Anti-apoptotic Actions of Allopregnanolone and Ganaxolone Mediated Through Membrane Progesterone Receptors (PAQRs) in Neuronal Cells.

Frontiers in Endocrinology
Peter Thomas, Yefei Pang

Abstract

The neurosteroids progesterone and allopregnanolone regulate numerous neuroprotective functions in neural tissues including inhibition of epileptic seizures and cell death. Many of progesterone's actions are mediated through the nuclear progesterone receptor (PR), while allopregnanolone is widely considered to be devoid of hormonal activity and instead acts through modulation of GABA-A receptor activity. However, allopregnanolone can also exert hormonal actions in neuronal cells through binding and activating membrane progesterone receptors (mPRs) belonging to the progestin and adipoQ receptor (PAQR) family. The distribution and functions of the five mPR subtypes (α, β, γ, δ, ε) in neural tissues are briefly reviewed. mPRδ has the highest binding affinity for allopregnanolone and is highly expressed throughout the human brain. Low concentrations (20 nM) of allopregnanolone act through mPRδ to stimulate G protein (Gs)-dependent signaling pathways resulting in reduced cell death and apoptosis in mPRδ-transfected cells. The 3-methylated synthetic analog of allopregnanolone, ganaxolone, is currently undergoing clinical trials as a promising GABA-A receptor-selective antiepileptic drug (AED). New data show that low concentrations (2...Continue Reading

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Citations

Jan 27, 2021·The Journal of Steroid Biochemistry and Molecular Biology·Inna S LevinaIgor V Zavarzin
Aug 18, 2021·Nature Neuroscience·Claire-Marie VacherAnna A Penn
Nov 6, 2021·Journal of Neuroendocrinology·Antonella Rosario Ramona CáceresMyriam Raquel Laconi

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Methods Mentioned

BETA
MDA
sedation
antisense oligonucleotides

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