Lee, Dongwon Yamamoto, Yukio Kim, Eunjoon Tanaka-Yamamoto, Keiko 2024-01-20T05:33:13Z 2024-01-20T05:33:13Z 2021-09-03 2015-11-18 0270-6474 https://pubs.kist.re.kr/handle/201004/124741 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. English SOC NEUROSCIENCE DELTA-2 GLUTAMATE-RECEPTOR SYNAPTIC PLASTICITY PURKINJE-CELLS PHOSPHATIDIC-ACID DENDRITIC SPINES NITRIC-OXIDE PKC PICK1 TRANSDUCTION PHOSPHORYLATION Functional and Physical Interaction of Diacylglycerol Kinase zeta with Protein Kinase C alpha Is Required for Cerebellar Long-Term Depression Article 10.1523/JNEUROSCI.1991-15.2015 1 JOURNAL OF NEUROSCIENCE, v.35, no.46, pp.15453 - 15465 JOURNAL OF NEUROSCIENCE 35 46 15453 15465 scie scopus 000366054500021 2-s2.0-84947775521 Neurosciences Neurosciences & Neurology Article DELTA-2 GLUTAMATE-RECEPTOR SYNAPTIC PLASTICITY PURKINJE-CELLS PHOSPHATIDIC-ACID DENDRITIC SPINES NITRIC-OXIDE PKC PICK1 TRANSDUCTION PHOSPHORYLATION cerebellum DGK zeta long-term depression PKC alpha Purkinje cells