Association of the putative susceptibility gene, transient receptor potential protein melastatin type 2, with bipolar disorder

Abstract

Disturbed intracellular calcium (Ca(2+)) homeostasis has been implicated in bipolar disorder (BD). Reduced mRNA levels of the transient receptor potential Ca(2+) permeable channel melastatin type 2, TRPM2, in B lymphoblast cell lines (BLCL) from bipolar I disorder (BD-I) patients showing elevated basal intracellular Ca(2+) ([Ca(2+)](B)), an index of altered intracellular Ca(2+) homeostasis, along with its location within a putative BD susceptibility locus (21q22.3), implicates the involvement of this gene in the Ca(2+) abnormalities and the genetic diathesis to BD. We tested this hypothesis by examining the association of selected single nucleotide polymorphisms (SNPs) and their haplotypes, spanning the TRPM2 gene, with BD and BLCL [Ca(2+)](B), in a case control design. The 5' TaqMan SNP assay was used to detect selected SNPs. BLCL [Ca(2+)](B) was determined by ratiometric fluorometry. SNP rs1618355 in intron 18 was significantly associated with BD as a whole (P < 7.0 x 10(-5); odds ratio (OR) = 2.60), and when stratified into BD-I (P < 7.0 x 10(-5), OR = 2.48) and BD-II (P = 7.0 x 10(-5), OR = 2.88) subgroups. In addition, the alleles of the individual SNPs forming a seven marker at-risk haplotype were in excess in BD (12.0% in BD vs. 0.9% in controls; P = 2.3 x 10(-12)). A weak relationship was also detected between BLCL [Ca(2+)](B) and TRPM2 SNP rs1612472 in intron 19. These findings suggest genetic variants of the TRPM2 gene increase risk for BD and support the notion that TRPM2 may be involved in the pathophysiology of BD.

TRP Channels

“…These include cardiovascular diseases, sensory deficits, abnormal sensitivities to pain, gastrointestinal diseases, additional renal and neurodegenerative diseases, certain cancers, asthma, and even psychiatric diseases. Consistent with this last possibility is the association of alterations in TRPM2 with bipolar disorder (236,237). Finally, TRP channels are exciting targets for drug development.…”

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…One of the putative susceptibility loci of BD-I is associated with the chromosomal region that encodes TRPM2 (Liu et al, 2001;Xu et al, 2006Xu et al, , 2009a. SNPs in the promoter region of Trpm2 are also significantly associated with BD-I.…”

Regulation of thermoTRPs by lipids

“…PIP2 regulates the apparent affinity of the TRPM2 channel to Ca 2C31 and, to further complicate this scenario, it has been suggested that the amyloid protein can be directly incorporated into neuronal membranes and form Ca 2C -permeable ion channels (amyloid channels 32 ), which could also contribute to increases in intracellular Ca 2C and which could further activate TRPM2 and cause neurotoxicity.…”

“…35 The TRPV3 channel is expressed in DRG, TG and spinal cord neurons as well as in cells from the skin, tongue and brain. 36 It is activated by temperatures that range between [31][32][33][34][35][36][37][38][39] C and by compounds such as camphor, thymol, carvacrol 36 and by the endogenous lipid farnesyl pyrophosphate or FPP. 37 This channel has been shown to be positively regulated by the depletion of PIP2.…”