title: Genetic Polymorphisms Affect Mouse and Human Trace Amine-Associated Receptor 1 Function.
abstract: Methamphetamine (MA) and neurotransmitter precursors and metabolites such as tyramine, octopamine, and β-phenethylamine stimulate the G protein-coupled trace amine-associated receptor 1 (TAAR1). TAAR1 has been implicated in human conditions including obesity, schizophrenia, depression, fibromyalgia, migraine, and addiction. Additionally TAAR1 is expressed on lymphocytes and astrocytes involved in inflammation and response to infection. In brain, TAAR1 stimulation reduces synaptic dopamine availability and alters glutamatergic function. TAAR1 is also expressed at low levels in heart, and may regulate cardiovascular tone. Taar1 knockout mice orally self-administer more MA than wild type and are insensitive to its aversive effects. DBA/2J (D2) mice express a non-synonymous single nucleotide polymorphism (SNP) in Taar1 that does not respond to MA, and D2 mice are predisposed to high MA intake, compared to C57BL/6 (B6) mice. Here we demonstrate that endogenous agonists stimulate the recombinant B6 mouse TAAR1, but do not activate the D2 mouse receptor. Progeny of the B6XD2 (BxD) family of recombinant inbred (RI) strains have been used to characterize the genetic etiology of diseases, but contrary to expectations, BXDs derived 30-40 years ago express only the functional B6 Taar1 allele whereas some more recently derived BXD RI strains express the D2 allele. Data indicate that the D2 mutation arose subsequent to derivation of the original RIs. Finally, we demonstrate that SNPs in human TAAR1 alter its function, resulting in expressed, but functional, sub-functional and non-functional receptors. Our findings are important for identifying a predisposition to human diseases, as well as for developing personalized treatment options.
authors.affiliation: Veterans Affairs Portland Health Care System, Portland, Oregon, United States of America.|The Methamphetamine Abuse Research Center, Oregon Health & Science University, Portland, Oregon, United States of America.|Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Xiao
authors.initials: X
authors.lastname: Shi
authors.affiliation: Veterans Affairs Portland Health Care System, Portland, Oregon, United States of America.|Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Nicole A R
authors.initials: NA
authors.lastname: Walter
authors.affiliation: Veterans Affairs Portland Health Care System, Portland, Oregon, United States of America.|Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: John H
authors.initials: JH
authors.lastname: Harkness
authors.affiliation: Veterans Affairs Portland Health Care System, Portland, Oregon, United States of America.|The Methamphetamine Abuse Research Center, Oregon Health & Science University, Portland, Oregon, United States of America.|Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Kim A
authors.initials: KA
authors.lastname: Neve
authors.affiliation: Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Williams
authors.affiliation: Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.|Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.affiliation: Veterans Affairs Portland Health Care System, Portland, Oregon, United States of America.|The Methamphetamine Abuse Research Center, Oregon Health & Science University, Portland, Oregon, United States of America.|Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: John K
authors.initials: JK
authors.lastname: Belknap
authors.affiliation: Veterans Affairs Portland Health Care System, Portland, Oregon, United States of America.|Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Eshleman
authors.affiliation: Veterans Affairs Portland Health Care System, Portland, Oregon, United States of America.|The Methamphetamine Abuse Research Center, Oregon Health & Science University, Portland, Oregon, United States of America.|Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Tamara J
authors.initials: TJ
authors.lastname: Phillips
authors.affiliation: Veterans Affairs Portland Health Care System, Portland, Oregon, United States of America.|The Methamphetamine Abuse Research Center, Oregon Health & Science University, Portland, Oregon, United States of America.|Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, Oregon, United States of America.|Department of Psychiatry, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Aaron
authors.initials: A
authors.lastname: Janowsky
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000242:Cyclic AMP / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D057809:HEK293 Cells; D006239:Haplotypes; D006801:Humans; D008694:Methamphetamine / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D000095383:Trace Amine-Associated Receptors
chemical_list: D000242:Cyclic AMP; D004298:Dopamine; D008694:Methamphetamine; D043562:Receptors, G-Protein-Coupled; D000095383:Trace Amine-Associated Receptors