Estradiol Modulates Translocator Protein (TSPO) and Steroid Acute Regulatory Protein (StAR) via Protein Kinase A (PKA) Signaling in Hypothalamic Astrocytes

Abstract

The ability of the central nervous system to synthesize steroid hormones has wide-ranging implications for physiology and pathology. Among the proposed roles of neurosteroids is the regulation of the LH surge. This involvement in the estrogen-positive feedback demonstrates the integration of peripheral steroids with neurosteroids. Within the female hypothalamus, estradiol from developing follicles stimulates progesterone synthesis in astrocytes, which activate neural circuits regulating gonadotropin (GnRH) neurons. Estradiol acts at membrane estrogen receptor-α to activate cellular signaling that results in the release of inositol trisphosphate-sensitive calcium stores that are sufficient to induce neuroprogesterone synthesis. The purpose of the present studies was to characterize the estradiol-induced signaling leading to activation of steroid acute regulatory protein (StAR) and transporter protein (TSPO), which mediate the rate-limiting step in steroidogenesis, ie, the transport of cholesterol into the mitochondrion. Treatment of primary cultures of adult female rat hypothalamic astrocytes with estradiol induced a cascade of phosphorylation that resulted in the activation of a calcium-dependent adenylyl cyclase, AC1, elevation of cAMP, and activation of both StAR and TSPO. Blocking protein kinase A activation with H-89 abrogated the estradiol-induced neuroprogesterone synthesis. Thus, together with previous results, these experiments completed the characterization of how estradiol action at the membrane leads to the augmentation of neuroprogesterone synthesis through increasing cAMP, activation of protein kinase A, and the phosphorylation of TSPO and StAR in hypothalamic astrocytes.

TSPO: kaleidoscopic 18-kDa amid biochemical pharmacology, control and targeting of mitochondria

“…This has relevance in the activation of steroidogenesis and has been described in estradiolinduced neuroprogesterone synthesis in the hypothalamic astrocytes (63).…”

The estrogenic retina: The potential contribution to healthy aging and age-related neurodegenerative diseases of the retina

“…Recently, oestradiol has showed to increase StAR and TSPO via activation of cAMP-PKA-dependent phosphorylation in hypothalamic astrocytes [70].…”

The changing landscape in translocator protein (TSPO) function

“…This steroidogenic function for TSPO was the most studied among all of its implicated properties. Given this putative link, up-or downregulation of TSPO expression in different tissues has been considered a direct indication of steroid hormone production in numerous studies [9][10][11]. Results that describe TSPO and steroidogenesis have been highlighted in recent literature reviews on this topic [12,13].…”