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.
Bibliographical noteFunding Information:
This work has been supported by NIH Grants R01DK091906, R01DK108893, and R01DK097838, and a 2017 Wallin Neuroscience Discovery Fund Award through the University of Minnesota (to C.H.-L.). M.D.E. was a recipient of an NIH F32 Postdoctoral Fellowship (F32DK108402).
Copyright © 2019 American Chemical Society.
- Melanocyte-stimulating hormones
- melanocortin receptors
- single nucleotide polymorphisms
PubMed: MeSH publication types
- Journal Article