Role of calmodulin in the activation of tryptophan hydroxylase.
Tryptophan hydroxylase can be activated 2.0- to 2.5-fold in vitro by ATPa dn Mg2+. This apparent phosphorylation effect is not dependent on cyclic nucleotides but is dependent on the presence of calcium. The activation of tryptophan hydroxylase by ATP-Mg2+ reduces the apparent Km of the enzyme for its cofactor, 6-methyltetrahydropterin, from 0.21 to 0.09 mM. The addition of certain antipsychotic drugs known to bind to calmodulin in a phosphorylation reaction mixture prevents the activation to tryptophan hydroxylase by ATP-Mg2+ in the concentration-dependent fashion. External addition of purified calmodulin protects the enzyme from the drug-induced effects. Preparation of calmodulin-free tryptophan hydroxylase by affinity chromatography on fluphenazine-Sepharose 4B yields an enzyme that is no longer activated by ATP-Mg2+, whereas the readdition of calmodulin to a calmodulin-free enzyme restores the responsiveness of tryptophan hydroxylase to ATP-Mg2+. This restoration is dependent on Ca2+. Taken together, these results indicate that the activation of tryptophan hydroxylase by phosphorylating conditions is dependent on both calcium and calmodulin.
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000502:physiology*; D002147:Calmodulin / Q000502:physiology*; D002417:Cattle; D004533:Egtazic Acid / Q000494:pharmacology; D004789:Enzyme Activation; D010640:Phenothiazines / Q000494:pharmacology; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D014365:Tryptophan Hydroxylase / Q000378:metabolism*
D014150:Antipsychotic Agents; D002135:Calcium-Binding Proteins; D002147:Calmodulin; D010640:Phenothiazines; D004533:Egtazic Acid; D000255:Adenosine Triphosphate; D014365:Tryptophan Hydroxylase; D011494:Protein Kinases; D002118:Calcium