Functional and Physical Interaction of Diacylglycerol Kinase with Protein Kinase Is Required for Cerebellar Long-Term Depression
- Functional and Physical Interaction of Diacylglycerol Kinase with Protein Kinase Is Required for Cerebellar Long-Term Depression
- 이동원; 유키오 야마모토; Kim Eunjoon; 게이코 야마모토
- synaptic plasticity; DGKz; cerebellum; PKCa
- Issue Date
- Journal of neuroscience
- VOL 35, NO 46, 15453-15465
- The balance between positive and negative regulators required for synaptic plasticity must be well organized at synapses. Protein kinase c (PKC ) 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 regulation are not clearly understood. Here, we analyzed the role of
diacylglycerol kinase (DGK ), a kinase that physically interacts with PKC as well as postsynaptic density protein 95 (PSD-95) family proteins and functionally suppresses PKC by metabolizing diacylglycerol (DAG), in the regulation of cerebellar LTD. In Purkinje cells of DGK -deficient mice, LTD was impaired and PKC was less localized in dendrites and synapses. This impaired LTD was rescued by virus-driven expression of wild-type DGK , but not by a kinase-dead mutant DGK or a mutant lacking the ability to localize at synapses, indicating that both the kinase activity and synaptic anchoring functions of DGK are necessary for LTD. In addition, experiments using another DGK mutant and immunoprecipitation analysis revealed an inverse regulatory mechanism, in which PKC phosphorylates, inactivates, and then is released from DGK , is required for LTD. These results indicate that DGK is localized to synapses, through its interaction with PSD-95 family proteins, to promote synaptic localization of PKC , but maintains PKC in a minimally activated state by suppressing local DAG until its activation and release from DGK during LTD. Such local and reciproc l regulation of positive and negative regulators may contribute to the fine-tuning of synaptic signaling.
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