Neuropeptide Y and gamma-melanocyte stimulating hormone (γ-MSH) share a common pressor mechanism of action

Gruber, Kenneth A.; Fan, Wei; Åkerberg, Helena; Larhammar, Dan; Chee, Melissa J.; Colmers, William F.; Cone, Roger D.

doi:10.1007/s12020-008-9141-3

Cited by 6 publications

(5 citation statements)

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“…While there is some debate over whether the cardiovascular effects of exogenously administered γ-MSH are mediated via the melanocortin MC 3 receptor (Gruber et al, 2009; Mioni et al, 2003; Ni et al, 2006b), the importance of the melanocortin MC 3 receptor in mediating natriuresis is established. Gamma-MSH plays a critical role in reflex natriuresis after unilateral nephrectomy (Lin et al, 1987; Ni et al, 1998).…”

Section: Physiology Of the Melanocortin Mc3 Receptormentioning

confidence: 99%

Physiological roles of the melanocortin MC3 receptor

Renquist

Lippert

Sebag

et al. 2011

European Journal of Pharmacology

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The melanocortin MC 3 receptor remains the most enigmatic of the melanocortin receptors with regard to its physiological functions. The receptor is expressed both in the CNS and in multiple tissues in the periphery. It appears to be an inhibitory autoreceptor on proopiomelanocortin neurons, yet global deletion of the receptor causes an obesity syndrome. Knockout of the receptor increases adipose mass without a readily measurable increase in food intake or decrease in energy expenditure. And finally, no melanocortin MC 3 receptor null humans have been identified and associations between variant alleles of the melanocortin MC 3 receptor and disease remain controversial, so the physiological role of the receptor in humans remains to be determined. KeywordsMelanocortin-3 receptor; melanocortin MC3 receptor; Melanocortin; Obesity; γ-MSH; Proopiomelanocortin Structure and function of the receptorThe melanocortin MC 3 receptor belongs to the G-Protein Coupled Receptor family (Gantz et al., 1993;Roselli-Rehfuss et al., 1993). It is positively coupled to adenylyl cyclases through Gs and, upon activation, stimulates cAMP production. A few studies suggest that overexpressed melanocortin MC 3 receptor activation can also induce calcium release from intracellular stores (Kim et al., 2002b;Konda et al., 1994;Mountjoy et al., 2001). The mechanism of calcium release is unclear and the role of IP 3 generation is controversial (Kim et al., 2002a;Konda et al., 1994;Mountjoy et al., 2001). Based on the discrepancy observed in this signaling cascade when studied in different in-vitro models, it will be important to validate the activation of calcium signaling in melanocortin MC 3 receptor neurons in exvivo or in-vivo models. Another pathway activated downstream of melanocortin MC 3 receptor is the MAPK pathway. Indeed, Chai et al. showed that, in HEK293 cells transfected with the melanocortin MC 3 receptor, NDP-αMSH triggers a significant phosphorylation of ERK1/2 (Chai et al., 2007). In addition, they established that melanocortin MC 3 receptormediated MAPK activation is PI3K dependant and pertussis toxin sensitive (Chai et al., 2007). Interestingly, as with the melanocortin MC 4 receptor (Nijenhuis et al., 2001), the melanocortin MC 3 receptor was reported to have a constitutive activity (Nijenhuis et al., 2001) but the physiological relevance of this finding is still unclear. Importantly, the © 2010 Elsevier B.V. All rights reserved. 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. , 1997). Like most G protein-coupled receptors, following activation, the melanocortin MC 3 receptor ...

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Section: Physiology Of the Melanocortin Mc3 Receptormentioning

confidence: 99%

Physiological roles of the melanocortin MC3 receptor

Renquist

Lippert

Sebag

et al. 2011

European Journal of Pharmacology

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“…Finally, there is both direct and indirect evidence that endogenous mammalian peptides with a stable hairpin structure (e.g., the NPY-PYY family , ) also show BBB transport. , Thus, synthetic peptide ligands of a multi-specific bile acid transporter have secondary structural requirements for trans-epithelial transport that are similar to those found in naturally occurring peptides with bacterial membrane and/or BBB transport activity. These latter peptides are present in bacteria, fungi, plants, and animals (insects through mammals).…”

Section: Resultsmentioning

confidence: 99%

Development of a Therapeutic Peptide for Cachexia Suggests a Platform Approach for Drug-like Peptides

Gruber

Gallazzi

et al. 2022

ACS Pharmacol. Transl. Sci.

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During the development of a melanocortin (MC) peptide drug to treat the condition of cachexia (a hypermetabolic state producing lean body mass wasting), we were confronted with the need for peptide transport across the blood–brain barrier (BBB): the MC-4 receptors (MC4Rs) for metabolic rate control are located in the hypothalamus, i.e., behind the BBB. Using the term “peptides with BBB transport”, we screened the medical literature like a peptide library. This revealed numerous “hits”peptides with BBB transport and/or oral activity. We noted several features common to most peptides in this class, including a dipeptide sequence of nonpolar residues, primary structure cyclization (whole or partial), and a Pro-aromatic motif usually within the cyclized region. Based on this, we designed an MC4R antagonist peptide, TCMCB07, that successfully treated many forms of cachexia. As part of our pharmacokinetic characterization of TCMCB07, we discovered that hepatobiliary extraction from blood accounted for a majority of the circulating peptide’s excretion. Further screening of the literature revealed that TCMCB07 is a member of a long-forgotten peptide class, showing active transport by a multi-specific bile salt carrier. Bile salt transport peptides have predictable pharmacokinetics, including BBB transport, but rapid hepatic clearance inhibited their development as drugs. TCMCB07 shares the general characteristics of the bile salt peptide class but with a much longer half-life of hours, not minutes. A change in its C-terminal amino acid sequence slows hepatic clearance. This modification is transferable to other peptides in this class, suggesting a platform approach for producing drug-like peptides.

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“…The pressor effects of γ 2 MSH are not thought to be mediated by MC 3 receptors but by activation of centrally expressed RFamide‐gated sodium channels/receptors . To investigate whether these pressor effects may underlie the renal effects of γ 2 MSH, we used a modified form of the native peptide, namely NDP‐γ 2 MSH, which has a high specificity for MC 3 receptors .…”

Section: Discussionmentioning

confidence: 99%

“…The pressor effects of c 2 MSH are not thought to be mediated by MC 3 receptors but by activation of centrally expressed RFamide-gated sodium channels/receptors. 1,10,11 To investigate whether these pressor effects may underlie the renal effects of c 2 MSH, we used a modified form of the native peptide, namely NDP-c 2 MSH, which has a high specificity for MC 3 receptors. 8 Furthermore, to specifically target delivery to the kidney, peptides were infused directly into the renal interstitium at a rate (500 fmol/min) that has been shown previously to maintain intrarenal concentrations in the physiological range (100 pmol/L).…”

Section: Discussionmentioning

confidence: 99%

[Nle³,d‐Phe⁶]‐γ₂‐melanocyte‐stimulating hormone possesses the renal excretory but not the cardiovascular actions of the native γ₂‐melanocyte‐stimulating hormone in anaesthetized rats

Cope

Flanagan

Houghton

et al. 2012

Clin Exp Pharma Physio

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The present study compared the cardiovascular and renal actions of γ(2) -melanocyte-stimulating hormone (γ(2) MSH) with those of the synthetic analogue [Nle(3) ,d-Phe(6) ]-γ(2) MSH (NDP-γ(2) MSH) and explored the effects of high dietary salt intake on the renal actions of NDP-γ(2) MSH. Both peptides were infused systemically (3-1000 nmol/kg) and intrarenally (500 fmol/min) into innervated and renally denervated rats fed either a normal (0.4% NaCl) or high-salt (4% NaCl; HS) diet. Mean arterial pressure (MAP), glomerular filtration rate (GFR), urinary sodium excretion (U(N) (a) V), urinary output (UV) and fractional sodium excretion were determined, as was expression of the melanocortin MC(3) receptor in inner medullary collecting duct (IMCD) epithelial cells. Both renal and systemic infusion of γ(2) MSH increased MAP by 23 ± 2% and 54 ± 4%, respectively, but equivalent doses of NDP-γ(2) MSH had no significant pressor effects. Both peptides had similar natriuretic and diuretic effects in rats fed a normal salt diet. However, NDP-γ(2) MSH increased U(N) (a) V and UV by two- to threefold in rats fed the normal salt diet and by six- to sevenfold in rats fed the HS diet. Furthermore, NDP-γ(2) MSH induced a 3.5-fold increase in GFR only in rats fed the HS diet. These renal effects of NDP-γ(2) MSH were not abolished by prior renal denervation. Rats fed the HS diet also exhibited a 4.5-fold increase in MC(3) receptor expression in IMCD epithelial cells. Intrarenal infusion of NDP-γ(2) MSH induced the natriuretic but not the cardiovascular effects exhibited by γ(2) MSH. The renal activities may be attributed to a direct binding of NDP-γ(2) MSH to MC(3) receptors expressed in IMCD cells, leading to a potent natriuretic effect that is independent of renal innervation.

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Neuropeptide Y and gamma-melanocyte stimulating hormone (γ-MSH) share a common pressor mechanism of action

Cited by 6 publications

References 67 publications

Physiological roles of the melanocortin MC3 receptor

Physiological roles of the melanocortin MC3 receptor

Development of a Therapeutic Peptide for Cachexia Suggests a Platform Approach for Drug-like Peptides

[Nle³,d‐Phe⁶]‐γ₂‐melanocyte‐stimulating hormone possesses the renal excretory but not the cardiovascular actions of the native γ₂‐melanocyte‐stimulating hormone in anaesthetized rats

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Neuropeptide Y and gamma-melanocyte stimulating hormone (γ-MSH) share a common pressor mechanism of action

Cited by 6 publications

References 67 publications

Physiological roles of the melanocortin MC3 receptor

Physiological roles of the melanocortin MC3 receptor

Development of a Therapeutic Peptide for Cachexia Suggests a Platform Approach for Drug-like Peptides

[Nle3,d‐Phe6]‐γ2‐melanocyte‐stimulating hormone possesses the renal excretory but not the cardiovascular actions of the native γ2‐melanocyte‐stimulating hormone in anaesthetized rats

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[Nle³,d‐Phe⁶]‐γ₂‐melanocyte‐stimulating hormone possesses the renal excretory but not the cardiovascular actions of the native γ₂‐melanocyte‐stimulating hormone in anaesthetized rats