Observations on the ligand selectivity of the melanocortin 2 receptor

Veo, Kristopher D.; Reinick, Christina; Liang, Liang; Moser, Emily; Angleson, Joseph K.; Dores, Robert M.

doi:10.1016/j.ygcen.2011.04.006

Cited by 15 publications

(6 citation statements)

References 44 publications

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“…The MC2-R is unique among MC-R in that it is the only receptor with sensitivity to a single melanocortin peptide ligand, ACTH (Veo, et al 2011). Our cell lines responded to ACTH with [Ca 2+ ] i flux in a manner that was consistent with their MC2-R expression patterns but they did not respond to the strong agonists of MC3-R, MTII and γ 2 -MSH, indicating a functional MC2-R. Additionally, our murine bone marrow derived macrophage cultures express the melanocortin peptide precursor, POMC, and the highly active form of its cleavage enzyme, PC1/3.…”

Section: Discussionmentioning

confidence: 99%

Functional melanocortin-2 receptors are expressed by mouse aorta-derived mesenchymal progenitor cells

Evans

Fernando

Ragolia

2012

Molecular and Cellular Endocrinology

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A local melanocortin system is active during tissue injury and inflammation. Thus far this system has been described as autocrine in nature where local production of pro-opiomelanocortin (POMC) peptides by leukocytes feeds back on melanocortin receptor (MC-R) expressing immune cells to quell inflammatory cytokine production. Here we present evidence that POMC peptides may generate extracellular matrix (ECM) changes by inducing matrix production by cells of the mesenchymal lineage through activation of the MC2-R. Using immunoblot, we determined that mouse aorta-derived mesenchymal progenitor cells express both MC2-R and MC3-R. These progenitors respond to treatment with ACTH by increasing collagen matrix synthesis as assessed by picrosirius red stain and 3H-proline incorporation. ACTH also induces transient increases in intracellular calcium ([Ca2+]i) as assessed using the fluorescent Ca2+ indicator, fura- 2. The ACTH-induced changes in [Ca2+]i are consistent with MC2-R signaling and consist of both an intracellular release and an extracellular influx of Ca2+. Both mouse aortic mesenchymal progenitors and mouse macrophage cells express POMC and the prohormone convertase 1/3 (PC1/3) indicating they have the potential to contribute to the local production of POMC peptides. These data demonstrate functional MC2-R expression in mouse aorta-derived mesenchymal progenitors and implicate both macrophage and mesenchymal cells as relevant sources of local POMC peptides.

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Section: Discussionmentioning

confidence: 99%

Functional melanocortin-2 receptors are expressed by mouse aorta-derived mesenchymal progenitor cells

Evans

Fernando

Ragolia

2012

Molecular and Cellular Endocrinology

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“…A classic example is the processing of the precursor proopiomelanocortin in the pituitary. In the anterior lobe of the pituitary, the precursor is converted into adrenocorticotropic hormone (ACTH), which binds to several subtypes of melanocortin receptors, such as MC2R, located in the adrenal gland; this receptor controls the production of glucocorticoids (cortisol) [ 9 10 ]. In the intermediate lobe of the pituitary and also in the brain, ACTH is further processed into alpha-melanocyte-stimulating hormone, which binds to melanocortin receptors with completely different affinities [ 11 ].…”

Section: Neuropeptide Synthesismentioning

confidence: 99%

Neuropeptidomics: Mass Spectrometry-Based Identification and Quantitation of Neuropeptides

Lee

2016

Genomics Inform

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Neuropeptides produced from prohormones by selective action of endopeptidases are vital signaling molecules, playing a critical role in a variety of physiological processes, such as addiction, depression, pain, and circadian rhythms. Neuropeptides bind to post-synaptic receptors and elicit cellular effects like classical neurotransmitters. While each neuropeptide could have its own biological function, mass spectrometry (MS) allows for the identification of the precise molecular forms of each peptide without a priori knowledge of the peptide identity and for the quantitation of neuropeptides in different conditions of the samples. MS-based neuropeptidomics approaches have been applied to various animal models and conditions to characterize and quantify novel neuropeptides, as well as known neuropeptides, advancing our understanding of nervous system function over the past decade. Here, we will present an overview of neuropeptides and MS-based neuropeptidomic strategies for the identification and quantitation of neuropeptides.

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“…Upon binding to its cognate receptor, corticotropin-releasing hormone receptor 1 (CRHR1) (25), which is expressed by corticotropic cells of the adenohypophysis, CRH stimulates the synthesis and secretion of adrenocorticotropic hormone (ACTH) as well as other bioactive molecules such as ␤-endorphin (26). ACTH engages the melanocortin 2 receptor expressed by cells of the adrenal cortex and stimulates the production and secretion of steroid hormones such as GC (27).…”

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confidence: 99%

The Nutrient and Energy Sensor Sirt1 Regulates the Hypothalamic-Pituitary-Adrenal (HPA) Axis by Altering the Production of the Prohormone Convertase 2 (PC2) Essential in the Maturation of Corticotropin-releasing Hormone (CRH) from Its Prohormone in Male Rats

Toorie

Cyr

Steger

et al. 2016

Journal of Biological Chemistry

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Understanding the role of hypothalamic neuropeptides and hormones in energy balance is paramount in the search for approaches to mitigate the obese state. Increased hypothalamicpituitary-adrenal axis activity leads to increased levels of glucocorticoids (GC) that are known to regulate body weight. The axis initiates the production and release of corticotropin-releasing hormone (CRH) from the paraventricular nucleus (PVN) of the hypothalamus. Levels of active CRH peptide are dependent on the processing of its precursor pro-CRH by the action of two members of the family of prohormone convertases 1 and 2 (PC1 and PC2). Here, we propose that the nutrient sensor sirtuin 1 (Sirt1) regulates the production of CRH post-translationally by affecting PC2. Data suggest that Sirt1 may alter the preproPC2 gene directly or via deacetylation of the transcription factor Forkhead box protein O1 (FoxO1). Data also suggest that Sirt1 may alter PC2 via a post-translational mechanism. Our results show that Sirt1 levels in the PVN increase in rats fed a high fat diet for 12 weeks. Furthermore, elevated Sirt1 increased PC2 levels, which in turn increased the production of active CRH and GC. Collectively, this study provides the first evidence supporting the hypothesis that PVN Sirt1 activates the hypothalamicpituitary-adrenal axis and basal GC levels by enhancing the production of CRH through an increase in the biosynthesis of PC2, which is essential in the maturation of CRH from its prohormone, pro-CRH.Since its discovery in 1981 (1), corticotropin-releasing hormone (CRH) 2 has been demonstrated to be involved in mediating various physiological processes, including those involved in organismal homeostasis. Renowned for its critical role in mediating the stress response (2), CRH functions to regulate metabolic, immunologic, and homeostatic changes both basally and under various pathologic conditions (3-5). CRH heterogeneously expresses in the periphery and the brain with high expression in the hypothalamic paraventricular nucleus (PVN) (6 -8). Arginine vasopressin (AVP) is also produced in the PVN and acts to synergize CRH actions. It is the CRH that is produced in the medial parvocellular division of the PVN that functions as the central regulator of the HPA axis (9). Levels of bioactive CRH are dependent on the post-translational processing of its precursor pro-CRH. Prohormone posttranslational processing is the mechanism by which all peptide hormones become biologically active (10, 11). In rodents and humans, aberrations in prohormone processing results in deleterious health consequences, including metabolic dysfunctions (12-17). CRH is initially produced as a large inactive precursor, preproCRH, that is made of 196 amino acids (18,19). After cleavage of the signal sequence, the prohormone (pro-CRH) enters the lumen of the rough endoplasmic reticulum and is routed to the trans-Golgi network where it undergoes enzymatic post-translational modifications to generate several intermediate forms as well as the bioactive CRH(1-41) peptid...

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Observations on the ligand selectivity of the melanocortin 2 receptor

Cited by 15 publications

References 44 publications

Functional melanocortin-2 receptors are expressed by mouse aorta-derived mesenchymal progenitor cells

Functional melanocortin-2 receptors are expressed by mouse aorta-derived mesenchymal progenitor cells

Neuropeptidomics: Mass Spectrometry-Based Identification and Quantitation of Neuropeptides

The Nutrient and Energy Sensor Sirt1 Regulates the Hypothalamic-Pituitary-Adrenal (HPA) Axis by Altering the Production of the Prohormone Convertase 2 (PC2) Essential in the Maturation of Corticotropin-releasing Hormone (CRH) from Its Prohormone in Male Rats

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