Vol. 54, Issue 1, 154-161, July 1998

Chimeric Melanocortin MC1 and MC3 Receptors: Identification of Domains Participating in Binding of Melanocyte-Stimulating Hormone Peptides

Helgi B. Schiöth, Philip Yook, Ruta Muceniece, Jarl E. S. Wikberg, and Michael Szardenings

Department of Pharmaceutical Pharmacology, Uppsala University, Uppsala, Sweden (H.B.S., P.Y., J.E.S.W., M.S.), and Laboratory of Pharmacology, Institute of Organic Synthesis, Riga, Latvia (R.M.)

The melanocortin receptors MC1 and MC3 are G protein-coupled receptors that have substantial structural similarities and bind melanocyte peptides but with different affinity profiles. We constructed a series of chimeric MC1/MC3 receptors to identify the epitopes that determine their selectivities for natural melanocyte peptides and synthetic analogues. The chimeric constructs were made by a polymerase chain reaction that used identical regions in or just outside transmembranes (TM) 1, 4, and 6 and divided the receptors into four segments. Saturation and competition studies on the expressed chimeric proteins indicate that TM1, TM2, TM3, and TM7 are involved in the subtype-specific binding of melanocyte peptides to these receptors. The results support the hypothesis that TM4 and TM5 may not contribute to the ligand-binding specificity of the MC receptors. This is the first report to describe the subtype-specific hormone-binding domains of the melanocortin receptor family.