Functional effects of polymorphisms on glucocorticoid receptor modulation of human anxiogenic substance-P gene promoter activity in primary amygdala neurones.
Expression or introduction 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 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.
['Hay|Colin W|CW|', 'Shanley|Lynne|L|', 'Davidson|Scott|S|', 'Cowie|Philip|P|', 'Lear|Marissa|M|', 'McGuffin|Peter|P|', 'Riedel|Gernot|G|', 'McEwan|Iain J|IJ|', 'MacKenzie|Alasdair|A|']
D000679:Amygdala D000818:Animals D000831:Animals, Newborn D001007:Anxiety D001483:Base Sequence D002478:Cells, Cultured D005576:Colforsin D003907:Dexamethasone D005786:Gene Expression Regulation D006801:Humans D008969:Molecular Sequence Data D009474:Neurons D020641:Polymorphism, Single Nucleotide D061251:Primary Cell Culture D011401:Promoter Regions, Genetic D051381:Rats D017207:Rats, Sprague-Dawley D011965:Receptors, Glucocorticoid D012689:Sequence Homology, Nucleic Acid D013373:Substance P
Glucocorticoid receptor TAC1 promoter Gene regulation Single nucleotide polymorphism Stress and anxiety