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

Colin Hay, Lynne Shanley, Scott Davidson, Philip Cowie, Marissa Lear, Peter McGuffin, Gernot Riedel, Iain J McEwan, Alasdair MacKenzie

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Abstract

Expression of the neuropeptide substance-P (SP; encoded by the TAC1 gene in humans and Tac1 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 Tac1 locus is up-regulated in primary 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 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.
Original languageEnglish
Pages (from-to)43-55
Number of pages13
JournalPsychoneuroendocrinology
Volume47
Early online date2 May 2014
DOIs
Publication statusPublished - Sep 2014

Fingerprint

Glucocorticoid Receptors
Substance P
Amygdala
Neurons
Genes
Colforsin
Dexamethasone
Rodentia
Anxiety
Alleles
Anti-Anxiety Agents
Response Elements
Electrophoretic Mobility Shift Assay
Computational Biology
Neuropeptides
Population
Single Nucleotide Polymorphism
Plasmids
Binding Sites
Pharmacology

Keywords

  • TAC1 promoter
  • glucocorticoid receptor
  • gene regulation
  • single nucleotide polymorphism
  • stress and anxiety

Cite this

Functional effects of polymorphisms on glucocorticoid receptor modulation of human anxiogenic substance-P gene promoter activity in primary amygdala neurones. / Hay, Colin; Shanley, Lynne; Davidson, Scott; Cowie, Philip; Lear, Marissa; McGuffin, Peter; Riedel, Gernot; McEwan, Iain J; MacKenzie, Alasdair.

In: Psychoneuroendocrinology, Vol. 47, 09.2014, p. 43-55.

Research output: Contribution to journalArticle

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