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The recent cloning of three melanocortin receptors suggests an unexpected diversity in this family of seven transmembrane G-protein linked receptors. Herein, we report the cloning, expression, and gene localization of a fourth human melanocortin receptor, the melanocortin-4 receptor. By Northern blot analysis and in situ hybridization, this receptor is expressed primarily in the brain, but its expression is notably absent in the adrenal cortex, melanocytes, and placenta. Agonist stimulation of COS-1 cells transiently transfected and L-cells permanently transfected with the coding region of the cloned melanocortin-4 receptor leads to increases in intracellular cyclic 3‘,5‘-adenosine monophosphate. The profile of the responses of the melanocortin-4 receptor to different melanocortins distinguishes it from melanocortin receptors previously described. Using the technique of fluorescent in situ hybridization, the gene …