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

Abstract

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.

Mutagenesis of GPR139 reveals ways to create gain or loss of function receptors

“…We also demonstrated that L‐Trp and L‐Phe activated GPR139‐dependent mitogen activated protein kinase‐ERK phosphorylation . Recently, Nøhr et al reported that GPR139 can be activated by adrenocorticotropic hormone (ACTH), α‐, and β‐melanocyte stimulating hormone (α‐MSH, and β‐MSH) . However, our recent data do not support that GPR139 is activated by ACTH, α‐MSH, and β‐MSH at physiologically relevant concentrations.…”

“…1 Recently, Nøhr et al reported that GPR139 can be activated by adrenocorticotropic hormone (ACTH), α-, and β-melanocyte stimulating hormone (α-MSH, and β-MSH). 9 However, our recent data do not support that GPR139 is activated by ACTH, α-MSH, and β-MSH at physiologically relevant concentrations. But we were able to demonstrate an in vitro interaction between GPR139 and the melanocortin receptors (MCRs, also known as melanocyte stimulating hormone receptors), which may be an artifactual result of recombinant expression.…”

STIM 1 activation of adenylyl cyclase 6 connects Ca 2+ and cAMP signaling during melanogenesis

“…Interestingly, αMSH was recently reported to activate an orphan G‐coupled receptor, GPR139. Upon overexpression in CHO cells, this orphan receptor was demonstrated to behave like a G q receptor (Nøhr et al , ). It is important to note that αMSH was reported to be 100‐fold less potent agonist of GPR139 in comparison with MC4R, a G s receptor (Nøhr et al , ).…”

Alcohol and Pain: A Translational Review of Preclinical and Clinical Findings to Inform Future Treatment Strategies

“…Antagonism of GPR139 with JNJ‐63533054 reduced both escalated drinking and hyperalgesia symptoms in alcohol‐dependent rats. The endogenous ligand for GPR139 is unclear at the present time, but may relate to either tryptophan/serotonin signaling (Liu et al, ), adrenocorticotropic hormone (ACTH), and/or melanocyte‐stimulating hormone (Nohr et al, ).…”