PMID- 22778217 OWN - NLM STAT- MEDLINE DCOM- 20121029 LR - 20211021 IS - 1945-7170 (Electronic) IS - 0013-7227 (Print) IS - 0013-7227 (Linking) VI - 153 IP - 9 DP - 2012 Sep TI - Progesterone increases the release of brain-derived neurotrophic factor from glia via progesterone receptor membrane component 1 (Pgrmc1)-dependent ERK5 signaling. PG - 4389-400 LID - 10.1210/en.2011-2177 [doi] AB - Progesterone (P4) is cytoprotective in various experimental models, but our understanding of the mechanisms involved is still incomplete. Our laboratory has implicated brain-derived neurotrophic factor (BDNF) signaling as an important mediator of P4's protective actions. We have shown that P4 increases the expression of BDNF, an effect mediated by the classical P4 receptor (PR), and that the protective effects of P4 were abolished using inhibitors of Trk receptor signaling. In an effort to extend our understanding of the interrelationship between P4 and BDNF signaling, we determined whether P4 influenced BDNF release and examined the role of the classical PR and a putative membrane PR, progesterone receptor membrane component-1 (Pgrmc1), as mediators of this response. Given recent data from our laboratory that supported the role of ERK5 in BDNF release, we also tested whether P4-induced BDNF release was mediated by ERK5. In this study, we found that P4 and the membrane-impermeable P4 (P4-BSA) both induced BDNF release from cultured C6 glial cells and primary astrocytes. Both these cells lack the classical nuclear/intracellular PR but express high levels of membrane-associated PR, including Pgrmc1. Using RNA interference-mediated knockdown of Pgrmc1 expression, we determined that P4-induced BDNF release was dependent on the expression of Pgrmc1, although pharmacological inhibition of the PR failed to alter the effects of P4. Furthermore, the BDNF release elicited by P4 was mediated by ERK5, and not ERK1/2. Collectively, our data describe that P4 elicits an increase in BDNF release from glia via a Pgrmc1-induced ERK5 signaling mechanism and identify Pgrmc1 as a potential therapeutic target for future hormone-based drug development for the treatment of such degenerative diseases as Alzheimer's disease as well as other diseases wherein neurotrophin dysregulation is noted. FAU - Su, Chang AU - Su C AD - Department of Pharmacology and Neuroscience, Institute for Aging and Alzheimer's Disease Research, University of North Texas Health Science Center at Fort Worth, 3400 Camp Bowie Boulevard, Fort Worth, Texas 76107, USA. FAU - Cunningham, Rebecca L AU - Cunningham RL FAU - Rybalchenko, Nataliya AU - Rybalchenko N FAU - Singh, Meharvan AU - Singh M LA - eng GR - P01 AG022550/AG/NIA NIH HHS/United States GR - P01 AG027956/AG/NIA NIH HHS/United States GR - AG022550/AG/NIA NIH HHS/United States GR - AG027956/AG/NIA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20120709 PL - United States TA - Endocrinology JT - Endocrinology JID - 0375040 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Membrane Proteins) RN - 0 (Pgrmc1 protein, rat) RN - 0 (RNA, Small Interfering) RN - 0 (Receptors, Progesterone) RN - 4G7DS2Q64Y (Progesterone) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 7) SB - IM MH - Animals MH - Astrocytes/drug effects/metabolism MH - Brain-Derived Neurotrophic Factor/*metabolism MH - Cell Line, Tumor MH - Cells, Cultured MH - Enzyme-Linked Immunosorbent Assay MH - Membrane Proteins/*metabolism MH - Mitogen-Activated Protein Kinase 7/*metabolism MH - Neuroglia/*drug effects/*metabolism MH - Progesterone/*pharmacology MH - RNA, Small Interfering MH - Rats MH - Receptors, Progesterone/*metabolism MH - Reverse Transcriptase Polymerase Chain Reaction PMC - PMC3423611 EDAT- 2012/07/11 06:00 MHDA- 2012/10/30 06:00 PMCR- 2013/09/01 CRDT- 2012/07/11 06:00 PHST- 2012/07/11 06:00 [entrez] PHST- 2012/07/11 06:00 [pubmed] PHST- 2012/10/30 06:00 [medline] PHST- 2013/09/01 00:00 [pmc-release] AID - en.2011-2177 [pii] AID - EN-11-2177 [pii] AID - 10.1210/en.2011-2177 [doi] PST - ppublish SO - Endocrinology. 2012 Sep;153(9):4389-400. doi: 10.1210/en.2011-2177. Epub 2012 Jul 9.