Comparison of Transcriptional Activation by Corticosteroids of Human MR (Ile-180) and Human MR Haplotype (Ile180Val)

Katsu, Y.; Zhang, J.; Ao, Y.; Baker, M. E.

doi:10.1101/2024.12.08.627066

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bioRxiv · 10.1101/2024.12.08.627066

Comparison of Transcriptional Activation by Corticosteroids of Human MR (Ile-180) and Human MR Haplotype (Ile180Val)

Katsu, Y.·Zhang, J.·Ao, Y.·Baker, M. E.

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Abstract

While the human mineralocorticoid receptor (MR) regulates electrolyte homeostasis through aldosterone activation of the kidney MR, the MR also is highly expressed in the brain, where the MR is activated by cortisol. Here, we report the half-maximal response (EC50) and fold-activation by cortisol, aldosterone and other corticosteroids of human MR rs5522, a haplotype containing valine at codon 180 instead of isoleucine found in wild-type MR (Ile-180). MR rs5522 (Val-180) has been studied for actions in the human brain involving coping with stress and depression. We compared the EC50 and fold-activation by corticosteroids of MR rs5522 and wild-type MR transfected into HEK293 cells with either the TAT3 promoter or the MMTV promoter. Parallel studies investigated the binding of MR antagonists, spironolactone and progesterone, to MR rs5522 to investigate their use as antagonists of MR rs5522. In HEK293 cells with the MMTV promoter, MR rs5522 had a slightly higher EC50 compared to wild-type MR and a similar fold-activation for all corticosteroids. In contrast, in HEK293 cells with the TAT3 promoter, MR rs5522 had a higher EC50 (lower affinity) and fold-activation for cortisol compared to wild-type MR (Ile-180), while compared to wild-type MR, the EC50s of MR rs5522 for aldosterone and corticosterone were slightly lower and fold-activation was higher. Spironolactone and progesterone had similar antagonist activity for MR rs5522 and MR (Ile-180) in the presence of MMTV and TAT3 promoters in HEK293 cells indicating these antagonists are potential regulators of brain MR rs5522 to treat hyperactivity that contributes to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

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Katsu, Y., Zhang, J., Ao, Y., Baker, M. E.. 2024-12-11. Comparison of Transcriptional Activation by Corticosteroids of Human MR (Ile-180) and Human MR Haplotype (Ile180Val). https://doi.org/10.1101/2024.12.08.627066

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