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PMID:23926250

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Citation

Kabayama, M, Sakoori, K, Yamada, K, Ornthanalai, VG, Ota, M, Morimura, N, Katayama, K, Murphy, NP and Aruga, J (2013) Rines E3 ubiquitin ligase regulates MAO-A levels and emotional responses. J. Neurosci. 33:12940-53

Abstract

Monoamine oxidase A (MAO-A), the catabolic enzyme of norepinephrine and serotonin, plays a critical role in emotional and social behavior. However, the control and impact of endogenous MAO-A levels in the brain remains unknown. Here we show that the RING finger-type E3 ubiquitin ligase Rines/RNF180 regulates brain MAO-A subset, monoamine levels, and emotional behavior. Rines interacted with MAO-A and promoted its ubiquitination and degradation. Rines knock-out mice displayed impaired stress responses, enhanced anxiety, and affiliative behavior. Norepinephrine and serotonin levels were altered in the locus ceruleus, prefrontal cortex, and amygdala in either stressed or resting conditions, and MAO-A enzymatic activity was enhanced in the locus ceruleus in Rines knock-out mice. Treatment of Rines knock-out mice with MAO inhibitors showed genotype-specific effects on some of the abnormal affective behaviors. These results indicated that the control of emotional behavior by Rines is partly due to the regulation of MAO-A levels. These findings verify that Rines is a critical regulator of the monoaminergic system and emotional behavior and identify a promising candidate drug target for treating diseases associated with emotion.

Links

PubMed Online version:10.1523/JNEUROSCI.5717-12.2013

Keywords

Acoustic Stimulation; Animals; Avoidance Learning/physiology; Brain/enzymology; Brain/ultrastructure; Dark Adaptation/genetics; Emotions/drug effects; Emotions/physiology; Exploratory Behavior/physiology; Gene Expression Regulation, Developmental/genetics; HEK293 Cells; Humans; Interpersonal Relations; Male; Maze Learning/physiology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Monoamine Oxidase/metabolism; Monoamine Oxidase Inhibitors/pharmacology; Mutation/genetics; Reaction Time/genetics; Reflex, Startle/genetics; Swimming/physiology; Tranylcypromine/pharmacology; Ubiquitin-Protein Ligases/genetics; Ubiquitin-Protein Ligases/metabolism; Ubiquitination/drug effects; Ubiquitination/genetics

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:RN180

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q64133

F

Seeded From UniProt

complete

MOUSE:RN180

acts_upstream_of_or_within

GO:0030534: adult behavior

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RN180

acts_upstream_of_or_within

GO:0000209: protein polyubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RN180

acts_upstream_of_or_within

GO:0032436: positive regulation of proteasomal ubiquitin-dependent protein catabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RN180

acts_upstream_of_or_within

GO:0031398: positive regulation of protein ubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RN180

acts_upstream_of_or_within

GO:0050790: regulation of catalytic activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RN180

acts_upstream_of_or_within

GO:0042428: serotonin metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RN180

acts_upstream_of_or_within

GO:0042415: norepinephrine metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RN180

acts_upstream_of_or_within

GO:1901360: organic cyclic compound metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:AOFA

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q3U827

F

Seeded From UniProt

complete

MOUSE:AOFA

enables

GO:0008131: primary amine oxidase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

Notes

See also

References

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