ERICH3: vesicular association and antidepressant treatment response.

Abstract

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.

• Authors: Duan Liu, Yongxian Zhuang, Lingxin Zhang, Huanyao Gao, Drew Neavin, Tania Carrillo-Roa, Yani Wang, Jia Yu, Sisi Qin, Daniel C Kim, Erica Liu, Thanh Thanh Le Nguyen, Joanna M Biernacka, Rima Kaddurah-Daouk, Boadie W Dunlop, W Edward Craighead, Helen S Mayberg, Elisabeth B Binder, Mark A Frye, Liewei Wang, Richard M Weinshilboum
• Journal: Molecular psychiatry (Mol Psychiatry) Vol. 26 Issue 6 Pg. 2415-2428 (06 2021) ISSN: 1476-5578 [Electronic] England
• PMID: 33230203 (Publication Type: Journal Article, Meta-Analysis, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2020. The Author(s).

Chemical References

• Antidepressive Agents
• Serotonin Uptake Inhibitors
• Serotonin

Topics

• Antidepressive Agents (therapeutic use)
• Depressive Disorder, Major (drug therapy, genetics)
• Genome-Wide Association Study
• Humans
• Serotonin (therapeutic use)
• Selective Serotonin Reuptake Inhibitors (therapeutic use)