The respective roles of tryptophan uptake and tryptophan hydroxylase in the regulation of serotonin synthesis in the central nervous system.

1. The rate limiting enzyme for the synthesis of serotonin (5-HT) in brain, tryptophan hydroxylase, is not saturated under normal physiological conditions. 2. Therefore, any decrease or increase in brain tryptophan levels results in a reduction or a stimulation of 5-HT synthesis respectively. Thus, mechanisms controlling brain tryptophan levels, i.e. the concentration of free tryptophan in serum and the intrinsic activity of the tryptophan carrier in neuronal membranes, exert in fact a tonic regulation of 5-HT synthesis in central serotoninergic neurons. 3. Changes in the rate of 5-HT synthesis can also involve modifications in the intrinsic activity of tryptophan hydroxylase. This occurs in vivo following the intrastriatal injection of kainic acid and in vitro during the depolarization of brain slices. In both cases, an activation of tryptophan hydroxylase due to an increase in its apparent Vmax is detected in soluble extracts. 4. The depolarization-induced activation of tryptophan hydroxylase in brain slices very likely involves a Ca2+-dependent phosphorylation process. 5. Rapid changes in tryptophan hydroxylase activity produced by a phosphorylation-dephosphorylation process may be involved in the phasic regulation of 5-HT synthesis in serotoninergic neurons.