Functional and Physical Interaction of Diacylglycerol Kinase zeta with Protein Kinase C alpha Is Required for Cerebellar Long-Term Depression

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The balance between positive and negative regulators required for synaptic plasticity must be well organized at synapses. Protein kinase C alpha (PKC alpha) 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 alpha regulation are not clearly understood. Here, we analyzed the role of diacylglycerol kinase zeta (DGK zeta), a kinase that physically interacts with PKC alpha as well as postsynaptic density protein 95 (PSD-95) family proteins and functionally suppresses PKC alpha by metabolizing diacylglycerol (DAG), in the regulation of cerebellar LTD. In Purkinje cells of DGK zeta-deficient mice, LTD was impaired and PKC alpha was less localized in dendrites and synapses. This impaired LTD was rescued by virus-driven expression of wild-type DGK zeta, but not by a kinase-dead mutant DGK zeta or a mutant lacking the ability to localize at synapses, indicating that both the kinase activity and synaptic anchoring functions of DGK zeta are necessary for LTD. In addition, experiments using another DGK zeta mutant and immunoprecipitation analysis revealed an inverse regulatory mechanism, in which PKC alpha phosphorylates, inactivates, and then is released from DGK zeta, is required for LTD. These results indicate that DGK zeta is localized to synapses, through its interaction with PSD-95 family proteins, to promote synaptic localization of PKC alpha, but maintains PKC alpha in a minimally activated state by suppressing local DAG until its activation and release from DGK zeta during LTD. Such local and reciprocal regulation of positive and negative regulators may contribute to the fine-tuning of synaptic signaling.
Publisher
SOC NEUROSCIENCE
Issue Date
2015-11
Language
English
Article Type
Article
Keywords

DELTA-2 GLUTAMATE-RECEPTOR; SYNAPTIC PLASTICITY; PURKINJE-CELLS; AMPA RECEPTOR; DENDRITIC SPINES; LENTIVIRAL VECTORS; PHOSPHATIDIC-ACID; NITRIC-OXIDE; PKC; POTENTIATION

Citation

JOURNAL OF NEUROSCIENCE, v.35, no.46, pp.15453 - 15465

ISSN
0270-6474
DOI
10.1523/JNEUROSCI.1991-15.2015
URI
http://hdl.handle.net/10203/205533
Appears in Collection
BS-Journal Papers(저널논문)
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