Central receptors mediating the cardiovascular actions of melanocyte stimulating hormones

Ni, Xi Ping; Butler, Andrew A.; Cone, Roger D.; Humphreys, Michael H.

doi:10.1097/01.hjh.0000249702.49854.fa

Cited by 81 publications

(66 citation statements)

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“…The physiological relevance of peripherally administered melanocortin receptor agonists has resulted in linking the MC3R to cardiovascular effects using γ-MSH and derivatives thereof, as reviewed [23,40,41,43,59,75]. More recent studies however, have clearly associated the MC4R’s involvement in the regulation of blood pressure using human patients with dysfunctional MC4R polymorphisms as well treatment with a melanocortin receptor agonist [28].…”

Section: 0 Discussionmentioning

confidence: 99%

γ2-Melanocyte stimulation hormone (γ2-MSH) truncation studies results in the cautionary note that γ2-MSH is not selective for the mouse MC3R over the mouse MC5R

et al. 2010

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The melanocortin system has been implicated in a multitude of physiological pathways including obesity, satiety, energy homeostasis, sexual behavior, pigmentation, sodium regulation, hypertension, and many others. Based upon studies of the endogenous melanocortin receptor agonists at the cloned human melanocortin receptor proteins, it was concluded that the γ-MSH related agonist ligands are selective for the MC3 versus the MC4 and MC5 receptors. In attempts to understand and identify the specific amino acids of γ 2 -MSH important for MC3R selectivity, we have performed Nand C-terminal truncation studies and pharmacologically characterized twenty-eight ligands at the mouse MC1 and MC3-5 melanocortin receptors. The C-terminal Trp-Asp 9 -Arg 10 -Phe 11 residues are important for nM potency at the mMC3R and the Arg 7 -Trp 8 residues are important for mMC5R nM potency. We observed the unanticipated results that several of the C-terminal truncated analogues possessed nM agonist potency at the mMC3 and mMC5Rs which lead us to performed a comparative side-by-side study of the mouse and human MC5R. These data resulted in μM γ 2 -MSH analogue potency at the hMC5R, consistent with previous reports, however at the mMC5R, nM γ 2 -MSH analogue potency was observed. Thus, these data support the hypothesis of important species specific differences in γ-MSH related ligand potency at the rodent versus human MC5R subtype that is critical for the interpretation of in vivo rodent physiological studies. These results prompted us to examine the affects of a peripherally administered melanocortin agonist on hypothalamic gene expression levels of the MC3R, MC4R, and MC5R. The super potent non-selective NDP-MSH agonist was administered i.p. and resulted in significantly decreased levels of mMC3R and mMC5R hypothalamic mRNA versus saline control. These data provide for the first time data demonstrating peripherally administered NDP-MSH can modify hypothalamic melanocortin receptor expression levels. KeywordsMelanotropin; heart; blood pressure; obesity; receptor brain expression; GPCR © 2010 Elsevier Inc. All rights reserved. * Reprint request should be addressed to Dr. Carrie Haskell-Luevano, University of Florida, Department of Pharmacodynamics, P. O. Box 100487, Gainesville, FL 32610-0487. Phone (352) Fax (352) 273-7723, carrie@cop.ufl.edu.. Publisher's Disclaimer: 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 citable 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. NIH Public Access Author ManuscriptPeptides. Author manuscript; available in PMC 2011 December 1. Published in final edited form as:Peptides. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA...

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Section: 0 Discussionmentioning

confidence: 99%

γ2-Melanocyte stimulation hormone (γ2-MSH) truncation studies results in the cautionary note that γ2-MSH is not selective for the mouse MC3R over the mouse MC5R

et al. 2010

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“…Chronic hypothalamic MCR activation can increase arterial pressure despite reduced food intake, whereas the inhibition of MCR significantly increases body weight without raising arterial pressure [57, 157]. Furthermore, acute central administration of α-MSH increases the mean arterial pressure and heart rate in wild-type animals but not in MC4R knockout mice [158, 159]. In normal animals, chronic MC4R antagonism slows the heart rate in a sustained manner and slightly reduces blood pressure despite hyperphagia and rapid weight gain [59, 160, 161].…”

Section: Role In Blood Pressurementioning

confidence: 99%

The Role of the Melanocortin System in Metabolic Disease: New Developments and Advances

Hill

Faulkner²

2016

Neuroendocrinology

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Obesity is increasing in prevalence across all sectors of society, and with it a constellation of associated ailments including hypertension, type 2 diabetes, and eating disorders. The melanocortin system is a critical neural system underlying the control of body weight and other functions. Deficits in the melanocortin system may promote or exacerbate the comorbidities of obesity. This system has therefore generated great interest as a potential target for treatment of obesity. However, drugs targeting melanocortin receptors are plagued by problematic side effects, including undesirable increases in sympathetic nervous system activity, heart rate, and blood pressure. Circumnavigating this roadblock will require a clearer picture of the precise neural circuits that mediate the functions of melanocortins. Recent, novel experimental approaches have significantly advanced our understanding of these pathways. We here review the latest advances in our understanding of the role of melanocortins in food intake, reward pathways, blood pressure, glucose control, and energy expenditure. The evidence suggests that downstream melanocortin-responsive circuits responsible for different physiological actions do diverge. Ultimately, a more complete understanding of melanocortin pathways and their myriad roles should allow treatments tailored to the mix of metabolic disorders in the individual patient.

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“…The MC3R is primarily expressed in hypothalamus, especially in the arcuate nucleus, the ventromedial nucleus and the posterior hypothalamic region ( Jegou et al 2000 ). It is also expressed in several peripheral tissues, including the placenta, gut, heart, kidney, and peritoneal macrophages ( Chhajlani 1996 ; Gantz et al 1993 ; Getting et al 2003 ; Ni et al 2006 ). Based on its wide distribution, the MC3R has been shown to be involved in regulating cardiovascular function ( Mioni et al 2003 ; Versteeg et al 1998 ), natriuresis ( Chandramohan et al 2009 ; Ni et al 2006 ), and inflammation ( Catania et al 2004 ; Getting et al 2006 ; Getting et al 2008 ).…”

Section: Introductionmentioning

confidence: 99%

Functions of DPLIY motif and helix 8 of human melanocortin-3 receptor

Zhao

Zhili²,

Tao

2015

Journal of Molecular Endocrinology

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The melanocortin-3 receptor (MC3R) is a member of family A G protein-coupled receptors (GPCRs). The MC3R remains the most enigmatic of the melanocortin receptors with regard to its physiological functions, especially the role in energy homeostasis. The N/DPxxY motif and the eighth helix (helix 8) in the carboxyl terminus of GPCRs have been identified to be important for receptor expression, ligand binding, signal transduction and internalization. To gain a better understanding of the structure-function relationship of MC3R, we performed systematic study of all the 20 residues in this domain using alanine-scanning mutagenesis. We showed that although all mutants were expressed normally on cell surface, eleven residues were important for ligand binding and one was indispensable for downstream cAMP generation. F347A showed constitutive activity in cAMP signaling while all the other mutants had normal basal activities. We studied the signaling capacity of nine mutants in the ERK1/2 signaling pathway. All of these mutants showed normal basal ERK1/2 phosphorylation levels. The pERK1/2 levels of six binding- or signaling-defective mutants were enhanced upon agonist stimulation. The unbalanced cAMP and pERK1/2 signaling pathways suggested the existence of biased signaling in MC3R mutants. In summary, we showed that the DPLIY motif and Helix 8 was important for MC3R activation and signal transduction. Our data led to a better understanding of the structure-function relationship of MC3R.

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Central receptors mediating the cardiovascular actions of melanocyte stimulating hormones

Cited by 81 publications

References 45 publications

γ2-Melanocyte stimulation hormone (γ2-MSH) truncation studies results in the cautionary note that γ2-MSH is not selective for the mouse MC3R over the mouse MC5R

γ2-Melanocyte stimulation hormone (γ2-MSH) truncation studies results in the cautionary note that γ2-MSH is not selective for the mouse MC3R over the mouse MC5R

The Role of the Melanocortin System in Metabolic Disease: New Developments and Advances

Functions of DPLIY motif and helix 8 of human melanocortin-3 receptor

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