title: The Bcl-2 gene polymorphism rs956572AA increases inositol 1,4,5-trisphosphate receptor-mediated endoplasmic reticulum calcium release in subjects with bipolar disorder.
abstract: BACKGROUND
  Bipolar disorder (BPD) is characterized by altered intracellular calcium (Ca(2+)) homeostasis. Underlying mechanisms involve dysfunctions in endoplasmic reticulum (ER) and mitochondrial Ca(2+) handling, potentially mediated by B-cell lymphoma 2 (Bcl-2), a key protein that regulates Ca(2+) 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 Ca(2+) 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 Ca(2+) dynamics.
  
  
  RESULTS
  Compared with GG homozygotes, variant AA-which expresses significantly reduced Bcl-2 messenger RNA and protein-exhibited elevated basal cytosolic Ca(2+) and larger increases in inositol 1,4,5-trisphosphate receptor-mediated cytosolic Ca(2+) elevations, the latter in parallel with enhanced depletion of the ER Ca(2+) 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 Ca(2+) content or in basal store-operated Ca(2+) entry.
  
  
  CONCLUSIONS
  These results demonstrate that, in patients with BPD, abnormal Bcl-2 gene expression in the AA variant contributes to dysfunctional Ca(2+) homeostasis through a specific ER inositol 1,4,5-trisphosphate receptor-dependent mechanism.
authors.affiliation: Laboratory of Molecular Pathophysiology and Experimental Therapeutics, Mood and Anxiety Disorders Program, National Institute of Mental Health, Bethesda, Maryland, USA.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Machado-Vieira
authors.forename: Natalia B
authors.initials: NB
authors.lastname: Pivovarova
authors.forename: Ruslan I
authors.initials: RI
authors.lastname: Stanika
authors.forename: Peixiong
authors.initials: P
authors.lastname: Yuan
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.forename: Rulun
authors.initials: R
authors.lastname: Zhou
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Zarate
authors.forename: Wayne C
authors.initials: WC
authors.lastname: Drevets
authors.forename: Christine A
authors.initials: CA
authors.lastname: Brantner
authors.forename: Amber
authors.initials: A
authors.lastname: Baum
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Laje
authors.forename: Francis J
authors.initials: FJ
authors.lastname: McMahon
authors.forename: Guang
authors.initials: G
authors.lastname: Chen
authors.forename: Jing
authors.initials: J
authors.lastname: Du
authors.forename: Husseini K
authors.initials: HK
authors.lastname: Manji
authors.forename: S Brian
authors.initials: SB
authors.lastname: Andrews
mesh_terms: D000328:Adult; D001714:Bipolar Disorder / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000235:genetics; D016009:Chi-Square Distribution; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; D019253:Proto-Oncogene Proteins c-bcl-2; D002118:Calcium