| First Author | Lee D | Year | 2015 |
| Journal | J Neurosci | Volume | 35 |
| Issue | 46 | Pages | 15453-65 |
| PubMed ID | 26586831 | Mgi Jnum | J:227844 |
| Mgi Id | MGI:5703673 | Doi | 10.1523/JNEUROSCI.1991-15.2015 |
| Citation | Lee D, et al. (2015) Functional and Physical Interaction of Diacylglycerol Kinase zeta with Protein Kinase Calpha Is Required for Cerebellar Long-Term Depression. J Neurosci 35(46):15453-65 |
| abstractText | The balance between positive and negative regulators required for synaptic plasticity must be well organized at synapses. Protein kinase Calpha (PKCalpha) 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 PKCalpha regulation are not clearly understood. Here, we analyzed the role of diacylglycerol kinase zeta (DGKzeta), a kinase that physically interacts with PKCalpha as well as postsynaptic density protein 95 (PSD-95) family proteins and functionally suppresses PKCalpha by metabolizing diacylglycerol (DAG), in the regulation of cerebellar LTD. In Purkinje cells of DGKzeta-deficient mice, LTD was impaired and PKCalpha was less localized in dendrites and synapses. This impaired LTD was rescued by virus-driven expression of wild-type DGKzeta, but not by a kinase-dead mutant DGKzeta or a mutant lacking the ability to localize at synapses, indicating that both the kinase activity and synaptic anchoring functions of DGKzeta are necessary for LTD. In addition, experiments using another DGKzeta mutant and immunoprecipitation analysis revealed an inverse regulatory mechanism, in which PKCalpha phosphorylates, inactivates, and then is released from DGKzeta, is required for LTD. These results indicate that DGKzeta is localized to synapses, through its interaction with PSD-95 family proteins, to promote synaptic localization of PKCalpha, but maintains PKCalpha in a minimally activated state by suppressing local DAG until its activation and release from DGKzeta 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 zeta (DGKzeta) creates optimal conditions for the induction of cerebellar long-term depression (LTD). DGKzeta works by regulating localization and activity of protein kinase Calpha (PKCalpha), an important mediator of LTD, so that PKCalpha effectively responds to the stimulation that triggers LTD. |
