A functional cDNA clone for the rat neurotensin receptor was isolated by combining molecular cloning in an RNA expression vector with an electrophysiological assay in Xenopus oocytes. The neurotensin receptor consists of 424 amino acids with seven putative transmembrane domains and belongs to the family of G protein-coupled receptors. The cloned receptor expressed in mammalian cells or in Xenopus oocytes shows a selective and high-affinity binding to neurotensin peptides and undergoes potent desensitization by repeated application of neurotensin. The neurotensin receptor mRNA is expressed in both the brain and the peripheral tissues at different levels. This investigation discloses the molecular nature of the neurotensin receptor, which mediates the diverse neuronal and peripheral actions of neurotensin by effecting the G protein-associated second messenger system.