The role of endoplasmic reticulum stress response in the pathophysiology of bipolar disorder

最近，一个功能多态性（-116 C/G）的XBP 1基因的报道有助于双相情感障碍（BPD）的遗传危险因素。此外，在培养的BPD患者淋巴细胞中，G等位基因的内质网（ER）应激反应受损，在三种主要情绪稳定剂中，仅丙戊酸盐可挽救ER应激反应的受损。在这种情况下，不同基因型的BPD患者对情绪稳定剂的反应可能不同。因此，我们研究了-116 C/G多态性与BPD患者锂盐反应的相关性。我们发现锂盐治疗对携带-116 C等位基因的日本BPD患者比携带G等位基因纯合子的BPD患者更有效，BPD患者细胞内钙（Ca^2+）稳态紊乱，其机制可能与蛋白激酶C（PKC）和钙调素系统失调有关。在这项研究中，我们研究了细胞内瞬时Ca^<2+>增加， ...更多信息 由毒胡萝卜素（一种肌质/内质网Ca^2+-ATP酶泵（SERCA）的抑制剂）和一种容量性Ca^2+内流，随后加入细胞外Ca^2+诱导，在健康受试者血小板中存在或不存在PKC/钙调素调节剂的情况下，为了阐明SERCA在Ca^<2+>稳态中的作用，并评估PKC和钙调素系统如何调节两种Ca^<2+>稳态，2+>响应。此外，我们还检测了情绪障碍患者中毒胡萝卜素引起的短暂Ca^<2+>增加和容量性Ca 2+内流。PKC和钙调素系统对正常人血小板瞬时C^<2+>升高和容性Ca 2+内流具有相反的调节作用。与重性抑郁障碍和正常对照组相比，BPD患者PKC激活对容量性Ca^2+内流的抑制作用显著增强，而PKC抑制的刺激作用显著减弱。这些结果提示，BPD中PKC活性的增加可能激活了容量性Ca^2+内流的抑制作用。少

Recently, a functional polymorphism (-116C/G) of the XBP1 gene was reported to contribute to the genetic risk factor for bipolar disorder (BPD). Moreover, the endoplasmic reticulum (ER) stress response were impaired in cultured lymphocytes from BPD patients with G allele and only valproate rescued the impairment of the ER stress response among three major mood stabilizers. In this context, it is likely that BPD patients with different genotype respond differently to mood stabilizers. Therefore, we investigated the association of-116C/G polymorphism and lithium response in patients with BPD. We found that lithium treatment is more effective in Japanese BPD patients with-116C allele carrier than in those with G allele homozygous.Disturbed intracellular calcium (Ca^<2+>) homeostasis has been implicated in BPD, 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 ind … More uced by thapsigargin, a 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 Ca2+ entry in patients with mood disorders. PKC and calmodulin systems have opposite regulatory effects on the transient C^<2+> increase and capacitative Ca2+ 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 BPD 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 BPD. Less