TY - JOUR T1 - Overexpression of diacylglycerol kinase eta (DGKη) prolongs Gαq-coupled GPCR signaling JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.113.091280 SP - mol.113.091280 AU - Joseph E. Rittiner AU - Victoria E. Brings AU - Mark J. Zylka Y1 - 2014/01/01 UR - http://molpharm.aspetjournals.org/content/early/2014/03/07/mol.113.091280.abstract N2 - Multiple genome-wide association studies have linked diacylglycerol kinase eta (DGKη) to bipolar disorder (BPD). Moreover, DGKη expression is increased in tissue from patients with BPD. However, how increased levels of this lipid kinase might affect cellular functions is unclear. Here, we overexpressed mouse DGKη in HEK293 cells to examine substrate specificity and signaling downstream of endogenous G protein-coupled receptors (GPCRs). We found that DGKη can phosphorylate diacylglycerol (DAG) with different acyl side chains (8:0, 12:0, 18:1). In addition, overexpression of DGKη prolonged calcium mobilization after stimulating muscarinic receptors with carbachol and after stimulating purinergic receptors with ATP. This effect required DGKη catalytic activity, as assessed using a kinase-dead (G389D) mutant and multiple truncation constructs. DGKη was localized throughout the cytosol and did not translocate to the plasma membrane after stimulation with carbachol. Since protein kinase C (PKC) can be activated by DAG and promotes receptor desensitization, we also examined functional interactions between PKC and DGKη. We found that acute activation of PKC with phorbol 12-myristate 13-acetate (PMA) shortened carbachol-evoked calcium responses and occluded the effect of overexpressed DGKη. Moreover, the effect of DGKη on carbachol-evoked calcium mobilization was abolished by inhibiting PKC activity. Overexpression of DGKη also reduced baseline and carbachol-evoked, but not PMA-evoked, phosphorylation of extracellular signal-related kinase (ERK), a downstream effector of PKC. Taken together, our data suggest that DGKη prolongs GPCR signaling by reducing PKC activation. As a result, increased expression of DGKη could dysregulate GPCR activity and PKC-dependent signaling pathways in BPD. ER -