%0 Journal Article
%T Functional and Physical Interaction of Diacylglycerol Kinase ¦Æ with Protein Kinase C¦Á Is Required for Cerebellar Long-Term Depression
%A Dongwon Lee
%A Eunjoon Kim
%A Keiko Tanaka-Yamamoto
%A Yukio Yamamoto
%J The Journal of Neurosience
%D 2015
%R 10.1523/JNEUROSCI.1991-15.2015
%X The balance between positive and negative regulators required for synaptic plasticity must be well organized at synapses. Protein kinase C¦Á (PKC¦Á) is a major mediator that triggers long-term depression (LTD) at synapses between parallel fibers and Purkinje cells in the cerebellum. However, the precise mechanisms involved in PKC¦Á regulation are not clearly understood. Here, we analyzed the role of diacylglycerol kinase ¦Æ (DGK¦Æ), a kinase that physically interacts with PKC¦Á as well as postsynaptic density protein 95 (PSD-95) family proteins and functionally suppresses PKC¦Á by metabolizing diacylglycerol (DAG), in the regulation of cerebellar LTD. In Purkinje cells of DGK¦Æ-deficient mice, LTD was impaired and PKC¦Á was less localized in dendrites and synapses. This impaired LTD was rescued by virus-driven expression of wild-type DGK¦Æ, but not by a kinase-dead mutant DGK¦Æ or a mutant lacking the ability to localize at synapses, indicating that both the kinase activity and synaptic anchoring functions of DGK¦Æ are necessary for LTD. In addition, experiments using another DGK¦Æ mutant and immunoprecipitation analysis revealed an inverse regulatory mechanism, in which PKC¦Á phosphorylates, inactivates, and then is released from DGK¦Æ, is required for LTD. These results indicate that DGK¦Æ is localized to synapses, through its interaction with PSD-95 family proteins, to promote synaptic localization of PKC¦Á, but maintains PKC¦Á in a minimally activated state by suppressing local DAG until its activation and release from DGK¦Æ during LTD. Such local and reciprocal regulation of positive and negative regulators may contribute to the fine-tuning of synaptic signaling.

SIGNIFICANCE STATEMENT Many studies have identified signaling molecules that mediate long-term synaptic plasticity. In the basal state, the activities and concentrations of these signaling molecules must be maintained at low levels, yet be ready to be boosted, so that synapses can undergo synaptic plasticity only when they are stimulated. However, the mechanisms involved in creating such conditions are not well understood. Here, we show that diacylglycerol kinase ¦Æ (DGK¦Æ) creates optimal conditions for the induction of cerebellar long-term depression (LTD). DGK¦Æ works by regulating localization and activity of protein kinase C¦Á (PKC¦Á), an important mediator of LTD, so that PKC¦Á effectively responds to the stimulation that triggers LTD
%U http://www.jneurosci.org/content/35/46/15453