Views on the co-evolution of the melanocortin-2 receptor, MRAPs, and the hypothalamus/pituitary/adrenal-interrenal axis

Dores, Robert M.; Garcia, Yesenia

doi:10.1016/j.mce.2014.12.022

Cited by 35 publications

(18 citation statements)

References 84 publications

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“…The dual topology MRAP2 protein arose more than 500 million years ago at about the same time as MC receptors, and gene duplication events gave rise to MRAP and additional MC receptors (24,39). We can speculate that the antiparallel MRAP dimer is needed for binding to MC receptors or for MRAP stability, requirements that were bypassed in the fusion proteins, but additional work will be required to test these ideas.…”

Section: Discussionmentioning

confidence: 99%

Adrenocorticotropic Hormone (ACTH) Responses Require Actions of the Melanocortin-2 Receptor Accessory Protein on the Extracellular Surface of the Plasma Membrane

Malik

Dolan

Maben

et al. 2015

Journal of Biological Chemistry

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Background:Signaling by G protein-coupled melanocortin-2 receptors requires MRAP, a transmembrane accessory protein that forms antiparallel homodimers. Results: Mutational analysis of MRAP-MRAP-receptor fusion proteins established that MRAP oriented with an extracellular amino terminus is essential. Conclusion: MRAP acts on the outside of the cell in the ACTH-MRAP-MRAP-receptor signaling complex. Significance: The results provide insight into molecular mechanisms of GPCR accessory proteins.

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Section: Discussionmentioning

confidence: 99%

Adrenocorticotropic Hormone (ACTH) Responses Require Actions of the Melanocortin-2 Receptor Accessory Protein on the Extracellular Surface of the Plasma Membrane

Malik

Dolan

Maben

et al. 2015

Journal of Biological Chemistry

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“…Amino acid positions where amino acid substitutions as a result of a spontaneous point mutation that resulted in type 1 FGD and blocked activation of the mutant receptor (Chung et al 2008) Subsequent studies revealed that the protein required for the functional activation of tetrapod and teleost MC2R orthologs is the melanocortin-2 receptor accessory protein (MRAP or MRAP1; Metherell et al 2005). The MRAPs will be discussed in greater detail in the section on MCR physiology; however, it is now clear that the trafficking of tetrapod and teleost MC2R orthologs to the plasma membrane, and the activation of these orthologs by ACTH requires the formation of a MC2R/MRAP1 heterodimer (for reviews see, , Webb & Clark 2010, Dores & Garcia 2015. In addition, the mrap1 gene is expressed in glucocorticoid producing cells (i.e.…”

Section: ) (B)mentioning

confidence: 99%

“…Average values and standard errors of the mean were graphed using KaleidaGraph software (v 4.1; www.synergy.com), and the EC 50 value for each ligand was determined (A). The EC 50 value for the wt MC2R/mMRAP1 transfection was compared with the EC 50 value for each mutant MC2R/mMRAP1 using the Student's t-test ( (Vale et al 1981), and the hypothalamus/pituitary/ interrenal (HPI) axis in amphibians and teleosts (Dores & Garcia 2015). ACTH released from the anterior pituitary binds to MC2R on adrenal cortex cells (HPA axis) or to MC2R on interrenal cells (HPI axis), and leads to the synthesis and release of glucocorticoids from these steroid hormone-producing cells.…”

Section: Tm4mentioning

confidence: 99%

“…Another peculiarity of MC5R is the co-expression of the m5r gene and the mc2r gene in the adrenal cortex cells of a bird (Takeuchi & Takahashi 1998), and the interrenal tissue of an amphibian (Dores & Garcia 2015) and several teleost fishes , Metz et al 2005, Aluru & Vijayan 2008, Kobayashi et al 2011b. At present, it is unclear what role MC5R may be playing in the response to ACTH stimulation at these glucocorticoid-producing cells, and whether interactions between MRAP1 and MC5R in these cells play a role in the ligand selectivity of MC5R.…”

Section: Mc5rmentioning

confidence: 99%

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60 YEARS OF POMC: Melanocortin receptors: evolution of ligand selectivity for melanocortin peptides

Dores

Liang

Davis

et al. 2016

Journal of Molecular Endocrinology

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The evolution of the melanocortin receptors (MCRs) is linked to the evolution of adrenocorticotrophic hormone (ACTH), the melanocyte-stimulating hormones (MSHs), and their common precursor pro-opiomelanocortin (POMC). The origin of the MCRs and POMC appears to be grounded in the early radiation of the ancestral protochordates. During the genome duplications that have occurred during the evolution of the chordates, the organization plan for POMC was established, and features that have been retained include, the high conservation of the amino acid sequences of α-MSH and ACTH, and the presence of the HFRW MCR activation motif in all of the melanocortin peptides (i.e. ACTH, α-MSH, β-MSH, γ-MSH, and δ-MSH). For the MCRs, the chordate genome duplication events resulted in the proliferation of paralogous receptor genes, and a divergence in ligand selectivity. While most gnathostome MCRs can be activated by either ACTH or the MSHs, teleost and tetrapod MC2R orthologs can only be activated by ACTH. The appearance of the accessory protein, MRAP1, paralleled the emergence of teleost and tetrapods MC2R ligand selectivity, and the dependence of these orthologs on MRAP1 for trafficking to the plasma membrane. The accessory protein, MRAP2, does not affect MC2R ligand selectivity, but does influence the functionality of MC4R orthologs. In this regard, the roles that these accessory proteins may play in the physiology of the five MCRs (i.e. MC1R, MC2R, MC3R, MC4R, and MC5R) are discussed.

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“…MC2R plays a critical role in the HPI axis35 and is specifically activated by ACTH, while the other MCRs can be activated by the MSHs as well as ACTH7. The acute stress application at the stage of the formation of all fins resulted in altered transcript levels of mc2r which showed an up-regulation after application of the stressor, with peak values at 0.5 h and 1 h post stress to return to basal levels at 2 h and 24 h post stress (Fig.…”

Section: Discussionmentioning

confidence: 92%

α-MSH and melanocortin receptors at early ontogeny in European sea bass (Dicentrarchus labrax, L.)

Tsalafouta

Gorissen

Pelgrim

et al. 2017

Sci Rep

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Temporal patterns of whole-body α-MSH concentrations and of transcripts of melanocortin receptors during early development as well as the endocrine response (α-MSH, cortisol, MCR mRNAs) to stress at the end of the larval period were characterized in Dicentrarchus labrax. Immunohistochemistry showed α-MSH positive cells in the pituitary pars intermedia in all stages examined. As development proceeds, α-MSH content gradually increases; mRNA levels of mc2r and mc4r remain low until first feeding where peak values are observed. Mc1r expression was constant during development, pomc mRNA levels remain low until the stage of flexion after which a significant increase is observed. At the stage of the formation of all fins, whole-body cortisol and α-MSH concentrations responded with peak values at 2 h post stress. Additionally, the stress challenge resulted in elevated transcript levels of pomc, mc2r and mc4r but not in mc1r, with a pattern characterized by peak values at 1 h post stress and a strong correlation with whole body α-MSH concentrations was found. Our data provide for the first time a view on the importance of the α-MSH stress response in early development of European sea bass, an additional and relatively poorly understood signal involved in the stress response in teleosts.

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Views on the co-evolution of the melanocortin-2 receptor, MRAPs, and the hypothalamus/pituitary/adrenal-interrenal axis

Cited by 35 publications

References 84 publications

Adrenocorticotropic Hormone (ACTH) Responses Require Actions of the Melanocortin-2 Receptor Accessory Protein on the Extracellular Surface of the Plasma Membrane

Adrenocorticotropic Hormone (ACTH) Responses Require Actions of the Melanocortin-2 Receptor Accessory Protein on the Extracellular Surface of the Plasma Membrane

60 YEARS OF POMC: Melanocortin receptors: evolution of ligand selectivity for melanocortin peptides

α-MSH and melanocortin receptors at early ontogeny in European sea bass (Dicentrarchus labrax, L.)

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