Involvement of protein kinase in the regulation of beta-adrenergic receptors by antidepressants.
The role of serotonin (5-HT) and protein kinases in the regulation of the beta-receptor induced by typical and atypical antidepressants was investigated. Treatment with either mianserin or maprotiline for seven days produced a significant decrease in the beta-receptor density measured 6h after the last dose. The reduction in beta-receptors disappeared within 24h. However, combined treatment of mianserin or maprotiline with either fluoxetine or 5-hydroxytryptophan significantly decreased beta-receptors even 24h after the last dose. Following treatment with p-chlorophenylalanine the reduction in beta-receptors induced by desipramine was reversible within 24h. These results demonstrate that an increase in the synaptic 5-HT availability may contribute to the prolongation of the beta-receptor down-regulation by antidepressants. The intraventricular infusion of 12-0-tetradecanoyl-phorbol-13-acetate (TPA), a potent protein kinase C (PK-C) activator for seven days caused a significant decrease in beta-receptors, while forskolin or dibutyryl cyclic adenosine monophosphate had no influence on the receptor. The TPA-induced and desipramine-induced decreases in beta-receptors were not additive, suggesting that a similar mechanism is involved. The infusion of the PK-C inhibitor 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7) caused an inhibition of the desipramine-induced decrease in beta-receptors. It is suggested that the beta-receptor down-regulation by antidepressants might be also regulated by PK-C through 5-HT-Ca2+-inositol-phospholipid systems.
Asakura
M
M
Department of Neuropsychiatry, St. Marianna University School of Medicine, Kanagawa, Japan.
Tsukamoto
T
T
Kubota
H
H
Osada
K
K
Imafuku
J
J
Nishizaki
J
J
Sato
A
A
Nakanishi
J
J
Shimbo
K
K
Shibata
M
M
D015116:5,7-Dihydroxytryptamine / Q000494:pharmacology; D006916:5-Hydroxytryptophan / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D003994:Bucladesine / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003891:Desipramine / Q000494:pharmacology; D005473:Fluoxetine / Q000494:pharmacology; D007276:Injections, Intraventricular; D008297:Male; D008376:Maprotiline / Q000494:pharmacology; D008803:Mianserin / Q000494:pharmacology; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors
D000928:Antidepressive Agents; D047428:Protein Kinase Inhibitors; D011943:Receptors, Adrenergic, beta; D005473:Fluoxetine; D008803:Mianserin; D008376:Maprotiline; D015116:5,7-Dihydroxytryptamine; D003994:Bucladesine; D006916:5-Hydroxytryptophan; D011494:Protein Kinases; D003891:Desipramine