Open AccessSingle Nucleotide Polymorphisms in the Melanocortin His-Phe-Arg-Trp Sequences Decrease Tetrapeptide Potency and Efficacy
Author(s) -
Marshall D. Winget,
Mark D. Ericson,
Katie T. Freeman,
Carrie HaskellLuevano
Publication year - 2019
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00198
Subject(s) - melanocortin , proopiomelanocortin , tetrapeptide , melanocortin 3 receptor , receptor , melanocortin receptor , agonist , melanocortin 4 receptor , single nucleotide polymorphism , endocrinology , medicine , biology , acth receptor , g protein coupled receptor , potency , chemistry , gene , adrenocorticotropic hormone , genetics , biochemistry , in vitro , hormone , peptide , genotype
The melanocortin receptors are stimulated by agonists (α-MSH, β-MSH, γ-MSH, and ACTH) processed from the proopiomelanocortin (POMC) gene transcript and possess a common His-Phe-Arg-Trp tetrapeptide sequence critical for receptor activation. Deficiency in POMC signaling in humans is associated with adrenal insufficiency, altered pigmentation, and rapid, early onset weight gain. Herein, 12 single nucleotide polymorphisms (SNPs) deposited into the Variation Viewer database within the His-Phe-Arg-Trp sequences of ACTH/α-MSH, β-MSH, and γ-MSH were substituted into tetrapeptide scaffolds to examine the in vitro signaling effects of these polymorphisms at the cloned melanocortin receptors. Every polymorphism decreased agonist potency and/or efficacy at the melanocortin receptors assayed, indicating that polymorphisms within the signaling sequence of POMC-derived agonists negatively impacts receptor activation. Future work to incorporate these substitutions into the full-length POMC agonists would confirm these findings, identifying new patient populations that might benefit from therapeutic regiments to treat POMC-deficient signaling.