title: Progesterone receptor signalling in retinal photoreceptor neuroprotection.
abstract: 'Norgestrel', a synthetic form of the female hormone progesterone has been identified as potential drug candidate for the treatment of the degenerative eye disease retinitis pigmentosa. However, to date, no work has looked at the compound's specific cellular target. Therefore, this study aimed to identify the receptor target of Norgestrel and begin to examine its potential mechanism of action in the retina. In this work, we identify and characterize the expression of progesterone receptors present in the C57 wild type and rd10 mouse model of retinitis pigmentosa. Classical progesterone receptors A and B (PR A/B), progesterone receptor membrane components 1 and 2 (PGRMC1, PGRMC2) and membrane progesterone receptors α, β and γ were found to be expressed. All receptors excluding PR A/B were also found in the 661W photoreceptor cell line. PGRMC1 is a key regulator of apoptosis and its expression is up-regulated in the degenerating rd10 mouse retina. Activated by Norgestrel through nuclear trafficking, siRNA knock down of PGRMC1 abrogated the protective properties of Norgestrel on damaged photoreceptors. Furthermore, specific inhibition of PGRMC1 by AG205 blocked Norgestrel-induced protection in stressed retinal explants. Therefore, we conclude that PGRMC1 is crucial to the neuroprotective effects of Norgestrel on stressed photoreceptors. The synthetic progestin 'Norgestrel' has been identified as a potential therapeutic for the treatment of Retinitis Pigmentosa, a degenerative eye disease. However, the mechanism behind this neuroprotection is currently unknown. In this work, we identify 'Progesterone Receptor Membrane Component 1' as the major progesterone receptor eliciting the protective effects of Norgestrel, both in vitro and ex vivo. This furthers our understanding of Norgestrel's molecular mechanism, which we hope will help bring Norgestrel one step closer to the clinic.
authors.affiliation: Cell Development and Disease Laboratory, Biochemistry Department, Bioscience Research Institute, University College Cork, Cork, Ireland.
authors.forename: Alice C Wyse
authors.initials: AC
authors.lastname: Jackson
authors.affiliation: Cell Development and Disease Laboratory, Biochemistry Department, Bioscience Research Institute, University College Cork, Cork, Ireland.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Roche
authors.affiliation: Cell Development and Disease Laboratory, Biochemistry Department, Bioscience Research Institute, University College Cork, Cork, Ireland.
authors.forename: Ashleigh M
authors.initials: AM
authors.lastname: Byrne
authors.affiliation: Cell Development and Disease Laboratory, Biochemistry Department, Bioscience Research Institute, University College Cork, Cork, Ireland.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Ruiz-Lopez
authors.affiliation: Cell Development and Disease Laboratory, Biochemistry Department, Bioscience Research Institute, University College Cork, Cork, Ireland.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Cotter
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005260:Female; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000066829:Neuroprotection / Q000187:drug effects / Q000502:physiology*; D009644:Norgestrel / Q000494:pharmacology*; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000096:biosynthesis*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D008565:Membrane Proteins; C508868:PGRMC1 protein, mouse; D011980:Receptors, Progesterone; C101118:progesterone receptor A; D009644:Norgestrel
keywords: Norgestrel; PGRMC1; neuroprotection; photoreceptor; progesterone; retinal degeneration