ArticleThe Journal of biological chemistry2012
Constitutive cholesterol-dependent endocytosis of melanocortin-4 receptor (MC4R) is essential to maintain receptor responsiveness to α-melanocyte-stimulating hormone (α-MSH).
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 35 citations in OpenAlex.
- Identification of serum metabolic traits of AIWG in first-episode schizophrenia patients.BMC psychiatry · 2024Trial
- The role of accessory proteins and co-factors in regulation of melanocortin-4 receptor signalling: An update.Journal of neuroendocrinology · 2026Review
- Development of a genetically encoded melanocortin sensor for high sensitivity in vivo imaging.Molecular metabolism · 2025Article
- Arrestin-independent internalization of the GLP-1 receptor is facilitated by a GRK, clathrin, and caveolae-dependent mechanism.The FEBS journal · 2025Article
- Article
- A unique melanocortin-4-receptor signaling profile for obesity-associated constitutively active variants.Journal of molecular endocrinology · 2023Article
- Smith-Lemli-Opitz syndrome: A pathophysiological manifestation of the Bloch hypothesis.Frontiers in molecular biosciences · 2023Review
- Cholesterol-dependent endocytosis of GPCRs: implications in pathophysiology and therapeutics.Biophysical reviews · 2021Review
- Article
- Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation.Cell reports · 2021Article
- Genetic Deletion of KLHL1 Leads to Hyperexcitability in Hypothalamic POMC Neurons and Lack of Electrical Responses to Leptin.Frontiers in neuroscience · 2021Article
- The melanocortin pathway and control of appetite-progress and therapeutic implications.The Journal of endocrinology · 2019Review
- Immunoglobulin G modulation of the melanocortin 4 receptor signaling in obesity and eating disorders.Translational psychiatry · 2019Article
- Lipid stress inhibits endocytosis of melanocortin-4 receptor from modified clathrin-enriched sites and impairs receptor desensitization.The Journal of biological chemistry · 2017Article
- Long Term Osmotic Mini Pump Treatment with Alpha-MSH Improves Myocardial Function in Zucker Diabetic Fatty Rats.Molecules (Basel, Switzerland) · 2017Article
- Integrated microRNA‑gene analysis of coronary artery disease based on miRNA and gene expression profiles.Molecular medicine reports · 2016Article
- Temporal cAMP Signaling Selectivity by Natural and Synthetic MC4R Agonists.Molecular endocrinology (Baltimore, Md.) · 2015Article
- The change in cerebral glucose metabolism after electroacupuncture: a possible marker to predict the therapeutic effect of deep brain stimulation for refractory anorexia nervosa.International journal of clinical and experimental medicine · 2015Article
- Mild lipid stress induces profound loss of MC4R protein abundance and function.Molecular endocrinology (Baltimore, Md.) · 2014Article
- Molecular pathways: sterols and receptor signaling in cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2014Review
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
Melanocortin-4 receptor (MC4R) is a G-protein-coupled receptor expressed in the hypothalamus where it controls feeding behavior. MC4R cycles constitutively and is internalized at the same rate in the presence or absence of stimulation by the agonist, melanocyte-stimulating hormone (α-MSH). This is different from other G-protein-coupled receptors, such as β(2)-adrenergic receptor (β(2)AR), which internalizes more rapidly in response to agonist stimulation. Here, it is found that in immortalized neuronal Neuro2A cells expressing exogenous receptors, constitutive endocytosis of MC4R and agonist-dependent internalization of β(2)AR were equally sensitive to clathrin depletion. Inhibition of MC4R endocytosis by clathrin depletion decreased the number of receptors at the cell surface that were responsive to the agonist, α-MSH, by 75%. Mild membrane cholesterol depletion also inhibited constitutive endocytosis of MC4R by ∼5-fold, while not affecting recycling of MC4R or agonist-dependent internalization of β(2)AR. Reduced cholesterol did not change the MC4R dose-response curve to α-MSH, but it decreased the amount of cAMP generated per receptor number indicating that a population of MC4R at the cell surface becomes nonfunctional. The loss of MC4R function increased over time (25-50%) and was partially reversed by mutations at putative phosphorylation sites (T312A and S329A). This was reproduced in hypothalamic GT1-7 cells expressing endogenous MC4R. The data indicate that constitutive endocytosis of MC4R is clathrin- and cholesterol-dependent. MC4R endocytosis is required to maintain MC4R responsiveness to α-MSH by constantly eliminating from the plasma membrane a pool of receptors modified at Thr-312 and Ser-329 that have to be cycled to the endosomal compartment to regain function.
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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.