The pancreatic islet β-cell autoantigen of relative molecular mass 64,000 (64K), which is a major target of autoantibodies associated with the development of insulin-dependent diabetes mel-litus (IDDM) has been identified as glutamic acid decarboxylase, the biosynthesizing enzyme of the inhibitory neurotransmitter GABA (γ-aminobutyric acid). Pancreatic β cells and a subpopulation of central nervous system neurons express high levels of this enzyme. Autoantibodies against glutamic acid decarboxylase with a higher titre and increased epitope recognition compared with those usually associated with IDDM are found in stiff-man syndrome, a rare neurological disorder characterized by a high coincidence with IDDM.

Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase.

2. Evidence for A m i n o Acids as T ransmi t t e r s . . . . . . . . . . . . . . . . . . . . 99 2.1. Synthesis and Storage . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 2.2. Synapt ic Release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 2.3. Postsynapt ic Act ion . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 2.4. Postsynapt ic An tagon i s t s . . . . . . . . . . . . . . . . . . . . . . . . . 103 2.5. Inac t iva t ion and R e m o v a l . . . . . . . . . . . . . . . . . . . . . . . . . 104

Amino acid transmitters in the mammalian central nervous system

Bicuculline, an antagonist of GABA and synaptic inhibition in the spinal cord of the cat.

Metabolism and role of glutamate in mammalian brain.

RECENT studies have stressed the important physiological role of certain amino acids in the brain. Analytical determinations revealed high concentrations of glutamic and aspartic acids as well as of glutamine and N-acetylaspartate. y-Aminobutyric acid (GABA), is especially interesting, not only because of its high concentration, but also because of its exclusive presence in the CNS, particularly in grey matter. Numerous biochemical studies have been dedicated to the metabolic interrelationships existing among this group of amino acids and the glycolytic and tricarboxylic cycles, as well as with the mechanism of ammonia removal in brain. Some of these amino acids may serve as anions, making up for part of the inorganic anion deficit, or as important substrates in intermediary metabolism. Experimental observations have shown that these amino acids may have different physiological actions. Both glutamic and aspartic acids have a powerful excitatory action. On the contrary, GABA has a general depressant action on different neuronal responses while glutamine and N-acetylaspartic acid have no effect. It has been suggested that some of these amino acids are important in maintaining the normal excitability of neuronal membranes acting in a rather unspecific way, while others have suggested a synaptic role for them (see CURTIS, PHILLIS and WATKINS, 1959, 1960; CURTIS and WATKINS, 1960; FLOREY, 1964). The function of this group of amino acids seems to be related to the complex structure of the CNS and the existence of numerous compartments and metabolic pools. With radioisotope experiments it has been found that only a small fraction of the total glutamate is rapidly interchanged, while the rest remains rather inactive (BERL, TAKACAKI and PURPURA, 1961b). Similarly, only a small fraction of GABA appears to be active (BERL, LAJTHA and WAELSCH, 1961~). Furthermore some of these amino acids apparently can exchange across cell membranes, and this exchange is accelerated by stimulation of nerve cells (LUXORO, 1960).

R. Wayne Albers

Papers

The distribution of glutamic decarboxylase in the nervous system of the rhesus monkey.

The Distribution of Glutamic-γ-Aminobutyric Transaminase in the Nervous System of the Rhesus Monkey