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PMID:28213524

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Citation

Wang, J, Luo, J, Aryal, DK, Wetsel, WC, Nass, R and Benovic, JL (2017) G protein-coupled receptor kinase-2 (GRK-2) regulates serotonin metabolism through the monoamine oxidase AMX-2 in . J. Biol. Chem. 292:5943-5956

Abstract

G protein-coupled receptors (GPCRs) regulate many animal behaviors. GPCR signaling is mediated by agonist-promoted interactions of GPCRs with heterotrimeric G proteins, GPCR kinases (GRKs), and arrestins. To further elucidate the role of GRKs in regulating GPCR-mediated behaviors, we utilized the genetic model system Our studies demonstrate that loss-of-function strains are egg laying-defective and contain low levels of serotonin (5-HT) and high levels of the 5-HT metabolite 5-hydroxyindole acetic acid (5-HIAA). The egg laying defect could be rescued by the expression of wild type but not by catalytically inactive or by the selective expression of in hermaphrodite-specific neurons. The addition of 5-HT or inhibition of 5-HT metabolism also rescued the egg laying defect. Furthermore, we demonstrate that AMX-2 is the primary monoamine oxidase that metabolizes 5-HT in , and we also found that loss-of-function strains have abnormally high levels of AMX-2 compared with wild-type nematodes. Interestingly, GRK-2 was also found to interact with and promote the phosphorylation of AMX-2. Additional studies reveal that 5-HIAA functions to inhibit egg laying in a manner dependent on the 5-HT receptor SER-1 and the G protein GOA-1. These results demonstrate that GRK-2 modulates 5-HT metabolism by regulating AMX-2 function and that 5-HIAA may function in the SER-1 signaling pathway.

Links

PubMed PMC5392585 Online version:10.1074/jbc.M116.760850

Keywords

Animals; Caenorhabditis elegans/genetics; Caenorhabditis elegans/metabolism; Caenorhabditis elegans Proteins/biosynthesis; Caenorhabditis elegans Proteins/genetics; Caenorhabditis elegans Proteins/metabolism; G-Protein-Coupled Receptor Kinases/biosynthesis; G-Protein-Coupled Receptor Kinases/genetics; GTP-Binding Protein alpha Subunits, Gi-Go/genetics; GTP-Binding Protein alpha Subunits, Gi-Go/metabolism; Gene Expression Regulation, Enzymologic/physiology; Hydroxyindoleacetic Acid/metabolism; Monoamine Oxidase/genetics; Monoamine Oxidase/metabolism; Receptors, Serotonin, 5-HT2/genetics; Receptors, Serotonin, 5-HT2/metabolism; Serotonin/genetics; Serotonin/metabolism; Signal Transduction/physiology

Significance

Annotations

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

CAEEL:GRK2

involved_in

GO:0006468: protein phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:GRK2

involved_in

GO:0042429: serotonin catabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:GRK2

involved_in

GO:1901046: positive regulation of oviposition

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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