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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.

Abstract：

: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 γ₂-MSH important for MC3R selectivity, we have performed N- and C-terminal truncation studies and pharmacologically characterized twenty-eight ligands at the mouse MC1 and MC3-5 melanocortin receptors. The C-terminal Trp-Asp⁹-Arg¹⁰-Phe¹¹ residues are important for nM potency at the mMC3R and the Arg⁷-Trp⁸ residues are important for mMC5R nM potency. We observed the unanticipated results that several of the C-terminal truncated analogs possessed nM agonist potency at the mMC3 and mMC5Rs which lead us to perform a comparative side-by-side study of the mouse and human MC5R. These data resulted in μM γ₂-MSH analog potency at the hMC5R, consistent with previous reports, however at the mMC5R, nM γ₂-MSH analog 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.

journal_name

Peptides

journal_title

Peptides

authors

Joseph CG,Yao H,Scott JW,Sorensen NB,Marnane RN,Mountjoy KG,Haskell-Luevano C

doi

10.1016/j.peptides.2010.08.025

subject

Has Abstract

pub_date

2010-12-01 00:00:00

pages

2304-13

issue

eissn

0196-9781

issn

1873-5169

pii

S0196-9781(10)00383-9

journal_volume

pub_type

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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.