DGK iota regulates presynaptic release during mGluR-dependent LTD

Diacylglycerol (DAG) is an important lipid second messenger. DAG signalling is terminated by conversion of DAG to phosphatidic acid (PA) by diacylglycerol kinases (DGKs). The neuronal synapse is a major site of DAG production and action; however, how DGKs are targeted to subcellular sites of DAG generation is largely unknown. We report here that postsynaptic density (PSD)-95 family proteins interact with and promote synaptic localization of DGK iota. In addition, we establish that DGK iota acts presynaptically, a function that contrasts with the known postsynaptic function of DGK zeta, a close relative of DGK iota. Deficiency of DGK iota in mice does not affect dendritic spines, but leads to a small increase in presynaptic release probability. In addition, DGK iota(-/-) synapses show a reduction in metabotropic glutamate receptor-dependent long-term depression (mCluR-LTD) at neonatal (similar to 2 weeks) stages that involve suppression of a decrease in presynaptic release probability. Inhibition of protein kinase C normalizes presynaptic release probability and mGluR-LTD at DGK iota(-/-) synapses. These results suggest that DGK iota requires PSD-95 family proteins for synaptic localization and regulates presynaptic DAG signalling and neurotransmitter release during mGluR-LTD. The EMBO Journal (2011) 30, 165-180. doi:10.1038/emboj.2010.286; Published online 30 November 2010This work was supported by the NIH R01-CA95463 grant (to MKT), the Neuroscience Program (to S-YC; 2009-0081468), and the National Creative Research Initiative Program of the Korean Ministry of Education, Science, and Technology (to EK). A part of this work was technically supported by the core facility service of the 21C Frontier Brain Research Center.