Molecular characterization of the melanin-concentrating-hormone receptor

Orphan G-protein-coupled receptors (GPCRs) are cloned proteins with structu ral characteristics common to the GPCRs but that bind unidentified ligands. Orphan GPCRs have been used as targets to identify novel transmitter molec ules(1). Here we describe the isolation from brain extracts and the charact erization of the natural ligand of a particular orphan GPCR (SLC-1) that is sequentially homologous to the somatostatin receptors(2,3). We show that t he natural ligand of this receptor is the neuropeptide melanin-concentratin g hormone (MCH)(4), MCH is a cyclic peptide that regulates a variety of fun ctions in the mammalian brain, in particular feeding behaviour(5,6). We dem onstrate that nanomolar concentrations of MCH strongly activate SLC-1-relat ed pathways through G alpha(i) and/or G alpha(q) proteins. We have analysed the tissue localization of the MCH receptor and find that it is expressed in several brain regions, in particular those involved in olfactory learnin g and reinforcement mechanisms, indicating that therapies targeting the MCH receptor should act on the neuronal regulation of food consumption.