Evidence for involvement of protein kinases in the regulation of serotonin synthesis and turnover in the mouse brain in vivo.
Inhibition of cAMP-dependent protein kinase (PKA) with N-[2-methylamino)ethyl]-5-isoquinolinesulfonamide (H-8) almost completely antagonized the increase in 5-HTP accumulation and 5-HIAA/5-HT ratio in hypothalamus induced by NAS-181, a 5-HT(1B) receptor antagonist, but had no effect when the mice were treated with NAS-181 together with WAY-100,635, a selective 5-HT(1A) receptor antagonist. Inhibition of Ca(2+)-calmodulin-dependent protein kinase (CaM kinase II) with the calmodulin antagonist N-(4-aminobutyl)-5-chloro-2-naphtalenesulfonamide (W-13) did not antagonise the effect of NAS-181 alone, but counteracted that evoked by the combined treatment with NAS-181 and WAY-100,635. The results indicate that activation of tryptophan hydroxylase by reducing the tone from terminal 5-HT(1B) receptors involves PKA whereas the depolarisation-induced activation of tryptophan hydroxylase involves CaM kinase II. The increase in the 5-HIAA/5-HT ratio may under the experimental conditions used suggest CaM kinase II-induced phosphorylation of synapsin I resulting in increased 5-HT release.
Stenfors
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Department of Bioscience, Local Discovery, AstraZeneca Södertälje R&D, Södertälje, Sweden. carina.stenfors@astrazeneca.com
Ross
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D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007031:Hypothalamus / Q000187:drug effects* / Q000201:enzymology; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D051379:Mice; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism*; D012701:Serotonin / Q000096:biosynthesis*; D013449:Sulfonamides / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D012701:Serotonin; C033772:N-(4-aminobutyl)-5-chloro-2-naphthalenesulfonamide; C053177:N-(2-(methylamino)ethyl)-5-isoquinolinesulfonamide; D011494:Protein Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases