Progesterone Increases the Release of Brain-Derived Neurotrophic Factor from Glia via Progesterone Receptor Membrane Component 1 (Pgrmc1)-Dependent ERK5 Signaling

Abstract

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.

Sex Hormones and Alzheimer’s Disease

“…At the same time, progesterone alters dopaminergic and GABAergic system activities in many brain regions mainly the hippocampus, amygdala and fusiform gyrus enhancing the memory and learning performances [52,53].…”

New Insights for Hormone Therapy in Perimenopausal Women Neuroprotection

“…In comparison to the mPRs, the single-transmembrane protein Pgrmc1 (molecular mass 25-28 kDa) and the related Pgrmc2 are a part of a multi-protein complex that binds to P4, other steroids, and to pharmaceutical compounds [123]. Besides the location to membrane surface, Pgrmc1 was reported to have subcellular localization: in endoplasmic reticulum, Golgi apparatus, and nuclei [125].…”

“…The consequences of activation of these signaling pathways are numerous and include influences on neurotrophin release [125], neural progenitor proliferation, regulation of intracellular Ca 2+ levels, and regulation of cell viability [57,127,131] all of which can contribute to the overall health and function of the brain.…”

Progesterone Antagonism of Neurite Outgrowth Depends on Microglial Activation via Pgrmc1/S2R

“…Although Pgrmc1 lacks a nuclear localization signal (preliminary analysis; data not shown), its higher molecular weight forms in the nucleus are candidates for transcriptional regulation (31). Pgrmc1 was also associated with the cell surface membranes of epithelial and cancer cells (32) and cultured astrocytes (33), and with Ca 2ϩ channel activity in hypothalamic GnRH neurons (13).…”

“…In rodent models P4 can be neuroprotective for ischemia (50), traumatic brain injury (49), and spinal cord injury (51). The induction of Pgrmc1 by P4 in astrocytes after brain injury (20) could contribute to neuroprotection, by P4-dependent release of brain-derived neurotrophic factor (33). The increased survival of CA1 neurons after ischemia could involve antiapoptotic actions of P4, such as mediated by Pgrmc1 in ovarian granulosa cells (52).…”