2. Academic Validation
  3. The Antipsychotic Drug Clozapine Suppresses the RGS4 Polyubiquitylation and Proteasomal Degradation Mediated by the Arg/N-Degron Pathway

The Antipsychotic Drug Clozapine Suppresses the RGS4 Polyubiquitylation and Proteasomal Degradation Mediated by the Arg/N-Degron Pathway

  • Neurotherapeutics. 2021 Jul;18(3):1768-1782. doi: 10.1007/s13311-021-01039-0.
Jun Hyoung Jeon 1,  Tae Rim Oh 1,  Seoyoung Park 1 2,  Sunghoo Huh 3,  Ji Hyeon Kim 1,  Binh Khanh Mai 4,  Jung Hoon Lee 1 2,  Se Hyun Kim 5 6,  Min Jae Lee 7 8
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, 03080, Korea.
  • 2 Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, 03080, Korea.
  • 3 Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, Korea.
  • 4 Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
  • 5 Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, Korea. sh3491@snu.ac.kr.
  • 6 Department of Psychiatry, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, 03080, Korea. sh3491@snu.ac.kr.
  • 7 Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, 03080, Korea. minjlee@snu.ac.kr.
  • 8 Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, 03080, Korea. minjlee@snu.ac.kr.
PMID: 33884581 DOI: 10.1007/s13311-021-01039-0
Abstract

Although diverse antipsychotic drugs have been developed for the treatment of schizophrenia, most of their mechanisms of action remain elusive. Regulator of G-protein signaling 4 (RGS4) has been reported to be linked, both genetically and functionally, with schizophrenia and is a physiological substrate of the arginylation branch of the N-degron pathway (Arg/N-degron pathway). Here, we show that the atypical antipsychotic drug clozapine significantly inhibits proteasomal degradation of RGS4 proteins without affecting their transcriptional expression. In addition, the levels of Arg- and Phe-GFP (artificial substrates of the Arg/N-degron pathway) were significantly elevated by clozapine treatment. In silico computational model suggested that clozapine may interact with active sites of N-recognin E3 ubiquitin ligases. Accordingly, treatment with clozapine resulted in reduced polyubiquitylation of RGS4 and Arg-GFP in the test tube and in cultured cells. Clozapine attenuated the activation of downstream effectors of G protein-coupled receptor signaling, such as MEK1 and ERK1, in HEK293 and SH-SY5Y cells. Furthermore, intraperitoneal injection of clozapine into rats significantly stabilized the endogenous RGS4 protein in the prefrontal cortex. Overall, these results reveal an additional therapeutic mechanism of action of clozapine: this drug posttranslationally inhibits the degradation of Arg/N-degron substrates, including RGS4. These findings imply that modulation of protein post-translational modifications, in particular the Arg/N-degron pathway, may be a novel molecular therapeutic strategy against schizophrenia.

Keywords

Clozapine; N-degron pathway; RGS4; Schizophrenia; Ubiquitination; Ubiquitin–proteasome system.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z