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Pregnenolone Biosynthesis in C6-2B Glioma Cell Mitochondria

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Pregnenolone Biosynthesis in C6-2B Glioma Cell Mitochondria Proc. Nail. Acad. Sci. USA Vol. 89, pp. 5113-5117, June 1992 Neurobiology Pregnenolone biosynthesis in C6-2B glioma cell mitochondria: Regulation by a mitochondrial diazepam binding inhibitor receptor (glial cells/steroidogenesis/benzodiazepines/diazepam binding inhibitor) VASSILIOS PAPADOPOULOS*, PATRIZIA GUARNERIt, KARL E. KRUEGERt, ALESSANDRO GUIDOTTIt, AND ERMINIO COSTAt *Department of Anatomy and Cell Biology and tFidia-Georgetown Institute for the Neurosciences, Georgetown University School of Medicine, 3900 Reservoir Road NW, Washington, DC 20007 Contributed by Erminio Costa, March 6, 1992 ABSTRACT The C6-2B glioma cell line, rich in mitochon- been proposed that glial cells can synthesize steroids de novo drial receptors that bind with high affinity to benzodiazepines, (6, 7). In fact, glial cells can convert cholesterol to preg- imidazopyridines, and isoquinolinecarboxamides (previously nenolone, which then may be further metabolized to preg- called peripheral-type benzodiazepine receptors), was investi- nenolone sulfate, 3f3-hydroxy-5-pregnene-20-one, 3/3- gated as a model to study the significance of the polypeptide hydroxy-5-androstene-17-one, 3a-hydroxy-5a-pregnane-20- diazepam binding inhibitor (DBI) and the putative DBI pro- one, and 5a-pregnane-3a,21-diol-20-one, which positively or cessing products on mitochondrial receptor-regulated ste- negatively modulate the GABA-gating of Cl- channels (4, 8). roidogenesis. DBI and its naturally occurring fragments have Although detailed characterization of this biosynthetic appa- been found to be present in high concentrations in C6-2B ratus in glial cells is far from complete, the cytochrome P450 glioma cells, to compete against specific isoquinolinecarboxa- side-chain-cleavage enzyme (P450scc), which participates in mide or 4'-chlorodiazepam binding to mitochondrial recogni- steroid biosynthesis by converting cholesterol to preg- tion sites with high affinity, and to stimulate mitochondrial nenolone, has been identified immunocytochemically in pri- pregnenolone formation. These data suggest that this cell type mary glial cultures and in specific rat brain regions (7, 9). may express both the receptor and the putative agonist ligand Two important findings prompted the present investiga- to regulate steroidogenesis. Therefore, we propose to term this tion: (i) the observations that in adrenal and testis receptors mitochondrial receptor MDR (mitochondrial DBI receptor) to located on the outer membrane of mitochondria and which indicate its responsiveness to DBI in steroid biosynthesis. In the recognize benzodiazepines, isoquinolinecarboxamides, and present work, we show that mitochondria of C6-2B cells imidazopyridines with high affinity-previously defined as convert (22R)-22-hydroxycholesterol to pregnenolone by a peripheral-type benzodiazepine receptors-regulate intram- mechanism blocked by aminoglutethimide. Immunoblotting itochondrial cholesterol transport, the rate-limiting step in high of steroidogenesis (10-12), and (ii) the demonstration that di- confirmed the presence of relatively levels cytochrome azepam binding inhibitor (DBI), a polypeptide abundant in P-450 cholesterol side-chain-cleavage enzyme in C6-2B cell steroidogenic cells (1, 13, 14), can stimulate pregnenolone mitochondria. Furthermore, isoquinolinecarboxamide binding formation in adrenocortical and testicular Leydig cell mito- sites associated with the 18-kDa mitochondrial polypeptide chondria by an interaction with these mitochondrial recep- subunit of the MDR are abundant in C6-2B glioma cell tors (15, 16). The present experiments show that rat glioma mitochondria (B 30 pmol/mg protein) and are coupled to C6-2B cells and mitochondria prepared from these cells the regulation of steroid biosynthesis. Occupancy of MDRs contain the P-45Scc enzyme and thereby convert cholesterol with nanomolar concentrations of the naturally occurring to pregnenolone. This enzymatic reaction can be activated by polypeptide, DBI, as well as its naturally occurring processing nanomolar amounts of DBI and the DBI fragment tetratria- product tetratriacontaneuropeptide [DBI-(17-50)] increases contaneuropeptide [TTN, DBI-(17-50)]. Since DBI, which is pregnenolone formation. Clonazepam and octadecaneuropep- synthesized and processed in glial cells (17), competes tide [DBI-(33-50)], which exhibit a higher affinity for r-ami- against the binding of the mitochondrial receptor ligands nobutyric acid type A receptors but a low affinity for MDR, 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquin- were ineffective in stimulating pregnenolone synthesis. These olinecarboxamide (PK 11195) and 4'-chlorodiazepam (4'CD) findings provide evidence that C6-2B cells exhibit a significant with an affinity comparable to its potency in the steroidogenic steroidogenic activity which resembles that found in peripheral effect, it appears to be the natural agonist for the receptor that endocrine organs and they suggest that MDRs and DBI are controls steroidogenesis in glial cells. Therefore, we suggest involved in the regulation of glial cell steroidogenesis. that this glial mitochondrial receptor be termed MDR (mito- chondrial DBI receptor). The specific interactions of steroids with putative membrane binding sites associated with the type A receptor for 'y-ami- METHODS nobutyric acid (GABAA receptor) (1-4) has prompted a reexamination of the rapid effects of various steroids on Cell Culture. The C6-2B subclone of the rat glioma C6 cell neuronal function as well as the investigation of the mecha- line was obtained from Gary Brooker at this institute (18). nisms that control the synthesis and release of steroids from These cells were adapted for growth in serum-free Aim V cells in the central nervous system. It appears that steroids of peripheral origin can be taken up from the circulation (5) by Abbreviations: GABA, y-aminobutyric acid; DBI, diazepam binding brain cells, where they bind to specific receptors to form inhibitor; MDR, mitochondrial DBI receptor(s); P450,,c, cholesterol transcription activating factors. In addition, it has recently side-chain-cleavage cytochrome P450 (EC 1.14.15.6); 4'CD, 4'- chlorodiazepam (Ro 5-4864); PK 11195, 1-(2-chlorophenyl)-N- methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide; PK 14105, The publication costs of this article were defrayed in part by page charge 1-(2-fluoro-5-nitrophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquin- payment. This article must therefore be hereby marked "advertisement" olinecarboxamide; TTN, tetratriacontaneuropeptide; ODN, octade- in accordance with 18 U.S.C. §1734 solely to indicate this fact. caneuropeptide. 5113 Downloaded by guest on September 30, 2021 5114 Neurobiology: Papadopoulos et al. Proc. Natl. Acad. Sci. USA 89 (1992) medium (GIBCO). Culture dishes (150 mm diameter) were gel, and subjected to electrophoresis. Proteins were then pretreated with 10 ml ofDulbecco's modified Eagle's medium transferred to nitrocellulose membranes (0.45 pm; Hoefer) (DMEM) supplemented with 10% fetal bovine serum and blotted with a rabbit anti-bovine adrenal P-450SCc anti- (GIBCO) for 4 hr and washed with phosphate-buffered saline. body, obtained from Oxygene (Dallas) or normal rabbit Cells were then plated and grown in Aim V medium. This immunoglobulin. The antigens were detected with goat anti- procedure did not significantly alter the growth rate of the rabbit IgG coupled to horseradish peroxidase (Bio-Rad) using C6-2B cells compared with their growth in serum-containing 3-amino-9-ethylcarbazole and hydrogen peroxide as sub- media. strate (19). Measurement of Mitochondrial Steroid Biosynthesis. Mito- DBI Extraction, Purification, and Assay. DBI was extracted chondria from C6-2B cells were prepared as previously and purified from rat brain as previously described (20). The described (12) and resuspended at a concentration of 2.0 mg purity of the preparations used (>95%) was established by of protein per ml in buffer A (10 mM potassium phosphate SDS/PAGE, amino acid composition, and chromatographic buffer, pH 7.0/0.25 M sucrose/5 mM MgCl2/20 mM KCI/15 characteristics on reverse-phase HPLC (14, 20). DBI-like mM triethanolamine HCI) containing 5 ,uM trilostane (WIN- immunoreactivity of cell extracts was determined by radio- 24540; Sterling-Winthrop Group), an inhibitor of preg- immunoassay (14, 20). Peptides were synthesized and char- nenolone metabolism (11). Various concentrations of MDR acterized as previously described (21). Protein was quantified ligands to be tested were then added in buffer A. The mixture by using the procedure of Bradford (22) with gammaglobulin was preincubated for 5 min at 370C, and the reaction was as a standard. started by addition of 15 mM malate (neutralized with 1 M NaOH) and 0.5 mM NADP. The incubation was continued RESULTS for 15 min at 37TC and the reaction was stopped by the Cholesterol Side-Chain Cleavage in C6-2B Mitchodria. addition of 4 vol of cold ethanol. [3H]Pregnenolone [1500 The first step in steroid biosynthesis is the conversion of cpm, 22.6 Ci/mmol (1 Ci = 37 GBq); NEN/DuPont] was cholesterol to pregnenolone, which is catalyzed by P-450.C in added to each sample to monitor the recovery of the extrac- inner mitochondrial membranes. This side-chain-cleavage tion. The samples were then extracted three times with 5 vol reaction occurs via multiple hydroxylation steps of the cho- of n-hexane and the ethanolic phase was evaporated to lesterol side chain. The rate of the side-chain-cleavage reac- dryness. Pregnenolone was measured by a specific
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