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

Publication ,  Journal Article
Wang, J; Luo, J; Aryal, DK; Wetsel, WC; Nass, R; Benovic, JL
Published in: J Biol Chem
April 7, 2017

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.

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Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

April 7, 2017

Volume

292

Issue

14

Start / End Page

5943 / 5956

Location

United States

Related Subject Headings

  • Signal Transduction
  • Serotonin
  • Receptors, Serotonin, 5-HT2
  • Monoamine Oxidase
  • Hydroxyindoleacetic Acid
  • Gene Expression Regulation, Enzymologic
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • G-Protein-Coupled Receptor Kinases
  • Caenorhabditis elegans Proteins
  • Caenorhabditis elegans
 

Citation

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Wang, J., Luo, J., Aryal, D. K., Wetsel, W. C., Nass, R., & Benovic, J. L. (2017). G protein-coupled receptor kinase-2 (GRK-2) regulates serotonin metabolism through the monoamine oxidase AMX-2 in Caenorhabditis elegans. J Biol Chem, 292(14), 5943–5956. https://doi.org/10.1074/jbc.M116.760850
Wang, Jianjun, Jiansong Luo, Dipendra K. Aryal, William C. Wetsel, Richard Nass, and Jeffrey L. Benovic. “G protein-coupled receptor kinase-2 (GRK-2) regulates serotonin metabolism through the monoamine oxidase AMX-2 in Caenorhabditis elegans.J Biol Chem 292, no. 14 (April 7, 2017): 5943–56. https://doi.org/10.1074/jbc.M116.760850.
Wang J, Luo J, Aryal DK, Wetsel WC, Nass R, Benovic JL. G protein-coupled receptor kinase-2 (GRK-2) regulates serotonin metabolism through the monoamine oxidase AMX-2 in Caenorhabditis elegans. J Biol Chem. 2017 Apr 7;292(14):5943–56.
Wang, Jianjun, et al. “G protein-coupled receptor kinase-2 (GRK-2) regulates serotonin metabolism through the monoamine oxidase AMX-2 in Caenorhabditis elegans.J Biol Chem, vol. 292, no. 14, Apr. 2017, pp. 5943–56. Pubmed, doi:10.1074/jbc.M116.760850.
Wang J, Luo J, Aryal DK, Wetsel WC, Nass R, Benovic JL. G protein-coupled receptor kinase-2 (GRK-2) regulates serotonin metabolism through the monoamine oxidase AMX-2 in Caenorhabditis elegans. J Biol Chem. 2017 Apr 7;292(14):5943–5956.

Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

April 7, 2017

Volume

292

Issue

14

Start / End Page

5943 / 5956

Location

United States

Related Subject Headings

  • Signal Transduction
  • Serotonin
  • Receptors, Serotonin, 5-HT2
  • Monoamine Oxidase
  • Hydroxyindoleacetic Acid
  • Gene Expression Regulation, Enzymologic
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • G-Protein-Coupled Receptor Kinases
  • Caenorhabditis elegans Proteins
  • Caenorhabditis elegans