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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Tao, Ya-xiong Mo, Xiu-lei |
| Description | Author Affiliation: Mo XL ( Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.) |
| Abstract | The melanocortin-4 receptor (MC4R) is a G protein-coupled receptor that plays an essential role in regulating energy homeostasis. Defects in MC4R are the most common monogenic form of obesity, with about 170 distinct mutations identified in human. In addition to the conventional G $_{s}$ -stimulated adenylyl cyclase pathway, it has been recently demonstrated that MC4R also activates mitogen-activated protein kinases, extracellular signal-regulated kinases 1 and 2 (ERK1/2). Herein, we investigated the potential of four MC4R ligands that are inverse agonists at the G $_{s}$ -cAMP signaling pathway, including agouti-related peptide (AgRP), MCL0020, Ipsen 5i and ML00253764, to regulate ERK1/2 activation (pERK1/2) in wild type and six naturally occurring constitutively active mutant (CAM) MC4Rs. We showed that these four inverse agonists acted as agonists for the ERK1/2 signaling cascade in wild type and CAM MC4Rs. Three mutants (P230L, L250Q and F280L) had significantly increased pERK1/2 level upon stimulation with all four inverse agonists, with maximal induction ranging from 1.6 to 4.2-fold. D146N had significantly increased pERK1/2 level upon stimulation with AgRP, MCL0020 or ML00253764, but not Ipsen 5i. The pERK1/2 levels of H76R and S127L were significantly increased only upon stimulation with AgRP or MCL0020. In summary, our studies demonstrated for the first time that MC4R inverse agonists at the G $_{s}$ -cAMP pathway could serve as agonists in the MAPK pathway. These results suggested that there were multiple activation states of MC4R with ligand-specific and/or mutant-specific conformations capable of differentially coupling the MC4R to distinct signaling pathways. |
| ISSN | 00063002 |
| Journal | Biochimica et Biophysica Acta (BBA) - Reviews on Cancer |
| Issue Number | 12 |
| Volume Number | 1832 |
| Language | English |
| Publisher | Elsevier |
| Publisher Date | 2013-12-01 |
| Publisher Place | Netherlands |
| Access Restriction | Open |
| Subject Keyword | Agouti-Related Protein Pharmacology Imidazoles Mitogen-Activated Protein Kinases Metabolism Mutation Genetics Oligopeptides Receptor, Melanocortin, Type 4 Amino Acid Sequence Anticarcinogenic Agents Cyclic AMP Extracellular Signal-Regulated MAP Kinases HEK293 Cells Molecular Sequence Data Phosphorylation Antagonists & Inhibitors Alpha-MSH Analogs & Derivatives Comparative Study Research Support, Non-U.S. Gov't Biochemistry |
| Content Type | Text |
| Resource Type | Article |
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