Progesterone receptors: form and function in brain

Abstract

Emerging data indicate that progesterone has multiple non-reproductive functions in the central nervous system to regulate cognition, mood, inflammation, mitochondrial function, neurogenesis and regeneration, myelination and recovery from traumatic brain injury. Progesterone-regulated neural responses are mediated by an array of progesterone receptors (PR) that include the classic nuclear PRA and PRB receptors and splice variants of each, the seven transmembrane domain 7TMPRbeta and the membrane-associated 25-Dx PR (PGRMC1). These PRs induce classic regulation of gene expression while also transducing signaling cascades that originate at the cell membrane and ultimately activate transcription factors. Remarkably, PRs are broadly expressed throughout the brain and can be detected in every neural cell type. The distribution of PRs beyond hypothalamic borders, suggests a much broader role of progesterone in regulating neural function. Despite the large body of evidence regarding progesterone regulation of reproductive behaviors and estrogen-inducible responses as well as effects of progesterone metabolite neurosteroids, much remains to be discovered regarding the functional outcomes resulting from activation of the complex array of PRs in brain by gonadally and/or glial derived progesterone. Moreover, the impact of clinically used progestogens and developing selective PR modulators for targeted outcomes in brain is a critical avenue of investigation as the non-reproductive functions of PRs have far-reaching implications for hormone therapy to maintain neurological health and function throughout menopausal aging.

Fig. 1

Gene structure and functional domains of rat cPRA and cPRB. In rat, the classical progesterone receptor is composed of 8 exons with a 3100-bp coding region and 5′- and 3′-untranslated region. Both cPRB and cPRA are transcribed from this gene, but use alternative initiation codons (red horizontal arrows) driven by different promoters. The cPRs have a highly conserved DNA binding domain (DBD), an activation function1 (AF1) domain immediately upstream of the DBD, a hinge region downstream of the DBD, as well as a ligand binding domain (LBD) and a C-terminal AF2 domain. An inhibition factor (IF) is present upstream of AF1. The N-terminus of cPRB contains an AF3 domain, which acts in synergy with AF1 and AF2.

Fig. 2

Splice variants of cPR. A) Variants can be generated through insertion of T or S between exon 3 and 4 as well as through insertion of a or b between exon 4 and 5. B) Alternatively, variants can be generated through exon skipping. In PR-c, exon 1 is omitted. In PR-S and PR-T, exons 1-3 are omitted, but the 5′-untranslated exons S and T are retained.

Fig. 3

Distribution of the 25 Dx PR transmembrane domain in the rat brain. The classical progesterone receptors PRA and PRB have been localized to regions throughout the brain using the indicated methods.

Fig. 4

Model of progesterone-induced neuroprotective signaling. Progestogen prevents synaptic dysfunction associated with aging and neurodegeneration through (1) ligand activation of a progesterone receptor, (2) which initiates second messenger signaling cascades (3) to promote neuronal survival. These signaling cascades converge on mitochondrial function to protect against against toxic insults and include the passive prevention signaling pathway and the active protection signaling pathway. In the passive prevention signaling pathway, both ERK/CREB/Bcl-2 and Akt pathways are simultaneously activated, which (4) enhances mitochondrial function and enables neurons to better withstand neurodegenerative insults. The active protection pathway acts to block Aβ-induced JNK activation and mitochondrial dysfunction.