Effects of endothelin-1 (ET-1) on glial cell line-derived neurotrophic factor (GDNF) production in cultured astrocytes were examined. Treatment of cultured astrocytes with ET-1 (100 nM) increased mRNA levels of GDNF in 1-6 It. The effect of ET-I was inhibited by BQ788, an ETB receptor antagonist, but not by FR139317, an ETA receptor antagonist. ET-1 stimulated release of GDNF into culture medium. Dexamethasone (I muM) and pyrrolidine dithiocarbamate (PDTC, 100 muM), which inhibit activation of NFkappaB, prevented the increases in GDNF mRNA by H2O2. In contrast, the effect of ET-1 was not affected by dexamethasone and PDTC. The increase of astrocytic GDNF mRNA by ET-1 was inhibited by BAPTA/AM (30 muM) and PD98059 (50 muM), but not by calphostin C, staurosporine, and cyclosporine A. These results suggest that ET-1 stimulated expression of astrocytic GDNF through ETB receptor-mediated increases in cytosolic Ca2+ and ERK activation. (C) 2003 Elsevier Science (USA). All rights reserved.