Amino acid residue L112 in the ACTH receptor plays a key role in ACTH or α-MSH selectivity. (15th February 2019)

• Record Type: Journal Article
• Authors: Yang, Yingkui; Chen, Min; Ventro, George; Harmon, Carroll M.
• Is Part Of: Molecular and cellular endocrinology. Volume 482(2019)
• Page Start: 11
• Page End: 17
• Publication Date: 2019-02-15
• Subjects: POMC -- MC2R -- GPCR -- ACTH -- α-MSH; hMC2R human Melanocortin 2 receptor -- hMC3R human melanocortin-3 receptor -- GPCR G-protein coupled receptor -- α−MSH α-melanocyte stimulating hormone -- TM transmembrane domains -- IBMX 3-Isobutyl-methylxanthine -- PCR Polymerase chain reaction -- FACs Flow cytometry; Endocrinology -- Periodicals; Molecular biology -- Periodicals; Cytology -- Periodicals; Endocrinology -- Periodicals; Hormones -- Periodicals; Endocrinologie -- Périodiques; Cytology; Endocrinology; Molecular biology; Periodicals; 573.4
• DOI: 10.1016/j.mce.2018.12.002
• Languages: English
• ISSNs: 0303-7207

Abstract

Abstract: The adrenocorticotropic hormone (ACTH) receptor, known as the melanocortin-2 receptor (MC2R), plays a key role in regulating adrenocortical function. MC2R is a subtype of the melanocortin receptor family and ACTH is only agonist for MC2R. Our previous result indicates that ACTH1-17 is the minimal peptide required for MC2R activation but DPhe7-ACTH1-17 has no activity at MC2R. In this study, we examined the molecular basis of the MC2R responsible for ligand selectivity using ACTH analogues and MC2R mutagenesis. Our results indicate that substitution of the 3TM of the MC2R with the corresponding region of the MC3R switches DPhe-ACTH1-17 from no activity to agonist. Further experiment indicates that substitution of the amino acid residue leucine to isoleucine in 112 (L112I) of the 3TM of the MC2R changes both DPhe-ACTH1-17 and ACTH1-15 from no activity to agonists. Surprisingly, mutation L112I switches α-MSH from no activity to agonist, suggesting that this residue plays a key role at MC2R for ligand ACTH or α-MSH selectivity. Highlights: MC2R regulates adrenocortical function. Our result indicates that mutation of the amino acid residue leucine to isoleucine in 112 (L112I) of the MC2R switches α-MSH from no activity to agonist. This study provides important information of the MC2R for ligand ACTH or α-MSH selectivity.