Effects of lithium and valproate on agonist-induced platelet intracellular calcium mobilization: relevance to myosin light chain kinase.
Serotonin (5-HT)- or thrombin-stimulated platelet intracellular calcium (Ca) mobilization has been reported to be enhanced in patients with bipolar disorders. However, the mechanism of this enhancement is unknown. As a preliminary study, the authors examined the effects of a myosin light chain kinase (MLCK) inhibitor, 1-(5-chloronaphthalene-1-sulfonyl)-1H-hexahydro-1,4-diazepine hydrochloride (ML-9), and two drugs that are mainstays of treatment for bipolar disorder, lithium and valproate, on 5-HT- or thrombin-induced Ca increase in the platelets of normal subjects. When preincubated with 30 microM ML-9, Ca responses to both agonists were enhanced. Valproate showed a dose-dependent attenuation of agonist-induced intracellular Ca rise, both in the absence and presence of ML-9. Although lithium alone had no significant effect on the Ca increase, a high concentration of lithium significantly decreased Ca mobilization only in the presence of ML-9. These results suggest that the enhanced Ca response observed in bipolar disorder might be relevant to decreased function of MLCK and that the mechanism of action of lithium may include a compensatory effect on MLCK modulation.
Suzuki
Katsuji
K
Department of Psychiatry, Hokkaido University Graduate School of Medicine, North 15, West 7, Sapporo 060-8638, Japan. kasuzuki@med.hokudai.ac.jp
Kusumi
Ichiro
I
Akimoto
Tatsuyuki
T
Sasaki
Yuki
Y
Koyama
Tsukasa
T
D000328:Adult; D018692:Antimanic Agents / Q000494:pharmacology*; D001381:Azepines / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D002118:Calcium / Q000097:blood*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008094:Lithium / Q000494:pharmacology*; D008297:Male; D009219:Myosin-Light-Chain Kinase / Q000037:antagonists & inhibitors / Q000097:blood*; D010865:Pilot Projects; D012701:Serotonin / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology; D014635:Valproic Acid / Q000494:pharmacology*
D018692:Antimanic Agents; D001381:Azepines; D004791:Enzyme Inhibitors; C056218:ML 9; D012701:Serotonin; D014635:Valproic Acid; D008094:Lithium; D009219:Myosin-Light-Chain Kinase; D013917:Thrombin; D002118:Calcium