title: The protein arginine methyltransferase PRMT5 promotes D2-like dopamine receptor signaling.
abstract: Protein arginine methylation regulates diverse functions of eukaryotic cells, including gene expression, the DNA damage response, and circadian rhythms. We showed that arginine residues within the third intracellular loop of the human D2 dopamine receptor, which are conserved in the DOP-3 receptor in the nematode Caenorhabditis elegans, were methylated by protein arginine methyltransferase 5 (PRMT5). By mutating these arginine residues, we further showed that their methylation enhanced the D2 receptor-mediated inhibition of cyclic adenosine monophosphate (cAMP) signaling in cultured human embryonic kidney (HEK) 293T cells. Analysis of prmt-5-deficient worms indicated that methylation promoted the dopamine-mediated modulation of chemosensory and locomotory behaviors in C. elegans through the DOP-3 receptor. In addition to delineating a previously uncharacterized means of regulating GPCR (heterotrimeric guanine nucleotide-binding protein-coupled receptor) signaling, these findings may lead to the development of a new class of pharmacological therapies that modulate GPCR signaling by changing the methylation status of these key proteins.
authors.affiliation: Department of Biological Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14260, USA.
authors.forename: Neah
authors.initials: N
authors.lastname: Likhite
authors.affiliation: Department of Biological Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14260, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Jackson
authors.affiliation: Bioengineering Laboratory, Department of Chemical and Biological Engineering, University at Buffalo, The State University of New York, Buffalo, NY 14260, USA.
authors.forename: Mao-Shih
authors.initials: MS
authors.lastname: Liang
authors.affiliation: Department of Biological Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14260, USA.
authors.forename: Michelle C
authors.initials: MC
authors.lastname: Krzyzanowski
authors.affiliation: Bioengineering Laboratory, Department of Chemical and Biological Engineering, University at Buffalo, The State University of New York, Buffalo, NY 14260, USA.
authors.forename: Pedro
authors.initials: P
authors.lastname: Lei
authors.affiliation: Department of Biological Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14260, USA.
authors.forename: Jordan F
authors.initials: JF
authors.lastname: Wood
authors.affiliation: Department of Biological Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14260, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Birkaya
authors.affiliation: Department of Biological Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14260, USA.
authors.forename: Kerry L
authors.initials: KL
authors.lastname: Michaels
authors.affiliation: Bioengineering Laboratory, Department of Chemical and Biological Engineering, University at Buffalo, The State University of New York, Buffalo, NY 14260, USA.
authors.forename: Stelios T
authors.initials: ST
authors.lastname: Andreadis
authors.affiliation: Department of Pharmacology and Toxicology, University at Buffalo, The State University of New York, Buffalo, NY 14214, USA. Department of Psychology, University at Buffalo, The State University of New York, Buffalo, NY 14214, USA. Research Institute on Addictions, University at Buffalo, The State University of New York, Buffalo, NY 14214, USA.
authors.forename: Stewart D
authors.initials: SD
authors.lastname: Clark
authors.affiliation: Department of Biological Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14260, USA. dmferkey@buffalo.edu mcyu@buffalo.edu.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Yu
authors.affiliation: Department of Biological Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14260, USA. dmferkey@buffalo.edu mcyu@buffalo.edu.
authors.forename: Denise M
authors.initials: DM
authors.lastname: Ferkey
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D001120:Arginine / Q000737:chemistry; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019295:Computational Biology; D017124:Conserved Sequence; D004298:Dopamine / Q000378:metabolism / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008124:Locomotion / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D008745:Methylation; D008969:Molecular Sequence Data; D000442:Octanols / Q000494:pharmacology; D009812:Odorants; D011484:Protein-Arginine N-Methyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
chemical_list: D029742:Caenorhabditis elegans Proteins; C494134:DOP-3 protein, C elegans; C581293:DRD2 protein, human; D000442:Octanols; D017448:Receptors, Dopamine D2; D043562:Receptors, G-Protein-Coupled; D001120:Arginine; C400529:PRMT5 protein, human; D011484:Protein-Arginine N-Methyltransferases; C584313:prmt-5 protein, C elegans; D004298:Dopamine