Activation and Endocytic Internalization of Melanocortin 3 Receptor in Neuronal Cells

Wachira, S. J. M.; Guruswamy, B.; Uradu, L.; Hughes‐Darden, Cleo; Denaro, Frank

doi:10.1196/annals.1397.093

Cited by 12 publications

(8 citation statements)

References 47 publications

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“…Nongenomic effects can also be elicited by ␥-MSH, and, for example, in neurons, MC 3 can be rapidly internalized on application of its ligand. 38 Thus, MC ligands can potentially regulate MC receptor expression in a variety of ways.…”

Section: Discussionmentioning

confidence: 99%

The Melanocortin Agonist AP214 Exerts Anti-Inflammatory and Proresolving Properties

Montero‐Melendez

Patel

Seed

et al. 2011

The American Journal of Pathology

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Synthetic and natural melanocortin (MC) peptides afford inhibitory properties in inflammation and tissue injury, but characterization of receptor involvement is still elusive. We used the agonist AP214 to test MC-dependent anti-inflammatory effects. In zymosan peritonitis, treatment of mice with AP214 (400 to 800 g/kg) inhibited cell infiltration, an effect retained in MC receptor type 1, or MC 1 , mutant mice but lost in MC 3 null mice. In vitro, cytokine release from zymosan-stimulated macrophages was affected by AP214, with approximately 80%, 30%, and 40% reduction in IL-1␤, tumor necrosis factor-␣, and IL-6, respectively. Inhibition of IL-1␤ release was retained in MC 1 mutant cells but was lost in MC 3 null cells. Furthermore, AP214 augmented uptake of zymosan particles and human apoptotic neutrophils by wild-type macrophages: this proresolving property was lost in MC 3 null macrophages. AP214 displayed its pro-efferocytotic effect also in vivo.

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Section: Discussionmentioning

confidence: 99%

The Melanocortin Agonist AP214 Exerts Anti-Inflammatory and Proresolving Properties

Montero‐Melendez

Patel

Seed

et al. 2011

The American Journal of Pathology

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“…To our knowledge, so far, no data are available about the localization of the MC4R in lipid rafts; however, one study suggests that the closely related MC3R subtype is located in lipid rafts (Wachira et al, 2007). The distribution of lipid rafts over the cell surface, their lipid composition and/or inventory of scaffolding proteins has been shown to strongly depend on the cell type and morphogenesis (Helms and A c c e p t e d M a n u s c r i p t 11 Zurzolo, 2004;Pontier et al, 2008;Simons and Toomre, 2000).…”

Section: Organization Of Mc4r Signalling In Specialized Membrane Micrmentioning

confidence: 99%

Alternative G protein coupling and biased agonism: New insights into melanocortin-4 receptor signalling

Breit

Büch

Boekhoff

et al. 2011

Molecular and Cellular Endocrinology

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Please cite this article as: Breit, A., Büch, T.R.H., Boekhoff, I., Solinski, H.J., Damm, E., Gudermann, T., Alternative G protein-coupling and biased agonism: new insights into melanocortin-4 receptor signalling, Molecular and Cellular Endocrinology (2010), doi:10.1016/j.mce.2010 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Abbreviations: ACTH, adrenocorticotropic hormone; cAMP, cyclic 3',5'-adenosine monophosphate; AGRP, agouti-related protein; CTX, cholera toxin; ER, endoplasmic reticulum; ERK-1/2, extracellular signal-regulated kinases; FSK, forskolin; GPCR, G proteincoupled receptors; GTPγS 35 , guanosine 5'-(3-O-thio)triphosphate; IRS, insulin receptor substrate; MGRN-1, mahogunin ring finger-1; MC4R, Melanocortin-4 receptor; MRAPs, melanocortin receptor accessory proteins; MSH, melanocyte-stimulating hormones; PKA, protein kinase A; PKC, protein kinase C; PI3K, phosphatidylinositol-3-kinase; PLC, phospholipase C; POMC, proopiomelanocortin; PTX, pertussis toxin; RAMPs, receptoractivity modifying proteins AbstractThe melanocortin-4 receptor (MC4R) is a prototypical G protein-coupled receptor (GPCR) that plays a considerable role in controlling appetite and energy homeostasis. Signalling initiated by MC4R is orchestrated by multiple agonists, inverse agonism and by interactions with accessory proteins. The exact molecular events translating MC4R signalling into its physiological role, however, are not fully understood. This review is an attempt to summarize new aspects of MC4R signalling in the context of its recently discovered alternative G protein coupling, and to give a perspective on how future research could improve our knowledge about the intertwining molecular mechanisms that are responsible for the regulation of energy homeostasis by the melanocortin system.

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“…Because the extent of ligand-promoted Ex-mMrgC endocytosis observed for BAM8-22 or ␥ 2 -MSH was rather low (ϳ20 and ϳ10%, respectively), we compared these values with those obtained with the human MC3R or MC4R ( Supplementary Fig. 1C), which have been established recently as GPCR that undergo robust endocytosis in HEK293 cells (Shinyama et al, 2003;Breit et al, 2006b;Wachira et al, 2007). As summarized in Supplementary Fig.…”

Section: Calcium Signaling and Receptor Endocytosis In Hek293 Cells Smentioning

confidence: 99%

Sensory Neuron-Specific Mas-Related Gene-X1 Receptors Resist Agonist-Promoted Endocytosis

Solinski

Boekhoff²,

Bouvier³

et al. 2010

Mol Pharmacol

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Human sensory neuron-specific mas-related gene X1 receptors (hMrgX1s) belong to the superfamily of G protein-coupled receptors (GPCRs), bind cleavage products of pro-enkephalin with high affinity, and have been suggested to participate in pain sensation. Murine or rat MrgC receptors exhibit high similarities with hMrgX1 in terms of expression pattern, sequence homology, and binding profile. Therefore, rodents have been used as an in vivo model to explore the physiological functions and pharmacodynamics of the hMrgX1. Agonist-promoted receptor endocytosis significantly affects the pharmacodynamics of a GPCR but is not yet investigated for hMrgX1. Therefore, we analyzed the effects of prolonged agonist exposure on cell surface protein levels of hMrgX1 and murine or rat MrgC in human embryonic kidney 293, Cos, F11, and ND-C cells. We observed that hMrgX1 are resistant and both MrgC are prone to agonist-promoted receptor endocytosis. In Cos cells, coexpression of ␤-arrestins strongly enhanced endocytosis of murine MrgC but did not alter cell surface expression of hMrgX1 receptors. These data define the hMrgX1 as one of the few members within the superfamily of GPCRs whose signaling is not regulated by agonist-promoted endocytosis and reveal species-specific differences in the regulation of Mrg receptor signaling. Given the importance of receptor endocytosis for the pharmacodynamics of a given ligand, our results may have a strong impact on the development of future drugs that suppose to control pain in humans but were tested in rodents.

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Activation and Endocytic Internalization of Melanocortin 3 Receptor in Neuronal Cells

Cited by 12 publications

References 47 publications

The Melanocortin Agonist AP214 Exerts Anti-Inflammatory and Proresolving Properties

The Melanocortin Agonist AP214 Exerts Anti-Inflammatory and Proresolving Properties

Alternative G protein coupling and biased agonism: New insights into melanocortin-4 receptor signalling

Sensory Neuron-Specific Mas-Related Gene-X1 Receptors Resist Agonist-Promoted Endocytosis

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