G protein-coupled receptor kinase-2 (GRK-2) regulates serotonin metabolism through the monoamine oxidase AMX-2 in Caenorhabditis elegans

Jianjun Wang, Jiansong Luo, Dipendra K. Aryal, William C. Wetsel, Richard Nass, Jeffrey L. Benovic

Research output: Contribution to journalArticle

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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 Caenorhabditis elegans. Our studies demonstrate that grk-2 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 grk-2 or by the selective expression of grk-2 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 C. elegans, and we also found that grk-2 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.

Original languageEnglish (US)
Pages (from-to)5943-5956
Number of pages14
JournalJournal of Biological Chemistry
Volume292
Issue number14
DOIs
StatePublished - Apr 7 2017

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G-Protein-Coupled Receptor Kinase 2
Monoamine Oxidase
Caenorhabditis elegans
Metabolism
Serotonin
G-Protein-Coupled Receptors
Ovum
Acetic Acid
Arrestins
G-Protein-Coupled Receptor Kinases
Enzyme inhibition
Heterotrimeric GTP-Binding Proteins
Animal Behavior
Defects
Phosphorylation
Serotonin Receptors
Genetic Models
Metabolites
GTP-Binding Proteins
Neurons

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

G protein-coupled receptor kinase-2 (GRK-2) regulates serotonin metabolism through the monoamine oxidase AMX-2 in Caenorhabditis elegans. / Wang, Jianjun; Luo, Jiansong; Aryal, Dipendra K.; Wetsel, William C.; Nass, Richard; Benovic, Jeffrey L.

In: Journal of Biological Chemistry, Vol. 292, No. 14, 07.04.2017, p. 5943-5956.

Research output: Contribution to journalArticle

Wang, Jianjun ; Luo, Jiansong ; Aryal, Dipendra K. ; Wetsel, William C. ; Nass, Richard ; Benovic, Jeffrey L. / G protein-coupled receptor kinase-2 (GRK-2) regulates serotonin metabolism through the monoamine oxidase AMX-2 in Caenorhabditis elegans. In: Journal of Biological Chemistry. 2017 ; Vol. 292, No. 14. pp. 5943-5956.
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