glutamate receptor subtypes [ 12-14]. Basic questions which arise concerning the role of amino acids in neurotransmission are: (i) does a particular neural pathway use the amino acid as a transmitter?; and (ii) what are the mechanisms of release, action and re-uptake? This overview deals primarily with the more recent data regarding the mechanism of SAA action and re-uptake, and highlights the signal transduction mechanisms by which the SAAs may exert their normal and pathogenic effects. The remaining aspects of the questions posed above are the subject of current research by C u h o d and coworkers [ S ] (and this colloquium). Further, more detailed coverage of the