The Antipsychotic Drug Clozapine Suppresses the RGS4 Polyubiquitylation and Proteasomal Degradation Mediated by the Arg/N-Degron Pathway
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 physiologi...
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| Autor*in: |
Jeon, Jun Hyoung [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2021 |
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| Schlagwörter: |
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| Anmerkung: |
© The American Society for Experimental NeuroTherapeutics, Inc. 2021 |
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| Übergeordnetes Werk: |
Enthalten in: NeuroRX - Springer-Verlag, 2006, 18(2021), 3 vom: 21. Apr., Seite 1768-1782 |
|---|---|
| Übergeordnetes Werk: |
volume:18 ; year:2021 ; number:3 ; day:21 ; month:04 ; pages:1768-1782 |
| Links: |
|---|
| DOI / URN: |
10.1007/s13311-021-01039-0 |
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SPR045644926 |
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| 520 | |a 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. | ||
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10.1007/s13311-021-01039-0 doi (DE-627)SPR045644926 (SPR)s13311-021-01039-0-e DE-627 ger DE-627 rakwb eng Jeon, Jun Hyoung verfasserin aut The Antipsychotic Drug Clozapine Suppresses the RGS4 Polyubiquitylation and Proteasomal Degradation Mediated by the Arg/N-Degron Pathway 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The American Society for Experimental NeuroTherapeutics, Inc. 2021 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. Schizophrenia (dpeaa)DE-He213 Clozapine (dpeaa)DE-He213 RGS4 (dpeaa)DE-He213 Ubiquitination (dpeaa)DE-He213 N-degron pathway (dpeaa)DE-He213 Ubiquitin–proteasome system (dpeaa)DE-He213 Oh, Tae Rim aut Park, Seoyoung aut Huh, Sunghoo aut Kim, Ji Hyeon aut Mai, Binh Khanh aut Lee, Jung Hoon aut Kim, Se Hyun aut Lee, Min Jae (orcid)0000-0002-3252-6467 aut Enthalten in NeuroRX Springer-Verlag, 2006 18(2021), 3 vom: 21. Apr., Seite 1768-1782 (DE-627)SPR031264964 nnns volume:18 year:2021 number:3 day:21 month:04 pages:1768-1782 https://dx.doi.org/10.1007/s13311-021-01039-0 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA AR 18 2021 3 21 04 1768-1782 |
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10.1007/s13311-021-01039-0 doi (DE-627)SPR045644926 (SPR)s13311-021-01039-0-e DE-627 ger DE-627 rakwb eng Jeon, Jun Hyoung verfasserin aut The Antipsychotic Drug Clozapine Suppresses the RGS4 Polyubiquitylation and Proteasomal Degradation Mediated by the Arg/N-Degron Pathway 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The American Society for Experimental NeuroTherapeutics, Inc. 2021 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. Schizophrenia (dpeaa)DE-He213 Clozapine (dpeaa)DE-He213 RGS4 (dpeaa)DE-He213 Ubiquitination (dpeaa)DE-He213 N-degron pathway (dpeaa)DE-He213 Ubiquitin–proteasome system (dpeaa)DE-He213 Oh, Tae Rim aut Park, Seoyoung aut Huh, Sunghoo aut Kim, Ji Hyeon aut Mai, Binh Khanh aut Lee, Jung Hoon aut Kim, Se Hyun aut Lee, Min Jae (orcid)0000-0002-3252-6467 aut Enthalten in NeuroRX Springer-Verlag, 2006 18(2021), 3 vom: 21. Apr., Seite 1768-1782 (DE-627)SPR031264964 nnns volume:18 year:2021 number:3 day:21 month:04 pages:1768-1782 https://dx.doi.org/10.1007/s13311-021-01039-0 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA AR 18 2021 3 21 04 1768-1782 |
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10.1007/s13311-021-01039-0 doi (DE-627)SPR045644926 (SPR)s13311-021-01039-0-e DE-627 ger DE-627 rakwb eng Jeon, Jun Hyoung verfasserin aut The Antipsychotic Drug Clozapine Suppresses the RGS4 Polyubiquitylation and Proteasomal Degradation Mediated by the Arg/N-Degron Pathway 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The American Society for Experimental NeuroTherapeutics, Inc. 2021 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. Schizophrenia (dpeaa)DE-He213 Clozapine (dpeaa)DE-He213 RGS4 (dpeaa)DE-He213 Ubiquitination (dpeaa)DE-He213 N-degron pathway (dpeaa)DE-He213 Ubiquitin–proteasome system (dpeaa)DE-He213 Oh, Tae Rim aut Park, Seoyoung aut Huh, Sunghoo aut Kim, Ji Hyeon aut Mai, Binh Khanh aut Lee, Jung Hoon aut Kim, Se Hyun aut Lee, Min Jae (orcid)0000-0002-3252-6467 aut Enthalten in NeuroRX Springer-Verlag, 2006 18(2021), 3 vom: 21. Apr., Seite 1768-1782 (DE-627)SPR031264964 nnns volume:18 year:2021 number:3 day:21 month:04 pages:1768-1782 https://dx.doi.org/10.1007/s13311-021-01039-0 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA AR 18 2021 3 21 04 1768-1782 |
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10.1007/s13311-021-01039-0 doi (DE-627)SPR045644926 (SPR)s13311-021-01039-0-e DE-627 ger DE-627 rakwb eng Jeon, Jun Hyoung verfasserin aut The Antipsychotic Drug Clozapine Suppresses the RGS4 Polyubiquitylation and Proteasomal Degradation Mediated by the Arg/N-Degron Pathway 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The American Society for Experimental NeuroTherapeutics, Inc. 2021 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. Schizophrenia (dpeaa)DE-He213 Clozapine (dpeaa)DE-He213 RGS4 (dpeaa)DE-He213 Ubiquitination (dpeaa)DE-He213 N-degron pathway (dpeaa)DE-He213 Ubiquitin–proteasome system (dpeaa)DE-He213 Oh, Tae Rim aut Park, Seoyoung aut Huh, Sunghoo aut Kim, Ji Hyeon aut Mai, Binh Khanh aut Lee, Jung Hoon aut Kim, Se Hyun aut Lee, Min Jae (orcid)0000-0002-3252-6467 aut Enthalten in NeuroRX Springer-Verlag, 2006 18(2021), 3 vom: 21. Apr., Seite 1768-1782 (DE-627)SPR031264964 nnns volume:18 year:2021 number:3 day:21 month:04 pages:1768-1782 https://dx.doi.org/10.1007/s13311-021-01039-0 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA AR 18 2021 3 21 04 1768-1782 |
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10.1007/s13311-021-01039-0 doi (DE-627)SPR045644926 (SPR)s13311-021-01039-0-e DE-627 ger DE-627 rakwb eng Jeon, Jun Hyoung verfasserin aut The Antipsychotic Drug Clozapine Suppresses the RGS4 Polyubiquitylation and Proteasomal Degradation Mediated by the Arg/N-Degron Pathway 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The American Society for Experimental NeuroTherapeutics, Inc. 2021 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. Schizophrenia (dpeaa)DE-He213 Clozapine (dpeaa)DE-He213 RGS4 (dpeaa)DE-He213 Ubiquitination (dpeaa)DE-He213 N-degron pathway (dpeaa)DE-He213 Ubiquitin–proteasome system (dpeaa)DE-He213 Oh, Tae Rim aut Park, Seoyoung aut Huh, Sunghoo aut Kim, Ji Hyeon aut Mai, Binh Khanh aut Lee, Jung Hoon aut Kim, Se Hyun aut Lee, Min Jae (orcid)0000-0002-3252-6467 aut Enthalten in NeuroRX Springer-Verlag, 2006 18(2021), 3 vom: 21. Apr., Seite 1768-1782 (DE-627)SPR031264964 nnns volume:18 year:2021 number:3 day:21 month:04 pages:1768-1782 https://dx.doi.org/10.1007/s13311-021-01039-0 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA AR 18 2021 3 21 04 1768-1782 |
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The Antipsychotic Drug Clozapine Suppresses the RGS4 Polyubiquitylation and Proteasomal Degradation Mediated by the Arg/N-Degron Pathway Schizophrenia (dpeaa)DE-He213 Clozapine (dpeaa)DE-He213 RGS4 (dpeaa)DE-He213 Ubiquitination (dpeaa)DE-He213 N-degron pathway (dpeaa)DE-He213 Ubiquitin–proteasome system (dpeaa)DE-He213 |
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The Antipsychotic Drug Clozapine Suppresses the RGS4 Polyubiquitylation and Proteasomal Degradation Mediated by the Arg/N-Degron Pathway |
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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. © The American Society for Experimental NeuroTherapeutics, Inc. 2021 |
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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. © The American Society for Experimental NeuroTherapeutics, Inc. 2021 |
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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. © The American Society for Experimental NeuroTherapeutics, Inc. 2021 |
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