Effects of calmodulin and protein kinase C modulators on transient Ca2+ increase and capacitative Ca2+ entry in human platelets: relevant to pathophysiology of bipolar disorder.
Disturbed intracellular calcium (Ca(2+)) homeostasis has been implicated in bipolar disorder, which mechanisms may be involved in the dysregulation of protein kinase C (PKC) and calmodulin systems. In this study, we investigated a transient intracellular Ca(2+) increase induced by thapsigargin, an inhibitor of sarco/endoplasmic reticulum Ca(2+)-ATPase pump (SERCA), and a capacitative Ca(2+) entry followed by addition of extracellular Ca(2+), in the presence or absence of PKC/calmodulin modulators in the platelets of healthy subjects in order to elucidate the role of SERCA in Ca(2+) homeostasis and to assess how both PKC and calmodulin systems regulate the two Ca(2+) responses. Moreover, we also examined the thapsigargin-elicited transient Ca(2+) increase and capacitative Ca(2+) entry in patients with mood disorders. PKC and calmodulin systems have opposite regulatory effects on the transient Ca(2+) increase and capacitative Ca(2+) entry in the platelets of normal subjects. The inhibitory effect of PKC activation on capacitative Ca(2+) entry is significantly increased and the stimulatory effect of PKC inhibition is significantly decreased in bipolar disorder compared to major depressive disorder and normal controls. These results suggest the possibility that increased PKC activity may activate the inhibitory effect of capacitative Ca(2+) entry in bipolar disorder. However, this is a preliminary study using a small sample, thus further studies are needed to examine the PKC and calmodulin modulators on the capacitative Ca(2+) entry in a larger sample.
Akimoto
Tatsuyuki
T
Department of Psychiatry, Hokkaido University Graduate School of Medicine, North 15-West 7, Kita-ku, Sapporo 060-8638, Japan.
Kusumi
Ichiro
I
Suzuki
Katsuji
K
Koyama
Tsukasa
T
D000328:Adult; D001714:Bipolar Disorder / Q000097:blood / Q000503:physiopathology*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D002118:Calcium / Q000097:blood*; D020013:Calcium Signaling / Q000187:drug effects*; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology
D002147:Calmodulin; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D013449:Sulfonamides; C017967:W 7; D019284:Thapsigargin; D011493:Protein Kinase C; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; C088060:bisindolylmaleimide; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium