Genetic polymorphisms affect mouse and human trace amine-associated receptor 1 function

Xiao Shi, Nicole A.R. Walter, John H. Harkness, Kim A. Neve, Robert Williams, Lu Lu, John K. Belknap, Amy J. Eshleman, Tamara J. Phillips, Aaron Janowsky

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere0152581
JournalPLoS ONE
Volume11
Issue number3
DOIs
StatePublished - Mar 1 2016

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Genetic Polymorphisms
Polymorphism
amines
genetic polymorphism
Methamphetamine
receptors
mice
Inbred DBA Mouse
Single Nucleotide Polymorphism
Alleles
Octopamine
Tyramine
Inborn Genetic Diseases
phenethylamine
Fibromyalgia
Lymphocytes
migraine
alleles
Metabolites
Trace amine-associated receptor 1

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Genetic polymorphisms affect mouse and human trace amine-associated receptor 1 function. / Shi, Xiao; Walter, Nicole A.R.; Harkness, John H.; Neve, Kim A.; Williams, Robert; Lu, Lu; Belknap, John K.; Eshleman, Amy J.; Phillips, Tamara J.; Janowsky, Aaron.

In: PLoS ONE, Vol. 11, No. 3, e0152581, 01.03.2016.

Research output: Contribution to journalArticle

Shi, X, Walter, NAR, Harkness, JH, Neve, KA, Williams, R, Lu, L, Belknap, JK, Eshleman, AJ, Phillips, TJ & Janowsky, A 2016, 'Genetic polymorphisms affect mouse and human trace amine-associated receptor 1 function', PLoS ONE, vol. 11, no. 3, e0152581. https://doi.org/10.1371/journal.pone.0152581
Shi, Xiao ; Walter, Nicole A.R. ; Harkness, John H. ; Neve, Kim A. ; Williams, Robert ; Lu, Lu ; Belknap, John K. ; Eshleman, Amy J. ; Phillips, Tamara J. ; Janowsky, Aaron. / Genetic polymorphisms affect mouse and human trace amine-associated receptor 1 function. In: PLoS ONE. 2016 ; Vol. 11, No. 3.
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