Disturbed intracellular calcium (Ca2+) 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 Ca2+ increase induced by thapsigargin, a inhibitor of sarco/endoplasmic reticulum Ca2+-ATPase pump (SERCA), and a capacitative Ca2+ entry followed by addition of extracellular Ca2+, in the presence or absence of PKC/calmodulin modulators in the platelets of healthy subjects in order to elucidate the role of SERCA in Ca2+ homeostasis and to assess how both PKC and calmodulin systems regulate the two Ca2+ responses. Moreover, we also examined the thapsigargin-elicited transient Ca2+ increase and capacitative Ca2+ entry in patients with mood disorders. PKC and calmodulin systems have opposite regulatory effects on the transient Ca2+ increase and capacitative Ca2+ entry in the platelets of normal subjects. The inhibitory effect of PKC activation on capacitative Ca2+ 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 Ca2+ 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 Ca2+ entry in a larger sample.