Potent and selective agonists of α-melanotropin (αMSH) action at human melanocortin receptor 5; linear analogs of α-melanotropin

Bednarek, Maria A.; MacNeil, Tanya; Tang, Rui; Fong, Tung M.; Cabello, M. Angeles; Maroto, Miguel; Teran, Ana

doi:10.1016/j.peptides.2007.02.011

Cited by 12 publications

(20 citation statements)

References 27 publications

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“…The analysis of ERK1/2 phosphorylation by western-blotting revealed that it was dose-dependent with an EC50 of 7.3nM, in agreement with published data for hMC5R-stimulated cAMP production (Bednarek et al, 2007). The maximum ERK1/2 activation was obtained with 1μM α-MSH, with an increase of around 8-fold above the basal levels.…”

Section: Activation Of Erk1/2 In Stably Mc5r-gfp Transfected Hek293 Csupporting

confidence: 89%

Melanocortin 5 receptor activates ERK1/2 through a PI3K-regulated signaling mechanism

Rodrigues

Pignatelli

Almeida

et al. 2009

Molecular and Cellular Endocrinology

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receptor activates ERK1/2 through a PI3K-regulated signaling mechanism. Molecular and Cellular Endocrinology, Elsevier, 2009, 303 (1-2) 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 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. A c c e p t e d M a n u s c r i p t SummaryMelanocortin 5 receptor (MC5R) is a G-protein coupled receptor (GPCR) with high affinity for α-MSH. To unravel some of the downstream cell-signaling pathways activated by this receptor, HEK293 cells were transiently and stably transfected with a vector encoding green fluorescent protein (GFP)-tagged MC5R. In these cells the receptor was correctly addressed to the cell surface and was functional, as shown by the MC5R-induced formation of intracellular cAMP. In fact, the MC5R agonist α-MSH induced a 10 or 16 fold increase (transient or stable cells, respectively) above the cAMP levels found in unstimulated cells. Moreover, in cells stably expressing MC5R-GFP, α-MSH promoted ERK1/2 phosphorylation in a dose-dependent manner (EC50=7.3nM) with the maximal effect occurring after 5min of agonist incubation. The signaling pathway conveyed through ERK1/2 is not linked to cAMP, since the phosphorylation of these kinases is unchanged by the inhibition of adenylyl cyclase. Also, ERK1/2 activation is not significantly affected by PKA, PKC and Akt/PKB specific inhibitors. However, α-MSH-induced ERK1/2 activation is abolished by the PI3K inhibitors wortmannin and LY294002. Altogether, these findings demonstrate that MC5R signals through a PI3K-regulated Akt-independent pathway leading to downstream activation of ERK1/2. The involvement of these MAPK suggests that MC5R could be implicated in cellular proliferation or differentiation mechanisms.

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Section: Activation Of Erk1/2 In Stably Mc5r-gfp Transfected Hek293 Csupporting

confidence: 89%

Melanocortin 5 receptor activates ERK1/2 through a PI3K-regulated signaling mechanism

Rodrigues

Pignatelli

Almeida

et al. 2009

Molecular and Cellular Endocrinology

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“…Cells transfected with hMCRs or HA-hCL were washed once with PBS and then incubated for 1 h with increasing concentrations of either ACTH 1-24 , ACTH 1-39 , a-MSH or a-CGRP at 37 8C under 5% CO 2 . NDP-a-MSH was used to stimulate the hMC5R as the physiological agonist for this receptor has not been characterised (Bednarek et al 2007). HA-hD2R transfected cells were washed once with PBS and incubated in DMEM without serum for 20 min and then incubated with 10 mM forskolin (Sigma-Aldrich) and increasing concentrations of quinpirole at 37 8C under 5% CO 2 .…”

Section: Measurement Of Adenylyl Cyclase Activitymentioning

confidence: 99%

hMRAPa increases αMSH-induced hMC1R and hMC3R functional coupling and hMC4R constitutive activity

Kay

Botha

Montgomery

et al. 2013

Journal of Molecular Endocrinology

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Human melanocortin 2 receptor accessory protein (hMRAPa) is hypothesised to have functions beyond promoting human melanocortin 2 receptor (hMC2R) functional expression. To understand these potential functions, we exogenously co-expressed hMRAPa-FLAG with each of the five hMCR subtypes in HEK293 cells and assessed hMCR subtype coupling to adenylyl cyclase. We also co-expressed each HA-hMCR subtype with hMRAPa-FLAG to investigate their subcellular localisation. hMRAPa-FLAG enhanced a-melanocyte stimulating hormone (a-MSH)-stimulated hMC1R and hMC3R but reduced NDP-a-MSH-stimulated hMC5R, maximum coupling to adenylyl cyclase. hMRAPa-FLAG specifically increased hMC4R constitutive coupling to adenylyl cyclase despite not co-localising with the HA-hMC4R in the cell membrane. hMRAPa-FLAG co-localised with HA-hMC1R or HA-hMC3R in the perinuclear region, in cytoplasmic vesicles and at the plasma membrane, while it co-localised with HA-hMC2R, HA-hMC4R and HA-hMC5R predominantly in cytoplasmic vesicles. These diverse effects of hMRAPa indicate that hMRAPa could be an important modulator of the central and peripheral melanocortin systems if hMRAPa and any hMCR subtype co-express in the same cell. Key Words" GPCR accessory protein " constitutive activity " subcellular localisation " melanocortin 4 receptor

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“…Hence, these observations indicated that Trp 9 is not required for efficient interactions of NDP-aMSH with hMC1bR, but is necessary for molecular recognition at hMC3-5R. These observations also suggested that the His 17,18,28 that, for example, the side chains in positions 4 and 5, which are N-terminal to the essential core of NDP-aMSH and MTII, are essential to high agonist potency at hMC5R. Among the analogs of NDP-aMSH tested in this study, Ava 9-10 -NDP-aMSH (15) and desTrp 9 -NDP-aMSH (18) emerged as the full, high potency agonists at hMC1bR which were not able to activate the hMC3-5R even at micromolar concentrations.…”

mentioning

confidence: 88%

“…Several analogs of the endogenous ligand, aMSH (26), with modified position 9 were also evaluated at hMC1b,3-5R (27)(28)(29)(30). Compounds 27 and 28 were less potent at hMC1bR than their NDP-aMSH counterparts (8,9).…”

Section: Analogs Of Amsh (26) and Ndp-amsh (1) Listed Inmentioning

confidence: 99%

“…For example, Pro 9 -aMSH (27) was a weak agonist at hMC1bR (EC 50 about 1 lM) which was unable to activate the hMC3-5R even at micromolar peptide concentrations. Another analog of aMSH (28), that with the slightly larger, 6-membered ring of Pip in position 9, was 10-fold more potent at hMC1bR than the Pro 9 peptide (27) and was also practically inactive at the counter screened receptors, hMC3-5R. In the subsequent two -aMSH (30) displayed higher agonist potency at hMC1bR (EC 50 about 50 nM and EC 50 about 5.6 nM, respectively) than compound 28, Pip 9 -aMSH, EC 50 5 91 nM, and similarly, were unable to interact efficiently with hMC3-5R.…”

Section: Analogs Of Amsh (26) and Ndp-amsh (1) Listed Inmentioning

confidence: 99%

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Analogs of α‐melanocyte stimulating hormone with high agonist potency and selectivity at human melanocortin receptor 1b: The role of Trp⁹ in molecular recognition

et al. 2007

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Every week for a half an hour, however, he gave undivided attention to each member of his laboratory, his postdoctoral students and visiting scientists. We all looked forward to those brief but so rewarding interactions. He expected us to be independent scientists, concise and clear about what we wanted to accomplish. He discussed our efforts and judgments, provided criticism and reassurance. And all the time we were absolutely in awe of this brilliant scientist, teacher, mentor, manager, statesman and businessman. He was our rock, always calm, friendly, and kind. We felt very fortunate to be part of ERB's world, participate in his research endeavors, and observe his extraordinary interactions with scientists, managers, business people and politicians. It was certainly a unique experience reaching far beyond the typical postdoctoral training. I treasure memories of Dr. Elkan R. Blout from the lab at Harvard Medical School. Equally warmly, I treasure memories of ERB and his family from the lab gatherings at the Harvard and Commonwealth Clubs or at his house.

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Potent and selective agonists of α-melanotropin (αMSH) action at human melanocortin receptor 5; linear analogs of α-melanotropin

Cited by 12 publications

References 27 publications

Melanocortin 5 receptor activates ERK1/2 through a PI3K-regulated signaling mechanism

Melanocortin 5 receptor activates ERK1/2 through a PI3K-regulated signaling mechanism

hMRAPa increases αMSH-induced hMC1R and hMC3R functional coupling and hMC4R constitutive activity

Analogs of α‐melanocyte stimulating hormone with high agonist potency and selectivity at human melanocortin receptor 1b: The role of Trp⁹ in molecular recognition

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Potent and selective agonists of α-melanotropin (αMSH) action at human melanocortin receptor 5; linear analogs of α-melanotropin

Cited by 12 publications

References 27 publications

Melanocortin 5 receptor activates ERK1/2 through a PI3K-regulated signaling mechanism

Melanocortin 5 receptor activates ERK1/2 through a PI3K-regulated signaling mechanism

hMRAPa increases αMSH-induced hMC1R and hMC3R functional coupling and hMC4R constitutive activity

Analogs of α‐melanocyte stimulating hormone with high agonist potency and selectivity at human melanocortin receptor 1b: The role of Trp9 in molecular recognition

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Analogs of α‐melanocyte stimulating hormone with high agonist potency and selectivity at human melanocortin receptor 1b: The role of Trp⁹ in molecular recognition