Glucocorticoids elevate GTP cyclohydrolase I mRNA levels in vivo and in PC12 cells

Abstract

GTP cyclohydrolase I (GTPCH) is the rate-limiting enzyme in the formation of tetrahydrobiopterin, the cofactor for catecholamine, indolamine and nitric oxide biosynthesis. The effect of glucocorticoids on GTPCH gene expression was examined by direct infusion of cortisol to rats and by incubation of PC12 cells with glucocorticoids. Northern blot analysis revealed that infusion of cortisol for 1 or 7 days elevated levels of the 3.6 kb GTPCH mRNA species in rat adrenal medulla, while the 1.2 kb mRNA species were only increased by 1 day cortisol. Cortisol administration to hypophysectomized animals elicited a 4-5-fold elevation in both forms of GTPCH mRNA. These results indicate that glucocorticoids may be directly involved in the regulation of adrenomedullary GTPCH mRNA levels by physiological stress. Incubation of PC12 cells with plasma from immobilized, but not control, animals increased the level of the 3.6 kb mRNA. Treatment of PC12 cells with dexamethasone for 12-48 h elicited a 4-6-fold elevation in both GTPCH mRNAs. Using the nuclear run-on assay, increased transcription of the GTPCH gene was observed in the rat adrenal medulla with immobilization stress, or in PC12 cells treated with dexamethasone. This is the first report that glucocorticoids can alter GTPCH expression.