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A polymorphism linked to bipolar affective disorder does not alter the CRE activity of constitutively activated trace amine receptor 4

Molecular Psychiatry volume 12, pages 900–902 (2007)Cite this article

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Altered levels of trace amines have been observed in neuropsychiatric disorders such as schizophrenia and bipolar affective disorder (BPAD) and therefore are of particular interest in this field.1 So far two G-protein coupled receptors (GPCR) that bind trace amines have been identified, which has led to the name ‘trace amine receptors’ (TA) being applied to an extended receptor subfamily with multiple members, and several pseudogenes, in both humans and rodents.2 The endogenous ligands for the remaining TA family members are still not known; therefore, they are considered orphan GPCRs.3 Several studies discuss a potential association of the human trace amine receptor 4 (TA4, also known as TRAR4 or TAAR6) to BPAD and schizophrenia.4, 5, 6, 7, 8 These observations make TA4 a potential target for neuropsychiatric disorders. Recently, a study was published in this journal linking a polymorphism of TA4 to BPAD. Since the frequency of the risk allele G is indicated with 89–93%,4, 5 the allele A of TA4 could rather be termed as protective against BPAD. The polymorphism in allele G versus allele A leads to the amino-acid exchange V265I in the sixth transmembrane domain of TA4.4 Here, we address the functional effect of this polymorphism on a molecular basis.

The generation of constitutively active receptors (CAMs) by mutagenesis has been shown to enable the study of receptor function in the absence of knowledge of the physiological ligand. We applied this approach to TA4. Both alleles of the human TA4 gene were cloned into pcDNA3 and pSecTag2 plasmids and their expression in HEK293 cells was confirmed using reverse transcriptase-PCR and immunocytochemistry, as described previously.9 To generate a CAM variant of TA4, mutations leading to an amino-acid exchange R130D were introduced into the so-called DRY-motif, which is known to promote constitutive activity in GPCRs.10 The activity of this mutant TA4CAM, transfected transiently into HEK293 cells, was compared to the activity of wild-type TA4 using PathwayFinder-GeneArrays (SuperArray Bioscience; HS-008 and HS-028). Replicates of this experiment indicated the increased expression of several genes with the cAMP resp. element (CRE) enhancer sequence in cells transfected with TA4CAM compared to wild-type TA4 (data not shown).

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Authors and Affiliations

  1. Neuroscience Research, Global Pharmaceutical Research and Development, Abbott, Ludwigshafen, Germany

    J Reiners, M Schmidt, L Unger & W Wernet

  2. Advanced Technology, Global Pharmaceutical Research and Development, Abbott, Abbott Park, IL, USA

    J Packer

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  1. J Reiners
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  2. M Schmidt
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  3. J Packer
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  4. L Unger
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  5. W Wernet
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Correspondence to J Reiners.

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Reiners, J., Schmidt, M., Packer, J. et al. A polymorphism linked to bipolar affective disorder does not alter the CRE activity of constitutively activated trace amine receptor 4. Mol Psychiatry 12, 900–902 (2007). https://doi.org/10.1038/sj.mp.4002043

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