The fact that in animals the concentration of glutamate and glutamine are higher in brain than in any other tissue initially attracted interest in attempting to understand the function or functions of these amino acids in the central nervous system. They were evidently required for protein synthesis and early studies established their close relationship to the Krebs tricarboxylic acid cycle and energy metabolism in brain. Glutamine formation in brain was also shown to be sensitive to elevations in plasma ammonia levels and to serve as the primary method for detoxifying this substance in brain in contrast to urea formation in liver. Also noted was the interesting observation that the increased levels of glutamine that occurred in hepatic encephalopathy was not accompanied by a concomitant decrease in glutamic acid levels. The level of these two amino acids were apparently not tightly coupled despite high levels of glutamine synthetase activity in brain and glutamic acid is the only established immediate precursor of glutamine. In recent years increasing evidence pointed to the probability that glutamic acid also functions as an excitatory neurotransmitter in the central nervous system. It appears that glutamate serving these various functions is compartmented into pools of different sizes which turn over at different rates and are not in rapid equilibrium with each other
Berl, Soll and Clarke, Donald Dudley PhD, "Cerebral glutamine/glutamate interrelationships and metabolic compartmentation / S. Berl and D. D. Clarke" (1984). Chemistry Faculty Publications. Paper 65.