Graphic illustrating the roles of 8 genes implicated in the present study in lithium-sensitive signaling pathways

Graphic illustrating the roles of 8 genes implicated in the present study in lithium-sensitive signaling pathways. Green lines denote enzymatic transformations or cofactor activations, red lines confirmed inhibitory actions, blue lines protein interactions of unknown nature from Lim et al (54) or hypothetical interactions. All colored genes contain at least one replicated SNP based on individual genotyping (teal) or pooled (yellow) data. G-protein coupled receptors (such as GPC51) activate the phosphatidyl inositol signaling pathway via G-protein (G) activation of phospholipase C (PLC, such as PLCG2). PLC cleaves PIP2 into IP3 and diacylglycerol (DAG). DAG is metabolized by DAG kinases (such as DGKH). DAG is a necessary cofactor for activation of most protein kinase C (PKC) isoforms. PKC cross-talks via disheveled (Dvl) with the Wnt/B-catenin signaling pathway. Dvl is activated by Wnt receptors (such as FZD2) and directly inhibited by nucleoredoxin (NXN) by binding the PDZ domain. A2BP1 also binds Dvl. Dvl inhibits glycogen synthase kinase-3 beta (GSK3B), which itself inhibits β-catenin. β-catenin is activitated by whirlin (DFNB31) via the Usher protein complex. Since it also contains PDZ domains, DFNB31 may also bind nucleoredoxin and Dvl. In the nucleus, β-catenin modulates the activity of TCF/LEF transcription factors (such as TCF7L1), which ultimately effects the expression of a large number of target genes. Lithium (Li+) lowers intracellular myo-inositol levels, reducing production of PIP2, and increases β–catenin signaling through inhibition of GSK3B.

Publication

A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder. () AE Baum, et al. Mol Psychiatry. ;13(2):197-207. Figure: F4. Homo sapiens

Disease mentions