The molecular cloning of the thyroid-stimulating hormone (TSH) receptor complementary DNA has allowed the determination of the primary structure of the protein. The TSH receptor possesses the seven-transmembrane domain characteristic of C protein-coupled receptors. As opposed to most of these receptors, it contains a long extracellular domain made of leucine-rich repeats. This ectodomain is involved in hormone binding. Immunocytochemistry showed the TSH receptor to be localized in the basolateral region of thyroid cells. Western blotting and immunoaffinity purification with monoclonal antibodies showed the TSH receptor in human thyroid to be expressed as two subunits (one extracellular α subunit and a membrane-spanning β subunit) held together by disulfide bonds. Mutagenesis experiments gave insights on receptor regions important for hormone binding and for coupling to adenylate cyclase and phospholipase C. The TSH receptor gene maps on chromosome 14q31. It comprises nine exons forming the extracellular domain, and a single large exon codes for the transmembrane and intracellular domains.