title: 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.
authors.affiliation: Departments of Obstetrics/Gynecology (C.C., J.K.) and Neurobiology (A.W., P.M.), David Geffen School of Medicine at UCLA, and Laboratory of Neuroendocrinology of the Brain Research Institute (A.W., P.M.), University of California, Los Angeles, Los Angeles, California 90095.
authors.forename: Claire
authors.initials: C
authors.lastname: Chen
authors.forename: John
authors.initials: J
authors.lastname: Kuo
authors.forename: Angela
authors.initials: A
authors.lastname: Wong
authors.forename: Paul
authors.initials: P
authors.lastname: Micevych
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism*; D005260:Female; D007031:Hypothalamus / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D011374:Progesterone / Q000096:biosynthesis*; D051381:Rats; D020318:Rats, Long-Evans; D011963:Receptors, GABA-A / Q000378:metabolism*; D015398:Signal Transduction; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D002352:Carrier Proteins; D010750:Phosphoproteins; D011963:Receptors, GABA-A; D000098682:Steroidogenic Acute Regulatory Protein; C069997:Tspo protein, rat; D011374:Progesterone; D004958:Estradiol; D017868:Cyclic AMP-Dependent Protein Kinases