DGK iota regulates presynaptic release during mGluR-dependent LTD

Abstract

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 2010