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Arginine Residue 155 in the Second Intracellular Loop Plays a Critical Role in Rat Melanin-Concentrating Hormone Receptor 1 Activation

Department of Pharmacology (Y.S., M.T., A.Y., K.M.), Saitama Medical School of Medicine, Iruma-gun, Saitama 350-0492; and Celestar Lexico-Sciences Inc. (S.S., K.I., H.D.), Makuhari, Chiba 261-8501, Japan

Address all correspondence and requests for reprints to: Yumiko Saito, Department of Pharmacology, Saitama Medical School, 38 Moro-Hongo, Moroyama-cho, Iruma-gun, Saitama 350-0492, Japan. E-mail: yumisait{at}saitama-med.ac.jp.

Melanin-concentrating hormone (MCH) receptor 1 (MCH1R) is a class A G protein-coupled receptor. The MCH system has been linked to a variety of physiological functions, including the regulation of feeding and energy metabolism. We recently reported the importance of a dibasic motif in the membrane-proximal C-terminal region for MCH1R function. Here we reveal that an Arg residue in intracellular loop 2 of MCH1R plays a critical role in receptor function. We analyzed the roles of two distinct motifs, BBXXB and BXBB (in which B is a basic residue and X is a nonbasic residue), located in the three intracellular loops of MCH1R. Triple-substitution mutants of intracellular loops 1 and 3 could still activate calcium mobilization, albeit with lower efficacy or potency. However, mutations in intracellular loop 2 led to a complete loss of induction of signal transduction without changing the high affinity constant (Kd) value. By analyzing a series of single-substitution mutants, a point mutation of Arg¹⁵⁵ in intracellular loop 2 was found to be responsible for the signaling pathway elicited by MCH. In addition, substitution at positions corresponding to Arg¹⁵⁵ in human MCH receptor 2 and rat somatostatin receptor 2 also markedly abolished their ligand-induced signaling capacities, indicating that this Arg is a recognition determinant in several G protein-coupled receptors.

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