Stimulation of the serotonin autoreceptor prevents the calcium-calmodulin-dependent increase of serotonin biosynthesis in rat raphe slices.
The role of the serotonin (5-hydroxytryptamine) autoreceptor in the regulation of the activity of tryptophan hydroxylase was investigated in rat raphe slices. The activity of tryptophan hydroxylase was estimated by measuring the accumulation of 5-hydroxytryptophan in the presence of inhibition of aromatic L-amino acid decarboxylase using 3-hydroxy-4-bromobenzyloxy-amine by HPLC with fluorescence detection. Serotonin and its agonists N,N-dimethyl-5-methoxytryptamine and 1-(m-chlorophenyl)-piperazine reduced the formation of 5-hydroxytryptophan to 50-60% at 10(-5) M. The effect of serotonin was reversed by 10(-5) M methiothepin, an antagonist of the serotonin autoreceptor. The calmodulin antagonists N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) and N-(6-aminohexyl)-1-naphthalenesulfonamide (W-5), dose-dependently reduced the basal formation of 5-hydroxytryptophan to 40-50% at 10(-6) and 10(-4) M, respectively. W-7 also reduced the activated formation by A-23187 or dibutyryl cyclic AMP in a dose-dependent manner. W-7 had no effect on 5-hydroxytryptophan formation reduced by serotonin at 10(-5) M. These results suggest that the role of the serotonin autoreceptor was related to the prevention of the calcium-calmodulin-dependent activation of tryptophan hydroxylase.
D006916:5-Hydroxytryptophan / Q000096:biosynthesis*; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology*; D002147:Calmodulin / Q000494:pharmacology*; D008297:Male; D008719:Methiothepin / Q000494:pharmacology; D008732:Methoxydimethyltryptamines / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000502:physiology*; D012701:Serotonin / Q000031:analogs & derivatives* / Q000096:biosynthesis* / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D014365:Tryptophan Hydroxylase / Q000378:metabolism
D002147:Calmodulin; D008732:Methoxydimethyltryptamines; D010879:Piperazines; D011985:Receptors, Serotonin; D013449:Sulfonamides; D012701:Serotonin; D008719:Methiothepin; D003994:Bucladesine; C017967:W 7; C034700:N-(6-aminohexyl)-1-naphthalenesulfonamide; D006916:5-Hydroxytryptophan; D014365:Tryptophan Hydroxylase; C015068:1-(3-chlorophenyl)piperazine; D002118:Calcium