[The mechanism of enhanced platelet intracellular calcium mobilization stimulated by serotonin--in the pathophysiology of mood disorders].
It has been reported that platelet intracellular calcium (Ca) response stimulated by serotonin (5-HT) is enhanced in unmedicated patients with some types of mood disorders compared to normal subjects. However, the mechanism of this enhancement has not been elucidated. In this study, at first, I examined whether the enhanced 5-HT-induced Ca response was specific to some types of mental disorder. Then, the relationship between the 5-HT-induced platelet intracellular Ca rise and the density of 5-HT2A receptors on the platelets of normal subjects was investigated. Furthermore, effects of modulators of two main signal transduction systems, protein kinase C (PKC) and calmodulin (CaM), on 5-HT-induced platelet intracellular Ca response in the platelets of normal subjects were examined. As a result, the specificity to bipolar disorder among several psychiatric disorders was observed in enhanced 5-HT-induced Ca mobilization. There was no correlation between Ca response to 5-HT and the Bmax of 5-HT2A receptors. Pretreatment with PKC activator (PMA) dose-dependently reduced the Ca response induced by 5-HT, while pretreatment with CaM antagonist (10-30 microM W-7), myosin light chain kinase inhibitor (30 microM ML-9) or Ca/CaM-dependent protein kinase II inhibitor (10 microM KN-93) increased the Ca response with no remarkable changes in basal Ca level. But PKC inhibitors (bisindolylmaleimide II and staurosporine) failed to increase the Ca response at every dose. Pre-incubation with 10 mM lithium reduced the enhanced Ca response to 5-HT induced by 30 microM W-7. These findings suggest the possibility that calmodulin dysfunction might be involved in the mechanism of enhanced intracellular Ca response to 5-HT in bipolar disorder.
Suzuki
K
K
Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
D000328:Adult; D000928:Antidepressive Agents / Q000494:pharmacology; D001792:Blood Platelets / Q000378:metabolism*; D002118:Calcium / Q000097:blood* / Q000502:physiology; D002147:Calmodulin / Q000502:physiology; D005260:Female; D006801:Humans; D008094:Lithium / Q000494:pharmacology; D008297:Male; D019964:Mood Disorders / Q000209:etiology*; D011493:Protein Kinase C / Q000502:physiology; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000097:blood; D012701:Serotonin / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
D000928:Antidepressive Agents; D002147:Calmodulin; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D012701:Serotonin; D008094:Lithium; D011493:Protein Kinase C; D002118:Calcium