title: G protein-coupled receptor kinase-2 (GRK-2) regulates serotonin metabolism through the monoamine oxidase AMX-2 inCaenorhabditis elegans.
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 systemCaenorhabditis elegansOur studies demonstrate thatgrk-2loss-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 inactivegrk-2or by the selective expression ofgrk-2in 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 inC. elegans, and we also found thatgrk-2loss-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.
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Wang
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
authors.forename: Jiansong
authors.initials: J
authors.lastname: Luo
authors.affiliation: Departments of Psychiatry and Behavioral Sciences.
authors.forename: Dipendra K
authors.initials: DK
authors.lastname: Aryal
authors.affiliation: Departments of Psychiatry and Behavioral Sciences.|Cell Biology, and.|Neurobiology and.|Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, North Carolina 27710, and.
authors.forename: William C
authors.initials: WC
authors.lastname: Wetsel
authors.affiliation: Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors.forename: Richard
authors.initials: R
authors.lastname: Nass
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, jeffrey.benovic@jefferson.edu.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Benovic
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D054768:G-Protein-Coupled Receptor Kinases / Q000096:biosynthesis* / Q000235:genetics; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008995:Monoamine Oxidase / Q000235:genetics / Q000378:metabolism*; D044348:Receptors, Serotonin, 5-HT2 / Q000235:genetics / Q000378:metabolism; D012701:Serotonin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D029742:Caenorhabditis elegans Proteins; C516620:GOA-1 protein, C elegans; D044348:Receptors, Serotonin, 5-HT2; C515315:SER-1 protein, C elegans; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D008995:Monoamine Oxidase; D054768:G-Protein-Coupled Receptor Kinases; C572772:GRK-2 protein, C elegans; D019206:GTP-Binding Protein alpha Subunits, Gi-Go
keywords: 5-hydroxyindole acetic acid; G protein; G protein-coupled receptor (GPCR); egg laying; monoamine oxidase; protein kinase; serotonin; signal transduction