We isolated a human endothelin-1 (ET-1) receptor cDNA from a human placenta cDNA library. The cDNA encodes a 427-amino acid protein with seven putative transmembrane domains. The rank order of the binding to the receptor expressed in COS-7 cells was: ET-1 greater than or equal to ET-2 much greater than ET-3. The receptor expressed in Xenopus oocytes showed a potent electrophysiological response to 1 x 10(-7) M ET-1 under voltage clamp at -60 mV, while a much weaker response was produced by 1 x 10(-7) M ET-3. Northern blot analysis with RNA from human tissues revealed a single band with a size of 4.3 kb in a wide variety of human tissues, especially highly in the blood vessel.