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Diacylglycerol kinase δ destabilizes serotonin transporter protein through the ubiquitin-proteasome system

Brain-specific diacylglycerol kinase (DGK) δ-knockout mice exhibited serotonin transporter (SERT) inhibitor-sensitive obsessive-compulsive disorder-like behaviors. Moreover, SERT protein levels were markedly increased in the DGKδ-deficient brain. However, its molecular mechanisms remain unclear. We found that the catalytic subdomain-a and the coiled-coil structure-containing region of DGKδ interacted with the C-terminal cytoplasmic region (CTC) of SERT. Moreover, the protein levels of full-length SERT and SERT-CTC alone were significantly decreased by DGKδ in a catalytic activity-dependent manner. A proteasome inhibitor, MG-132, inhibited DGKδ-dependent SERT degradation. Notably, DGKδ interacted with MAGE-D1 adaptor protein and Praja-1 E3 ubiquitin-protein ligase, and enhanced the ubiquitination of SERT through Praja-1. Taken together, these results indicate that DGKδ interacts with SERT and induces SERT degradation in an activity-dependent manner through the Praja-1 ubiquitin ligase-proteasome system. These new findings provide novel insights into serotonergic system regulation and the pathophysiology/therapeutics of serotonin-/SERT-related diseases such as obsessive-compulsive disorder, depression, autism and schizophrenia.

Related Products

Cat.No. Product Name Information
S2619 MG132 MG132 ((S,R,S)-(-)-MG132, Z-Leu-D-Leu-Leu-al) is a potent proteasome (ChTL, TL, and PGPH) inhibitor. MG132 also inhibits calpain (IC50=1.2 μM). MG132 can be used to induce animal models of Parkinson’s disease.

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Proteasome