Functional effects of polymorphisms on glucocorticoid receptor modulation of human anxiogenic substance-P gene promoter activity in primary amygdala neurones

PSYCHONEUROENDOCRINOLOGY

卷:47

Article

Hay, Colin W.¹  Shanley, Lynne¹  Davidson, Scott¹  Cowie, Philip¹  Lear, Marissa¹  McGuffin, Peter²  Riedel, Gernot¹  McEwan, Lain J.¹  MacKenzie, Alasdair¹ 

[1] Univ Aberdeen, Inst Med Sci, Sch Med Sci, Aberdeen AB39 3UW, Scotland

[2] Kings Coll London, Inst Psychiat, MRC SGDP Ctr, London SE5 8AF3, England

关键词: TAC1 promoter;    Glucocorticoid receptor;    Gene regulation;    Single nucleotide polymorphism;    Stress and anxiety;   

DOI  :  10.1016/j.psyneuen.2014.04.017

来源: Elsevier

【 摘 要 】

Expression or introduction of the neuropeptide substance-P (SP; encoded by the TAC1 gene in humans and Tad in rodents) in the amygdala induces anxiety related behaviour in rodents. In addition, pharmacological antagonism of the main receptor of SP in humans; NK1, is anxiolytic. In the current study, we show that the Tad locus is up-regulated in primary rat amygdala neurones in response to activation of the glucocorticoid receptor (GR); a classic component of the stress response. Using a combination of bioinformatics, electrophoretic mobility shift assays (EMSA) and reporter plasmid magnetofection into rat primary amygdala neurones we identified a highly conserved GR response sequence (2GR) in the human TAC1 promoter that binds GR in response to dexamethasone (Dex) or forskolin. We also identified a second GR binding site in the human promoter that was polymorphic and whose T-allele is only found in Japanese and Chinese populations. We present evidence that the T-allele of SNPGR increases the activity of the TAC1 promoter through de-sequestration or de-repression of 2GR. The identification of Dex/forskolin response elements in the TAC1 promoter in amygdala neurones suggests a possible link in the chain of molecular events connecting GR activation and anxiety. In addition, the discovery of a SNP which can alter this response may have implications for our understanding of the role of regulatory variation in susceptibility to stress in specific populations. (C) 2014 The Authors.

【 授权许可】

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