Mechanisms of altered Ca2+ signalling in transformed lymphoblastoid cells from patients with bipolar disorder

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Abstract

Altered Ca2+ signalling has been reported in the platelets and lymphoblastoid cells of patients with bipolar disorder. Recent genetic studies have suggested possible pathophysiological roles for mitochondria and endoplasmic reticulum, both of which are essential for the regulation of intracellular Ca2+ signalling. The goal of this study was to determine molecular mechanisms of altered intracellular Ca2+ signalling in bipolar disorder. Lymphoblastoid cell lines were established from patients with bipolar I disorder (n = 13) and controls (n = 11). Using Ca 2+ indicators, cytosolic and mitochondrial Ca2+ responses to the following three reagents were examined: platelet-activating factor; carbonyl cyanide m-chlorophenylhydrazone (CCCP), a mitochondrial uncoupler that abolishes mitochondrial Ca2+ uptake; and thapsigargin, an endoplasmic reticulum Ca2+ pump inhibitor. The 10-5 M thapsigargin-induced cytosolic Ca2+ response was significantly higher in patients with bipolar disorder (p < 0.05). Such difference was not seen when the effects of Ca2+ influx from outside the plasma membrane was eliminated using Ca2+-free measurement buffer. On the other hand, response to 10-7 M thapsigargin tended to be higher in patients with bipolar disorder when at the Ca2+-free conditions. CCCP-induced Ca2+ responses differed significantly between mitochondrial DNA 5178/10398 haplotypes (p = 0.001) that had been previously reported to be associated with bipolar disorder. These results suggest that all components, i.e. the store-operated calcium channel (SOCC), endoplasmic reticulum, and mitochondria, somehow contribute to the altered Ca2+ signalling in bipolar disorder.

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Kato, T., Ishiwata, M., Mori, K., Washizuka, S., Tajima, O., Akiyama, T., & Kato, N. (2003). Mechanisms of altered Ca2+ signalling in transformed lymphoblastoid cells from patients with bipolar disorder. International Journal of Neuropsychopharmacology, 6(4), 379–389. https://doi.org/10.1017/S1461145703003717

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