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Overexpression of Diacylglycerol Kinase η Enhances G α q -Coupled G Protein–Coupled Receptor Signaling

Molecular Pharmacology, ISSN: 0026-895X, Vol: 85, Issue: 5, Page: 800-810
2014
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Article Description

Multiple genome-wide association studies have linked diacylglycerol kinase η (DGK η ) to bipolar disorder (BPD). Moreover, DGK η expression is increased in tissue from patients with BPD. How increased levels of this lipid kinase might affect cellular functions is currently unclear. Here, we overexpressed mouse DGK η in human embryonic kidney 293 cells to examine substrate specificity and signaling downstream of endogenous G protein–coupled receptors (GPCRs). We found that DGK η can phosphorylate diacylglycerol (DAG) with different acyl side chains (8:0, 12:0, 18:1). In addition, overexpression of DGK η enhanced calcium mobilization after stimulating muscarinic receptors with carbachol and after stimulating purinergic receptors with ATP. This effect required DGK η catalytic activity, as assessed using a kinase-dead (G389D) mutant and multiple truncation constructs. DGK η 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 DGK η. We found that acute activation of PKC with phorbol 12-myristate 13-acetate shortened carbachol-evoked calcium responses and occluded the effect of overexpressed DGK η. Moreover, inhibition of PKC activity with bisindolylmaleimide I (BIM I) produced the same enhancing effect on carbachol-evoked calcium mobilization as overexpressed DGK η, and overexpression of DGK η produced no additional effect on calcium mobilization in the presence of BIM I. Taken together, our data suggest that DGK η enhances GPCR signaling by reducing PKC activation.

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