ERICH3: vesicular association and antidepressant treatment response.
Journal
Molecular psychiatry
ISSN: 1476-5578
Titre abrégé: Mol Psychiatry
Pays: England
ID NLM: 9607835
Informations de publication
Date de publication:
06 2021
06 2021
Historique:
received:
08
02
2020
accepted:
26
10
2020
revised:
30
09
2020
pubmed:
25
11
2020
medline:
12
10
2021
entrez:
24
11
2020
Statut:
ppublish
Résumé
Selective serotonin reuptake inhibitors (SSRIs) are standard of care for major depressive disorder (MDD) pharmacotherapy, but only approximately half of these patients remit on SSRI therapy. Our previous genome-wide association study identified a single-nucleotide polymorphism (SNP) signal across the glutamate-rich 3 (ERICH3) gene that was nearly genome-wide significantly associated with plasma serotonin (5-HT) concentrations, which were themselves associated with SSRI response for MDD patients enrolled in the Mayo Clinic PGRN-AMPS SSRI trial. In this study, we performed a meta-analysis which demonstrated that those SNPs were significantly associated with SSRI treatment outcomes in four independent MDD trials. However, the function of ERICH3 and molecular mechanism(s) by which it might be associated with plasma 5-HT concentrations and SSRI clinical response remained unclear. Therefore, we characterized the human ERICH3 gene functionally and identified ERICH3 mRNA transcripts and protein isoforms that are highly expressed in central nervous system cells. Coimmunoprecipitation identified a series of ERICH3 interacting proteins including clathrin heavy chain which are known to play a role in vesicular function. Immunofluorescence showed ERICH3 colocalization with 5-HT in vesicle-like structures, and ERICH3 knock-out dramatically decreased 5-HT staining in SK-N-SH cells as well as 5-HT concentrations in the culture media and cell lysates without changing the expression of 5-HT synthesizing or metabolizing enzymes. Finally, immunofluorescence also showed ERICH3 colocalization with dopamine in human iPSC-derived neurons. These results suggest that ERICH3 may play a significant role in vesicular function in serotonergic and other neuronal cell types, which might help explain its association with antidepressant treatment response.
Identifiants
pubmed: 33230203
doi: 10.1038/s41380-020-00940-y
pii: 10.1038/s41380-020-00940-y
pmc: PMC8141066
mid: NIHMS1641256
doi:
Substances chimiques
Antidepressive Agents
0
Serotonin Uptake Inhibitors
0
Serotonin
333DO1RDJY
Types de publication
Journal Article
Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2415-2428Subventions
Organisme : NIGMS NIH HHS
ID : U19 GM061388
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG046171
Pays : United States
Organisme : NCRR NIH HHS
ID : M01 RR000039
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH080880
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG061359
Pays : United States
Organisme : NIMH NIH HHS
ID : P50 MH077083
Pays : United States
Organisme : NCRR NIH HHS
ID : UL1 RR025008
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG051550
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH108348
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM028157
Pays : United States
Informations de copyright
© 2020. The Author(s).
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