Abstract
Diacylglycerol kinase γ (DGKγ) is a lipid kinase to convert diacylglycerol (DG) to phosphatidic acid (PA) and indirectly regulates protein kinase C γ (PKCγ) activity. We previously reported that the basal PKCγ upregulation impairs cerebellar long-term depression (LTD) in the conventional DGKγ knockout (KO) mice. However, the precise mechanism in impaired cerebellar LTD by upregulated PKCγ has not been clearly understood. Therefore, we first produced Purkinje cell-specific DGKγ KO (tm1d) mice to investigate the specific function of DGKγ in Purkinje cells and confirmed that tm1d mice showed cerebellar motor dysfunction in the rotarod and beam tests, and the basal PKCγ upregulation but not PKCα in the cerebellum of tm1d mice. Then, the LTD-induced chemical stimulation, K-glu (50 mM KCl + 100 µM, did not induce phosphorylation of PKCα and dissociation of GluR2 and glutamate receptor interacting protein (GRIP) in the acute cerebellar slices of tm1d mice. Furthermore, treatment with the PKCγ inhibitor, scutellarin, rescued cerebellar LTD, with the phosphorylation of PKCα and the dissociation of GluR2 and GRIP. In addition, nonselective transient receptor potential cation channel type 3 (TRPC3) was negatively regulated by upregulated PKCγ. These results demonstrated that DGKγ contributes to cerebellar LTD by regulation of the basal PKCγ activity.
Highlights
Long-term depression (LTD) is one of the synaptic plasticity at synapses between parallel fibers (PFs) and Purkinje cells and is important for cerebellar motor coordination
LTD is induced by co-stimulation of PFs and climbing fiber (CF), which trigger the activation of metabotropic glutamate receptor 1 signaling and the depolarization, leading to protein kinase C (PKC) activation [1,2,3]
Among Diacylglycerol kinase (DGK) subtypes, the γ isoform of DGK (DGKγ) is abundantly expressed in cerebellar Purkinje cells [14], and we recently reported that the conventional DGKγ KO mice showed impaired cerebellar LTD and motor dysfunction [15]
Summary
Long-term depression (LTD) is one of the synaptic plasticity at synapses between parallel fibers (PFs) and Purkinje cells and is important for cerebellar motor coordination. Constitutive active PKCγ mutant causes both the impairments of motor coordination and LTD [10] These reports indicate that the precise regulation of PKC activity is responsible for cerebellar LTD and motor coordination. We found abnormal upregulation of the basal PKCγ activity in DGKγ KO mice and that the PKCγ inhibitor normalized the impairment of LTD in DGKγ KO mice [15] These results suggested that the functional correlation between DGKγ and PKCγ is responsible for LTD induction. We confirmed that Purkinje cell-specific DGKγ KO (tm1d) mice showed impairment of motor coordination to the conventional DGKγ KO mice and found that the upregulated basal PKCγ activity negatively regulated PKCα inactivation during cerebellar LTD by the phosphorylation of a nonselective transient receptor potential cation channel type 3 (TRPC3). Our research demonstrates the important novel function of DGKγ and PKCγ in the cerebellar LTD and motor coordination
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