We have described the binding of [125I]endothelin-1 (ET-1) to cultured rat cerebellar granule cells. Binding of [125I]ET-1 was specific, saturable, and time-dependent. Scatchard analysis of saturation binding data indicated a single class of high affinity binding site with a KD of 95 pM, and a Bmax of 8110 receptors/cell. Functionally, the binding of ET-1 stimulated phosphatidylinositide (PI) hydrolysis in a dose- and time-dependent fashion. PI turnover was found to be inhibitable by 1 microM phorbol dibutyrate but not by 1 microgram/ml pertussis toxin, suggesting that the ET-1-mediated response is regulated by protein kinase C and a pertussis toxin-insensitive guanine nucleotide (GTP) binding protein.