ArticleProceedings of the National Academy of Sciences of the United States of America2013
Exposure of MC4R to agonist in the endoplasmic reticulum stabilizes an active conformation of the receptor that does not desensitize.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
What it found
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
13 citing papers in PubMed, 21 citations in OpenAlex.
- Hypothalamic opsin 3 suppresses MC4R signaling and potentiates Kir7.1 to promote food consumption.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Article
- Tyrosine phosphorylation of S1PR1 leads to chaperone BiP-mediated import to the endoplasmic reticulum.The Journal of cell biology · 2021Article
- Genetic Deletion of KLHL1 Leads to Hyperexcitability in Hypothalamic POMC Neurons and Lack of Electrical Responses to Leptin.Frontiers in neuroscience · 2021Article
- Mutations in MC4R facilitate the angiogenic activity in patients with orbital venous malformation.Experimental biology and medicine (Maywood, N.J.) · 2020Article
- Current Mechanistic and Pharmacodynamic Understanding of Melanocortin-4 Receptor Activation.Molecules (Basel, Switzerland) · 2019Review
- The melanocortin pathway and control of appetite-progress and therapeutic implications.The Journal of endocrinology · 2019Review
- Lipid stress inhibits endocytosis of melanocortin-4 receptor from modified clathrin-enriched sites and impairs receptor desensitization.The Journal of biological chemistry · 2017Article
- Temporal cAMP Signaling Selectivity by Natural and Synthetic MC4R Agonists.Molecular endocrinology (Baltimore, Md.) · 2015Article
- Intracellular signaling mechanisms of the melanocortin receptors: current state of the art.Cellular and molecular life sciences : CMLS · 2015Review
- Chaperoning G protein-coupled receptors: from cell biology to therapeutics.Endocrine reviews · 2014Review
- Mild lipid stress induces profound loss of MC4R protein abundance and function.Molecular endocrinology (Baltimore, Md.) · 2014Article
- A small molecule agonist THIQ as a novel pharmacoperone for intracellularly retained melanocortin-4 receptor mutants.International journal of biological sciences · 2014Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Melanocortin-4 receptor (MC4R) is a G protein-coupled receptor expressed in neurons of the hypothalamus where it regulates food intake. MC4R responds to an agonist, α-melanocyte-stimulating hormone (α-MSH) and to an antagonist/inverse agonist, agouti-related peptide (AgRP), which are released by upstream neurons. Binding to α-MSH leads to stimulation of receptor activity and suppression of food intake, whereas AgRP has opposite effects. MC4R cycles constantly between the plasma membrane and endosomes and undergoes agonist-mediated desensitization by being routed to lysosomes. MC4R desensitization and increased AgRP expression are thought to decrease the effectiveness of MC4R agonists as an antiobesity treatment. In this study, α-MSH, instead of being delivered extracellularly, is targeted to the endoplasmic reticulum (ER) of neuronal cells and cultured hypothalamic neurons. We find that the ER-targeted agonist associates with MC4R at this location, is transported to the cell surface, induces constant cAMP and AMP kinase signaling at maximal amplitude, abolishes desensitization of the receptor, and promotes both cell-surface expression and constant signaling by an obesity-linked MC4R variant, I316S, that otherwise is retained in the ER. Formation of the MC4R/agonist complex in the ER stabilizes the receptor in an active conformation that at the cell surface is insensitive to antagonism by AgRP and at the endosomes is refractory to routing to the lysosomes. The data indicate that targeting agonists to the ER can stabilize an active conformation of a G protein-coupled receptor that does not become desensitized, suggesting a target for therapy.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.