Persistently Elevated mTOR Complex 1-S6 Kinase 1 Disrupts DARPP-32-Dependent D

Dopamine and cAMP-Regulated Phosphoprotein 32 / metabolism Humans Mechanistic Target of Rapamycin Complex 1 Phosphorylation Receptors, Dopamine D1 / metabolism Ribosomal Protein S6 Kinases / metabolism Signal Transduction TOR Serine-Threonine Kinases / metabolism
D(1) dopamine receptor DARPP-32 Immediate early gene S6K1 Social behavior mTORC1

Journal

Biological psychiatry
ISSN: 1873-2402
Titre abrégé: Biol Psychiatry
Pays: United States
ID NLM: 0213264

Informations de publication

Date de publication:
01 06 2021
Historique:
received: 16 08 2020
revised: 17 10 2020
accepted: 22 10 2020
pubmed: 24 12 2020
medline: 29 6 2021
entrez: 23 12 2020
Statut: ppublish

Résumé

The serine-threonine kinase mTORC1 (mechanistic target of rapamycin complex 1) is essential for normal cell function but is aberrantly activated in the brain in both genetic-developmental and sporadic diseases and is associated with a spectrum of neuropsychiatric symptoms. The underlying molecular mechanisms of cognitive and neuropsychiatric symptoms remain controversial. The present study examines behaviors in transgenic models that express Rheb, the most proximal known activator of mTORC1, and profiles striatal phosphoproteomics in a model with persistently elevated mTORC1 signaling. Biochemistry, immunohistochemistry, electrophysiology, and behavior approaches are used to examine the impact of persistently elevated mTORC1 on D We report that persistently elevated mTORC1 signaling blocks canonical D1R signaling that is dependent on DARPP-32 (dopamine- and cAMP-regulated neuronal phosphoprotein). The immediate downstream effector of mTORC1, ribosomal S6 kinase 1 (S6K1), phosphorylates and activates DARPP-32. Persistent elevation of mTORC1-S6K1 occludes dynamic D1R signaling downstream of DARPP-32 and blocks multiple D1R responses, including dynamic gene expression, D1R-dependent corticostriatal plasticity, and D1R behavioral responses including sociability. Candidate biomarkers of mTORC1-DARPP-32 occlusion are increased in the brain of human disease subjects in association with elevated mTORC1-S6K1, supporting a role for this mechanism in cognitive disease. The mTORC1-S6K1 intersection with D1R signaling provides a molecular framework to understand the effects of pathological mTORC1 activation on behavioral symptoms in neuropsychiatric disease.

Sections du résumé

BACKGROUND
The serine-threonine kinase mTORC1 (mechanistic target of rapamycin complex 1) is essential for normal cell function but is aberrantly activated in the brain in both genetic-developmental and sporadic diseases and is associated with a spectrum of neuropsychiatric symptoms. The underlying molecular mechanisms of cognitive and neuropsychiatric symptoms remain controversial.
METHODS
The present study examines behaviors in transgenic models that express Rheb, the most proximal known activator of mTORC1, and profiles striatal phosphoproteomics in a model with persistently elevated mTORC1 signaling. Biochemistry, immunohistochemistry, electrophysiology, and behavior approaches are used to examine the impact of persistently elevated mTORC1 on D
RESULTS
We report that persistently elevated mTORC1 signaling blocks canonical D1R signaling that is dependent on DARPP-32 (dopamine- and cAMP-regulated neuronal phosphoprotein). The immediate downstream effector of mTORC1, ribosomal S6 kinase 1 (S6K1), phosphorylates and activates DARPP-32. Persistent elevation of mTORC1-S6K1 occludes dynamic D1R signaling downstream of DARPP-32 and blocks multiple D1R responses, including dynamic gene expression, D1R-dependent corticostriatal plasticity, and D1R behavioral responses including sociability. Candidate biomarkers of mTORC1-DARPP-32 occlusion are increased in the brain of human disease subjects in association with elevated mTORC1-S6K1, supporting a role for this mechanism in cognitive disease.
CONCLUSIONS
The mTORC1-S6K1 intersection with D1R signaling provides a molecular framework to understand the effects of pathological mTORC1 activation on behavioral symptoms in neuropsychiatric disease.

Identifiants

DOI: 10.1016/j.biopsych.2020.10.012 PMID: 33353667 PMC: PMC8076344
pubmed: 33353667
pii: S0006-3223(20)32021-7
doi: 10.1016/j.biopsych.2020.10.012
pmc: PMC8076344
mid: NIHMS1658624
pii:
doi:

Substances chimiques

DRD1 protein, human 0
Dopamine and cAMP-Regulated Phosphoprotein 32 0
PPP1R1B protein, human 0
Receptors, Dopamine D1 0
MTOR protein, human EC 2.7.1.1
Mechanistic Target of Rapamycin Complex 1 EC 2.7.11.1
Ribosomal Protein S6 Kinases EC 2.7.11.1
TOR Serine-Threonine Kinases EC 2.7.11.1

Types de publication

Journal Article Research Support, N.I.H., Extramural

Langues

eng

Sous-ensembles de citation

IM

Pagination

1058-1072

Subventions

Organisme : NIA NIH HHS
ID : P30 AG066507
Pays : United States
Organisme : NIDA NIH HHS
ID : P50 DA044123
Pays : United States
Organisme : NIDA NIH HHS
ID : R01 DA010309
Pays : United States

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2020 Society of Biological Psychiatry. All rights reserved.

Auteurs

Raozhou Lin (R)

Solomon Snyder Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, Maryland.

Lisa N Learman (LN)

Solomon Snyder Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, Maryland.

Chan-Hyun Na (CH)

Department of Neurology, School of Medicine, Johns Hopkins University, Baltimore, Maryland; Institute for Cell Engineering, School of Medicine, Johns Hopkins University, Baltimore, Maryland.

Santosh Renuse (S)

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota.

Kevin T Chen (KT)

Solomon Snyder Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, Maryland.

Po Yu Chen (PY)

Solomon Snyder Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, Maryland.

Gum-Hwa Lee (GH)

Solomon Snyder Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, Maryland.

Bo Xiao (B)

Solomon Snyder Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, Maryland.

Susan M Resnick (SM)

Laboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore, Maryland.

Juan C Troncoso (JC)

Department of Neurology, School of Medicine, Johns Hopkins University, Baltimore, Maryland; Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, Maryland.

Karen K Szumlinski (KK)

Department of Psychological and Brain Sciences and the Neuroscience Research Institute, University of California, Santa Barbara, California.

David J Linden (DJ)

Solomon Snyder Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, Maryland.

Joo-Min Park (JM)

Center for Cognition and Sociality, Institute for Basic Science, Daejeon, South Korea.

Alena Savonenko (A)

Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, Maryland.

Akhilesh Pandey (A)

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota.

Paul F Worley (PF)

Solomon Snyder Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, Maryland; Department of Neurology, School of Medicine, Johns Hopkins University, Baltimore, Maryland. Electronic address: pworley@jhmi.edu.

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Phosphoprotéines › Phosphoprotéine DARPP-32 régulée par la dopamine et l'AMPc › Persistently Elevated mTOR Complex 1-S6 Kinase...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Persistently Elevated mTOR Complex 1-S6 Kinase...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Sérine-thréonine kinases TOR › Complexe-1 cible mécanistique de la rapamycine › Persistently Elevated mTOR Complex 1-S6 Kinase...
questionsmedicales.fr › Métabolisme › Phosphorylation › Persistently Elevated mTOR Complex 1-S6 Kinase...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs aux neuromédiateurs › Récepteurs catécholaminergiques › Récepteurs dopaminergiques › Récepteur dopamine D1 › Persistently Elevated mTOR Complex 1-S6 Kinase...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Ribosomal Protein S6 Kinases › Persistently Elevated mTOR Complex 1-S6 Kinase...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Persistently Elevated mTOR Complex 1-S6 Kinase...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Sérine-thréonine kinases TOR › Persistently Elevated mTOR Complex 1-S6 Kinase...