Abstract
SummaryExpression 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.
Highlights
It is evident that susceptibility to many forms of human disease is caused by polymorphic variation in the regulatory elements controlling the expression of genes rather than by variation within the coding regions of these genes (Maurano et al, 2012)
We demonstrate that activated glucocorticoid receptor (GR) can up-regulate the activity of the human TAC1 promoter in primary amygdala neurones and identify the specific sequences involved
The conserved human TAC1 promoter is responsive to Dex in primary amygdala neurones
Summary
It is evident that susceptibility to many forms of human disease is caused by polymorphic variation in the regulatory elements controlling the expression of genes rather than by variation within the coding regions of these genes (Maurano et al, 2012). Substance P (SP), a neuropeptide that, along with the less well characterised neurokinin-A (NKA), is encoded by the human TAC1 gene (Tac in rodents) and is expressed in both the medial and central amygdala where it modulates anxiety levels (Ebner et al, 2008; Singewald et al, 2008; Zhao et al, 2009). An interesting clue as to the mechanism linking the stress response and the regulation of SP comes from studies that demonstrate co-localisation of the stress activated glucocorticoid receptor (GR) and Tac within cells of the central amygdala (Honkaniemi et al, 1992). Further animal studies have shown that the glucocorticoid and adrenergic systems, the two main stress activated pathways in the brain, act in concert to enhance memory formation by acting within the amygdala, hippocampus and prefrontal cortex (PFC) (van Stegeren et al, 2009)
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