The orphan G protein-coupled receptor GPR139 is activated by the peptides: Adrenocorticotropic hormone (ACTH), α-, and β-melanocyte stimulating hormone (α-MSH, and β-MSH), and the conserved core motif HFRW

Autor: Jacek Mokrosinski, Vignir Isberg, I. Sadaf Farooqi, Mohamed A. Shehata, Alexander S. Hauser, Daniel Sejer Pedersen, David E. Gloriam, Kirsten Andersen, Anne Cathrine Nøhr, Hans Bräuner-Osborne
Přispěvatelé: Mokrosinski, Jacek [0000-0001-5008-0457], Farooqi, Ismaa [0000-0001-7609-3504], Apollo - University of Cambridge Repository
Rok vydání: 2017
Předmět:
0301 basic medicine
Faculty of Health and Medical Sciences
medicine.medical_specialty
endocrine system
Pro-Opiomelanocortin
Melanocyte-stimulating hormone
Peptide receptor
Amino Acid Motifs
Nerve Tissue Proteins
CHO Cells
Adrenocorticotropic hormone
Article
Receptors
G-Protein-Coupled
Pro-opiomelanocortin (POMC)
03 medical and health sciences
Cellular and Molecular Neuroscience
Cricetulus
Adrenocorticotropic Hormone
selected
Internal medicine
beta-MSH
medicine
Animals
Orphan GPCR
Melanocyte-Stimulating Hormones
Independent research
business.industry
European research
Cell Biology
3. Good health
Adrenocorticotropic hormone (ACTH)
030104 developmental biology
Endocrinology
alpha-MSH
Research centre
Melanocytes
Receptor
Melanocortin
Type 4
Melanocyte stimulating hormone (MSH)
GPR139
business
Orphan G-Protein Coupled Receptor
hormones
hormone substitutes
and hormone antagonists
Zdroj: Jensen, A C N, Shehata, M A, Hauser, A S, Isberg, V, Mokrosinski, J, Farooqi, I S, Pedersen, D S, Gloriam, D E & Bräuner-Osborne, H 2017, ' The orphan G protein-coupled receptor GPR139 is activated by the peptides : Adrenocorticotropic hormone (ACTH), α-, and β-melanocyte stimulating hormone (α-MSH, and β-MSH), and the conserved core motif HFRW ', Neurochemistry International, vol. 102, pp. 105-113 . https://doi.org/10.1016/j.neuint.2016.11.012
Neurochemistry International
ISSN: 0197-0186
DOI: 10.1016/j.neuint.2016.11.012
Popis: GPR139 is an orphan G protein-coupled receptor that is expressed primarily in the brain. Not much is known regarding the function of GPR139. Recently we have shown that GPR139 is activated by the amino acids l-tryptophan and l-phenylalanine (EC50 values of 220 μM and 320 μM, respectively), as well as di-peptides comprised of aromatic amino acids. This led us to hypothesize that GPR139 may be activated by peptides. Sequence alignment of the binding cavities of all class A GPCRs, revealed that the binding pocket of the melanocortin 4 receptor is similar to that of GPR139. Based on the chemogenomics principle “similar targets bind similar ligands”, we tested three known endogenous melanocortin 4 receptor agonists; adrenocorticotropic hormone (ACTH) and α- and β-melanocyte stimulating hormone (α-MSH and β-MSH) on CHO-k1 cells stably expressing the human GPR139 in a Fluo-4 Ca2+-assay. All three peptides, as well as their conserved core motif HFRW, were found to activate GPR139 in the low micromolar range. Moreover, we found that peptides consisting of nine or ten N-terminal residues of α-MSH activate GPR139 in the submicromolar range. α-MSH1-9 was found to correspond to the product of a predicted cleavage site in the pre-pro-protein pro-opiomelanocortin (POMC). Our results demonstrate that GPR139 is a peptide receptor, activated by ACTH, α-MSH, β-MSH, the conserved core motif HFRW as well as a potential endogenous peptide α-MSH1-9. Further studies are needed to determine the functional relevance of GPR139 mediated signaling by these peptides.
Highlights • Using GPCRdb we found that the binding cavity of GPR139 is 49% similar to MC4R. • ACTH, α-MSH and β-MSH activate GPR139 in the low μM-range. • We predicted a novel possible cleavage site in POMC leading to the peptide α-MSH1-9. • α-MSH1-9 activates GPR139 in the high nM range.
Databáze: OpenAIRE
Externí odkaz: