The Bcl-2 gene polymorphism rs956572AA increases inositol 1,4,5-trisphosphate receptor-mediated endoplasmic reticulum calcium release in subjects with bipolar disorder

Background Bipolar disorder (BPD) is characterized by altered intracellular calcium (Ca²⁺) homeostasis. Underlying mechanisms involve dysfunctions in endoplasmic reticulum (ER) and mitochondrial Ca²⁺ handling, potentially mediated by B-cell lymphoma 2 (Bcl-2), a key protein that regulates Ca²⁺ signaling by interacting directly with these organelles, and which has been implicated in the pathophysiology of BPD. Here, we examined the effects of the Bcl-2 gene single nucleotide polymorphism (SNP) rs956572 on intracellular Ca²⁺ dynamics in patients with BPD. Methods Live cell fluorescence imaging and electron probe microanalysis were used to measure intracellular and intra-organelle free and total calcium in lymphoblasts from 18 subjects with BPD carrying the AA, AG, or GG variants of the rs956572 SNP. Analyses were carried out under basal conditions and in the presence of agents that affect Ca²⁺ dynamics. Results Compared with GG homozygotes, variant AAwhich expresses significantly reduced Bcl-2 messenger RNA and proteinexhibited elevated basal cytosolic Ca²⁺ and larger increases in inositol 1,4,5-trisphosphate receptormediated cytosolic Ca ²⁺ elevations, the latter in parallel with enhanced depletion of the ER Ca²⁺ pool. The aberrant behavior of AA cells was reversed by chronic lithium treatment and mimicked in variant GG by a Bcl-2 inhibitor. In contrast, no differences between SNP variants were found in ER or mitochondrial total Ca²⁺ content or in basal store-operated Ca²⁺ entry. Conclusions These results demonstrate that, in patients with BPD, abnormal Bcl-2 gene expression in the AA variant contributes to dysfunctional Ca²⁺ homeostasis through a specific ER inositol 1,4,5-trisphosphate receptordependent mechanism.