Up-regulation of GTP cyclohydrolase I and tetrahydrobiopterin by calcium influx

GTP cyclohydrolase I (GTPCH) catalyzes the first and rate-limiting reaction in the synthesis of tetrahydrobiopterin (BH4), an obligatory co-factor for monoamines and nitric oxide syntheses. Roles of calcium influx on transcript, protein and activity levels of GTPCH and BH4 availability were studied using primary cultured bovine adrenal medullary cells. Bovine GTPCH cDNA was isolated and used in Northern blot analyses. Ionomycin, A23187 and BayK8644 dramatically up-regulated GTPCH mRNA level. Depolarization by potassium or veratridine also induced GTPCH expression, which was abolished by EGTA. A23187 elevated GTPCH protein level, enzyme activity, and BH4 levels. Thus, calcium influx up-regulates GTPCH gene expression and BH4 levels which may contribute to neurotoxicity directly and/or via elevation of dopamine and nitric oxide. (C) 1999 Lippincott Williams & Wilkins.