Excitatory-sulphur-amino-acid-evoked neurotransmitter release from synaptosomes and primary neuronal cultures.

The dicarboxylic amino acids L-glutamate and L-aspartate are considered to be the major fast-acting neurotransmitters at excitatory synapses in the mammalian central nervous system (CNS) [ l ] . In addition, they are cytotoxic [2] and also epileptogenic, when administered focally into the brain or systemically in high doses [3]. Their actions are mediated by at least three receptor subtypes, generally designated with respect to the selective agonists N-methyl-D-aspartate (NMDA), quisqualate (QUIS), and kainate (KA) [ 11. Moreover, these same receptors, which mediate direct neuronal depolarization, are also thought to be involved in neuronal injury following excessive or prolonged excitatory pathway stimulation [4]. Thus, excitatory-amino-acid (EAA)-induced neuronal degeneration is strongly suspected as the major culprit in a number of human neuropathological disorders of uncertain aetiology, e.g. epilepsy, stroke, Huntington's chorea. Although the majority of evidence points towards glutamate (and aspartate), it is generally accepted that in a number of cases, the endogenous molecules which activate excitatory amino acid receptors in the CNS under both normal and pathological conditions have yet to be definitively identified. Thus, the actions and physiological role of other endogenous neuroactive compounds, namely quinolinic acid, y-glutamyl peptides and acidic sulphur-containing amino acids (SAAs) are currently being investigated by various groups. A number of observations have prompted considerable recent interest in the study of neuroactive SAAs which have generated an increased awareness of a possible functional role for these compounds in the CNS. The SAAs comprise the excitatory acidic compounds, namely L-cysteine sulphinate (CSA), L-cysteate (CA), L-homocysteine sulphinate (HSA), L-homocysteate (HCA) and S-sulpho-L-cysteine (SC) and the inhibitory compounds, taurine and hypotaurine. The main theme of this paper involves only discussion on current studies of the excitatory acidic SAAs, since these compounds, all of which bear a strong structural resemblance to glutamate or aspartate, exhibit both excitotoxic and epileptogenic properties, and are therefore considered as transmitter candidates. The process of neurotransmission involves biosynthesis and metabolism, evoked release, and receptor interaction, as well as physiological inactivation by high-affinity uptake into neurons and astrocytes. Support for the proposed role of the SAAs as transmitter candidates arises from a number of investigations. Thus: ( i ) in electrophysiological studies it has been shown that both Land D-enantiomers of the SAAs excite central neurons in a manner similar to the excitation induced by glutamate and aspartate [S-71; moreover, these