Possible involvement of tetrahydrobiopterin in the trophic effect of insulin-like growth factor-1 on rat pheochromocytoma-12 (PC12) cells

Abstract

Tetrahydrobiopterin (BH 4) has a trophic effect on pheochromocytoma-12 (PC12) cells such as insulin-like growth factor-1 (IGF-1). We investigated involvement of BH 4 in the trophic effect of IGF-1 on PC12 cells. IGF-1 (10–300 ng/ml) increased cellular BH 4 content in a dose-related manner. Cellular BH 4 content increased after 6–36 h incubation with IGF-1. IGF-1-induced increase in the cellular BH 4 content was blunted by 0.3 mM 2,4-diamino-6-hydroxypyrimidine (DAHP), an inhibitor for BH 4 synthesis. IGF-1 protected PC12 cells from the cell death induced by depletion of serum and nerve growth factor, which was attenuated by DAHP. The effects of IGF-1 on the cellular BH 4 content and cell viability were eliminated by 0.2 μM wortmannin. These results suggest that BH 4 is involved in the trophic effect of IGF-1 on PC12 cells and that the effect of IGF-1 on BH 4 synthesis is mediated by phosphatidylinositol 3-kinase.