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Carrie Haskellluevano - One of the best experts on this subject based on the ideXlab platform.
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multiresidue tetrapeptide substitutions yield a 140 fold selective Melanocortin 3 over Melanocortin 4 receptor agonist
ACS Medicinal Chemistry Letters, 2021Co-Authors: Mark D Ericson, Romessa Shaikh, Courtney M Larson, Katie T Freeman, Carrie HaskellluevanoAbstract:The five Melanocortin receptors regulate numerous physiological functions. Although many ligands have been developed for the Melanocortin-4 receptor (MC4R), the Melanocortin-3 receptor (MC3R) has b...
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structure activity relationships of the unique and potent agouti related protein agrp Melanocortin chimeric tyr c β asp his dphe arg trp asn ala phe dpr tyr nh2 peptide template
Journal of Medicinal Chemistry, 2005Co-Authors: Andrzej Wilczynski, Joseph W Scott, Krista R Wilson, And Arthur S Edison, Carrie HaskellluevanoAbstract:The Melanocortin receptor system consists of endogenous agonists, antagonists, G-protein coupled receptors, and auxiliary proteins that are involved in the regulation of complex physiological functions such as energy and weight homeostasis, feeding behavior, inflammation, sexual function, pigmentation, and exocrine gland function. Herein, we report the structure−activity relationship (SAR) of a new chimeric hAGRP−Melanocortin agonist peptide template Tyr-c[β-Asp-His-DPhe-Arg-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH2 that was characterized using amino acids previously reported in other Melanocortin agonist templates. Twenty peptides were examined in this study, and six peptides were selected for 1H NMR and computer-assisted molecular modeling structural analysis. The most notable results include the identification that modification of the chimeric template at the His position with Pro and Phe resulted in ligands that were nM mouse Melanocortin-3 receptor (mMC3R) antagonists and nM mouse Melanocortin-4 receptor (mMC4R) ...
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structure activity relationships of the Melanocortin tetrapeptide ac his dphe arg trp nh2 at the mouse Melanocortin receptors part 3 modifications at the arg position
Peptides, 2003Co-Authors: Jerry Ryan Holder, Rayna M. Bauzo, Zhimin Xiang, Carrie HaskellluevanoAbstract:The Melanocortin pathway is an important participant in obesity and energy homeostasis. The centrally located Melanocortin-3 and Melanocortin-4 receptors (MC3R, MC4R) are involved in the metabolic and food intake aspects of energy homeostasis and are stimulated by Melanocortin agonists such as α-melanocyte stimulation hormone (α-MSH). The Melanocortin agonists contain the putative message sequence “His-Phe-Arg-Trp”, and it has been well documented that inversion of chirality of the Phe to DPhe results in a dramatic increase in Melanocortin receptor potency. Herein, we report a tetrapeptide library based on the template Ac-His-DPhe-Arg-Trp-NH2, consisting of 17 members that have been modified at the His6 position (α-MSH numbering) and pharmacologically characterized for agonist activity at the mouse Melanocortin receptors MC1R, MC3R, MC4R, and MC5R. These studies provide further experimental evidence that the His6 position can determine MC4R versus MC3R agonist selectivity and that chemically nonreactive s...
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structure activity studies of the Melanocortin 4 receptor by in vitro mutagenesis identification of agouti related protein agrp Melanocortin agonist and synthetic peptide antagonist interaction determinants
Biochemistry, 2001Co-Authors: Carrie Haskellluevano, Roger D Cone, Eileen K. MonckAbstract:In vitro mutagenesis of the mouse Melanocortin-4 receptor (mMC4R) has been performed, based upon homology molecular modeling and previous Melanocortin receptor mutagenesis studies that identified putative ligand−receptor interactions. Twenty-three mMC4 receptor mutants were generated and pharmacologically characterized using several Melanocortin-based ligands [α-MSH, NDP-MSH, MTII, dNal (1‘)7-MTII, Nal(2‘)7-MTII, SHU9119, and SHU9005]. Selected mutant receptors possessing significant differences in the Melanocortin-based peptide agonist and/or antagonist pharmacology were further evaluated using the endogenous antagonist agouti-related protein fragment hAGRP(83−132) and hAGRP(109−118) molecules. These studies of the mouse MC4R provide further experimental data suggesting that the conserved Melanocortin receptor residues Glu92 (TM2), Asp114 (TM3), and Asp118 (TM3) (mouse MC4R numbering) are important for Melanocortin-based peptide molecular recognition. Additionally, the Glu92 and Asp118 mMC4R residues are...
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molecular basis for the interaction of nle4 d phe7 melanocyte stimulating hormone with the human Melanocortin 1 receptor melanocyte α msh receptor
Journal of Biological Chemistry, 1997Co-Authors: Yingkui Yang, Chris J. Dickinson, Carrie Haskellluevano, Ira GantzAbstract:Abstract The Melanocortin-1 receptor (MC1R) is a seven-transmembrane (TM) G-protein-coupled receptor whose natural ligands are the Melanocortin peptides, adrenocorticotropic hormone, and α-, β-, and γ- melanocyte stimulating hormone (MSH). To test a previously constructed three-dimensional model of the molecular interaction between the long-acting, superpotent α-MSH analog [Nle4,d-Phe7]MSH (NDP-MSH) and the human MC1R we examined the effects of site-directed receptor mutagenesis on the binding affinity and potency of NDP-MSH. In addition, we also examined the effects of these same mutations on the binding affinity and potency of the structurally related agonists α-MSH, γ-MSH, and Ac-Nle4-cyclic-[Asp5,His6,d-Phe7,Arg8,Trp9,Lys10]NH2(MT-II). Mutagenesis of acidic receptor residues Glu94 in TM2 and Asp117 or Asp121in TM3 significantly altered the binding affinity and potency of all four agonists suggesting that these receptor residues are important to the ligand-receptor interactions of all. A disproportionate change in agonist potency versus affinity observed with simultaneous mutation of these acidic residues (mutant constructs D117A/D121A or E94A/D117A/D121A) or introduction of a single positive charge (mutant construct D121K) also implicates these residues in receptor activation. In addition, results from the individual mutation of aromatic receptor residues Phe175, Phe196, and Phe257, and simultaneous mutation of multiple TM4, -5, and -6 tyrosine and phenylalanine residues suggests that aromatic-aromatic ligand-receptor interactions also participate in binding these Melanocortins to the MC1R. These experiments appear to have identified some of the critical receptor residues involved in the ligand-receptor interactions between these Melanocortins and the hMC1R.
Roger D Cone - One of the best experts on this subject based on the ideXlab platform.
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60 years of pomc regulation of feeding and energy homeostasis by α msh
Journal of Molecular Endocrinology, 2016Co-Authors: Erica J P Anderson, Roger D Cone, Isin Cakir, Sheridan J Carrington, Masoud Ghamarilangroudi, Taneisha Gillyard, Luis E Gimenez, Michael J LittAbstract:The Melanocortin peptides derived from pro-opioMelanocortin (POMC) were originally understood in terms of the biological actions of α-melanocyte-stimulating hormone (α-MSH) on pigmentation and adrenocorticotrophic hormone on adrenocortical glucocorticoid production. However, the discovery of POMC mRNA and Melanocortin peptides in the CNS generated activities directed at understanding the direct biological actions of Melanocortins in the brain. Ultimately, discovery of unique Melanocortin receptors expressed in the CNS, the Melanocortin-3 (MC3R) and Melanocortin-4 (MC4R) receptors, led to the development of pharmacological tools and genetic models leading to the demonstration that the central Melanocortin system plays a critical role in the regulation of energy homeostasis. Indeed, mutations in MC4R are now known to be the most common cause of early onset syndromic obesity, accounting for 2–5% of all cases. This review discusses the history of these discoveries, as well as the latest work attempting to understand the molecular and cellular basis of regulation of feeding and energy homeostasis by the predominant Melanocortin peptide in the CNS, α-MSH.
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Neuropeptide Y and gamma-melanocyte stimulating hormone (γ-MSH) share a common pressor mechanism of action
Endocrine, 2009Co-Authors: Kenneth A. Gruber, Wei Fan, Helena Akerberg, Dan Larhammar, Melissa J. S. Chee, William F. Colmers, Roger D ConeAbstract:Central circuits known to regulate food intake and energy expenditure also affect central cardiovascular regulation. For example, both the Melanocortin and neuropeptide Y (NPY) peptide families, known to regulate food intake, also produce central hypertensive effects. Members of both families share a similar C-terminal amino acid residue sequence, RF(Y) amide, a sequence distinct from that required for Melanocortin receptor binding. A recently delineated family of RFamide receptors recognizes both of these C-terminal motifs. We now present evidence that an antagonist with Y1 and RFamide receptor activity, BIBO3304, will attenuate the central cardiovascular effects of both gamma-melanocyte stimulating hormone (γ-MSH) and NPY. The use of synthetic Melanocortin and NPY peptide analogs excluded an interaction with Melanocortin or Y family receptors. We suggest that the anatomical convergence of NPY and Melanocortin neurons on cardiovascular control centers may have pathophysiological implications through a common or similar RFamide receptor(s), much as they converge on other nuclei to coordinately control energy homeostasis.
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conserved neurochemical pathways involved in hypothalamic control of energy homeostasis
The Journal of Comparative Neurology, 2007Co-Authors: Paul M Forlano, Roger D ConeAbstract:The Melanocortin system, which includes -melanocyte-stimulating hormone (-MSH) and its endogenous antagonist, agouti-related protein (AgRP), is fundamental for the central control of energy homeostasis in mammals. Recent studies have demonstrated that many neuropeptides involved in the control of ingestive behavior and energy expenditure, including Melanocortins, are also expressed and functional in teleost fishes. To test the hypothesis that the underlying neural pathways involved in energy homeostasis are conserved throughout vertebrate evolution, the neuroanatomical distribution of -MSH in relation to AgRP was mapped in a teleost (zebrafish, Danio rerio) by double-label immunocytochemistry. Zebrafish -MSH- and AgRP-immunoreactive (ir) cells are found in discrete populations in the ventral periventricular hypothalamus, the proposed arcuate homologue in teleosts. Major ascending projections are similar for both peptides, and dense ir-fibers innervate preoptic and ventral telencephalic nuclei homologous to paraventricular, lateral septal, and amygdala nuclei in mammals. Furthermore, -MSH and AgRP-ir somata and fibers are pronounced at 5 days post fertilization when yolk reserves are depleted and larvae begin to feed actively, which supports the functional significance of these peptides for feeding behavior. The conservation of Melanocortin peptide function and projection pathways further support zebrafish as an excellent genetic model system to investigate basic mechanisms involved in the central regulation of energy homeostasis. J. Comp. Neurol. 505:235–248, 2007. © 2007 Wiley-Liss, Inc.
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studies on the physiological functions of the Melanocortin system
Endocrine Reviews, 2006Co-Authors: Roger D ConeAbstract:The Melanocortin system refers to a set of hormonal, neuropeptidergic, and paracrine signaling pathways that are defined by components that include the five G protein-coupled Melanocortin receptors; peptide agonists derived from the proopioMelanocortin preprohormone precursor; and the endogenous antagonists, agouti and agouti-related protein. This signaling system regulates a remarkably diverse array of physiological functions including pigmentation, adrenocortical steroidogenesis, energy homeostasis, natriuresis, erectile responses, energy homeostasis, and exocrine gland secretion. There are many complex and unique aspects of Melanocortin signaling, such as the existence of endogenous antagonists, the agouti proteins, that act at three of the five Melanocortin receptors. However, there is an aspect of Melanocortin signaling that has facilitated highly reductionist approaches aimed at understanding the physiological functions of each receptor and peptide: in contrast to many peptides, the Melanocortin ago...
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a role for the endogenous opioid β endorphin in energy homeostasis
Endocrinology, 2003Co-Authors: Suzanne M Appleyard, Roger D Cone, Michael D Hayward, Juan I Young, Andrew A Butler, Marcelo Rubinstein, Malcolm J LowAbstract:ProopioMelanocortin (POMC) neurons in the hypothalamus are direct targets of the adipostatic hormone leptin and contribute to energy homeostasis by integrating peripheral and central information. The Melanocortin and beta-endorphin neuropeptides are processed from POMC and putatively coreleased at axon terminals. Melanocortins have been shown by a combination of pharmacological and genetic methods to have inhibitory effects on appetite and body weight. In contrast, pharmacological studies have generally indicated that opioids stimulate food intake. Here we report that male mice engineered to selectively lack beta-endorphin, but that retained normal Melanocortin signaling, were hyperphagic and obese. Furthermore, beta-endorphin mutant and wild-type mice had identical orexigenic responses to exogenous opioids and identical anorectic responses to the nonselective opioid antagonist naloxone, implicating an alternative endogenous opioid tone to beta-endorphin that physiologically stimulates feeding. These genetic data indicate that beta-endorphin is required for normal regulation of feeding, but, in contrast to earlier reports suggesting opposing actions of beta-endorphin and Melanocortins on appetite, our results suggest a more complementary interaction between the endogenously released POMC-derived peptides in the regulation of energy homeostasis.
Ronald Harning - One of the best experts on this subject based on the ideXlab platform.
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original research women s sexual health an effect on the subjective sexual response in premenopausal women with sexual arousal disorder by bremelanotide pt 141 a Melanocortin receptor agonist
The Journal of Sexual Medicine, 2006Co-Authors: Lisa E. Diamond, Raymond C. Rosen, Julia R. Heiman, Michael A. Perelman, Dennis Earle, Ronald HarningAbstract:ABSTRACT Introduction Melanocortins affect multiple physiological responses, including sexual behaviors. Bremelanotide is a synthetic peptide Melanocortin analog of α‐melanocyte‐stimulating hormone that is an agonist at Melanocortin receptors MC3R and MC4R. Aim To evaluate a single intranasal dose of bremelanotide for potential effects on physiological and subjective measurements of sexual arousal and desire in premenopausal women with sexual arousal disorder. Main Outcome Measures Change in vaginal pulse amplitude during neutral and erotic videos after treatment with bremelanotide or placebo and subjects’ perceptions of physiological and sexual response within 24 hours of treatment with bremelanotide or placebo. Methods Eighteen premenopausal women with a primary diagnosis of female sexual arousal disorder were randomly assigned to receive a single intranasal dose of 20 mg bremelanotide or matching placebo in a double‐blind manner during the first in‐clinic treatment session, and the alternate medication during the second in‐clinic treatment session. During each session, subjects viewed a 20‐minute neutral video followed by a 20‐minute sexually explicit video. Vaginal photoplethysmography was used to monitor vaginal vasocongestion and questionnaires were used to evaluate perceptions of sexual response within the following 24‐hour period. Results More women reported moderate or high sexual desire following bremelanotide treatment vs. placebo ( P = 0.0114), and a trend toward more positive responses regarding feelings of genital arousal occurred after bremelanotide compared with placebo ( P = 0.0833). Among women who attempted sexual intercourse within 24 hours after treatment, significantly more were satisfied with their level of sexual arousal following bremelanotide, compared with placebo ( P = 0.0256). Vaginal vasocongestion did not change significantly while viewing erotic videos following bremelanotide administration compared with placebo. Conclusion This preliminary evaluation suggests the potential for bremelanotide to positively affect desire and arousal in women with female sexual arousal disorder and indicates that bremelanotide is a promising candidate for further evaluation in an at‐home study. Diamond LE, Earle DC, Heiman JR, Rosen RC, Perelman MA, and Harning R. An effect on the subjective sexual response in premenopausal women with sexual arousal disorder by bremelanotide (PT‐141), a Melanocortin receptor agonist. J Sex Med 2006;3:628–638.
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original research women s sexual healthoriginal research women s sexual health an effect on the subjective sexual response in premenopausal women with sexual arousal disorder by bremelanotide pt 141 a Melanocortin receptor agonist
The Journal of Sexual Medicine, 2006Co-Authors: Lisa E. Diamond, Raymond C. Rosen, Julia R. Heiman, Michael A. Perelman, Dennis Earle, Ronald HarningAbstract:Introduction Melanocortins affect multiple physiological responses, including sexual behaviors. Bremelanotide is a synthetic peptide Melanocortin analog of α‐melanocyte‐stimulating hormone that is an agonist at Melanocortin receptors MC3R and MC4R.
Ana Luisa Kadekaro - One of the best experts on this subject based on the ideXlab platform.
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Melanocortin 1 receptor genotype an important determinant of the damage response of melanocytes to ultraviolet radiation
The FASEB Journal, 2010Co-Authors: Ana Luisa Kadekaro, Sancy A Leachman, Renny Kavanagh, Pamela B Cassidy, Sandy Schwemberger, George F. Babcock, Maureen A. Sartor, Viki B. Swope, Dorothy M. Supp, Kazumasa WakamatsuAbstract:The Melanocortin 1 receptor gene is a main determinant of human pigmentation, and a melanoma susceptibility gene, because its variants that are strongly associated with red hair color increase melanoma risk. To test experimentally the association between Melanocortin 1 receptor genotype and melanoma susceptibility, we compared the responses of primary human melanocyte cultures naturally expressing different Melanocortin 1 receptor variants to α-Melanocortin and ultraviolet radiation. We found that expression of 2 red hair variants abolished the response to α-Melanocortin and its photoprotective effects, evidenced by lack of functional coupling of the receptor, and absence of reduction in ultraviolet radiation-induced hydrogen peroxide generation or enhancement of repair of DNA photoproducts, respectively. These variants had different heterozygous effects on receptor function. Microarray data confirmed the observed differences in responses of melanocytes with functional vs. nonfunctional receptor to α-Melanocortin and ultraviolet radiation, and identified DNA repair and antioxidant genes that are modulated by α-Melanocortin. Our findings highlight the molecular mechanisms by which the Melanocortin 1 receptor genotype controls genomic stability of and the mutagenic effect of ultraviolet radiation on human melanocytes.—Kadekaro, A. L., Leachman, S., Kavanagh, R. J., Swope, V., Cassidy, P., Supp, D., Sartor, M., Schwemberger, S., Babcock, G., Wakamatsu, K., Ito, S., Koshoffer, A., Boissy, R. E., Manga, P., Sturm, R. A., Abdel-Malek, Z. A. Melanocortin 1 receptor genotype: an important determinant of the damage response of melanocytes to ultraviolet radiation.
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Melanocortin 1 receptor genotype an important determinant of the damage response of melanocytes to ultraviolet radiation
The FASEB Journal, 2010Co-Authors: Ana Luisa Kadekaro, Sancy A Leachman, Renny Kavanagh, Pamela B Cassidy, Sandy Schwemberger, George F. Babcock, Maureen A. Sartor, Viki B. Swope, Dorothy M. Supp, Kazumasa WakamatsuAbstract:The Melanocortin 1 receptor gene is a main determinant of human pigmentation, and a melanoma susceptibility gene, because its variants that are strongly associated with red hair color increase melanoma risk. To test experimentally the association between Melanocortin 1 receptor genotype and melanoma susceptibility, we compared the responses of primary human melanocyte cultures naturally expressing different Melanocortin 1 receptor variants to α-Melanocortin and ultraviolet radiation. We found that expression of 2 red hair variants abolished the response to α-Melanocortin and its photoprotective effects, evidenced by lack of functional coupling of the receptor, and absence of reduction in ultraviolet radiation-induced hydrogen peroxide generation or enhancement of repair of DNA photoproducts, respectively. These variants had different heterozygous effects on receptor function. Microarray data confirmed the observed differences in responses of melanocytes with functional vs. nonfunctional receptor to α-Melanocortin and ultraviolet radiation, and identified DNA repair and antioxidant genes that are modulated by α-Melanocortin. Our findings highlight the molecular mechanisms by which the Melanocortin 1 receptor genotype controls genomic stability of and the mutagenic effect of ultraviolet radiation on human melanocytes.—Kadekaro, A. L., Leachman, S., Kavanagh, R. J., Swope, V., Cassidy, P., Supp, D., Sartor, M., Schwemberger, S., Babcock, G., Wakamatsu, K., Ito, S., Koshoffer, A., Boissy, R. E., Manga, P., Sturm, R. A., Abdel-Malek, Z. A. Melanocortin 1 receptor genotype: an important determinant of the damage response of melanocytes to ultraviolet radiation.
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the Melanocortin 1 receptor and the uv response of human melanocytes a shift in paradigm
Photochemistry and Photobiology, 2008Co-Authors: Zalfa A Abdelmalek, Ana Luisa Kadekaro, Viki B. Swope, James J Knittel, Renny J StarnerAbstract:Cutaneous pigmentation is the major photoprotective mechanism against the carcinogenic and aging effects of UV. Epidermal melanocytes synthesize the pigment melanin, in the form of eumelanin or pheomelanin. Synthesis of the photoprotective eumelanin by human melanocytes is regulated mainly by the Melanocortins α-Melanocortin (α-MSH) and adrenocorticotropic hormone (ACTH), which bind the Melanocortin 1 receptor (MC1R) and activate the cAMP pathway that is required for UV-induced tanning. Melanocortins stimulate proliferation and melanogenesis and inhibit UV-induced apoptosis of human melanocytes. Importantly, Melanocortins reduce the generation of hydrogen peroxide and enhance repair of DNA photoproducts, independently of pigmentation. MC1R is a major contributor to the diversity of human pigmentation and a melanoma susceptibility gene. Certain allelic variants of this gene, namely R151C, R160W and D294H, are strongly associated with red hair phenotype and increased melanoma susceptibility. Natural expression of two of these variants sensitizes melanocytes to the cytotoxic effect of UV, and increases the burden of DNA damage and oxidative stress. We are designing potent Melanocortin analogs that mimic the effects of α-MSH as a strategy to prevent skin cancer, particularly in individuals who express MC1R genotypes that reduce but do not abolish MC1R function, or mutations in other melanoma susceptibility genes, such as p16.
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mc1r and the response of melanocytes to ultraviolet radiation
Mutation Research, 2005Co-Authors: Francois Rouzaud, Ana Luisa Kadekaro, Zalfa A Abdelmalek, Vincent J HearingAbstract:Abstract The constitutive color of our skin plays a dramatic role in our photoprotection from solar ultraviolet radiation (UVR) that reaches the Earth and in minimizing DNA damage that gives rise to skin cancer. More than 120 genes have been identified and shown to regulate pigmentation, one of the key genes being Melanocortin 1 receptor ( MC1R ) that encodes the Melanocortin 1 receptor (MC1R), a seven-transmembrane G protein-coupled receptor expressed on the surface of melanocytes. Modulation of MC1R function regulates melanin synthesis by melanocytes qualitatively and quantitatively. The MC1R is regulated by the physiological agonists α-melanocyte-stimulating hormone (αMSH) and adrenocorticotropic hormone (ACTH), and antagonist agouti signaling protein (ASP). Activation of the MC1R by binding of an agonist stimulates the synthesis of eumelanin primarily via activation of adenylate cyclase. The significance of cutaneous pigmentation lies in the photoprotective effect of melanin, particularly eumelanin, against sun-induced carcinogenesis. Epidermal melanocytes and keratinocytes respond to UVR by increasing their expression of αMSH and ACTH, which up-regulate the expression of MC1R, and consequently enhance the response of melanocytes to Melanocortins. Constitutive skin pigmentation dramatically affects the incidence of skin cancer. The pigmentary phenotype characterized by red hair, fair complexion, inability to tan and tendency to freckle is an independent risk factor for all skin cancers, including melanoma. The MC1R gene is highly polymorphic in human populations, and allelic variation at this locus accounts, to a large extent, for the variation in pigmentary phenotypes and skin phototypes (SPT) in humans. Several allelic variants of the MC1R gene are associated with the red hair and fair skin (RHC) phenotype, and carrying one of these variants is thought to diminish the ability of the epidermis to respond to DNA damage elicited by UVR. The MC1R gene is considered a melanoma susceptibility gene, and its significance in determining the risk for skin cancer is of tremendous interest.
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significance of the Melanocortin 1 receptor in regulating human melanocyte pigmentation proliferation and survival
Annals of the New York Academy of Sciences, 2003Co-Authors: Ana Luisa Kadekaro, Renny Kavanagh, Hiromi Kanto, Zalfa A AbdelmalekAbstract:: The characterization of the Melanocortin 1 receptor (MC1R) expressed on human melanocytes and the findings that certain mutations in the POMC gene or the MC1R gene result in red hair phenotype underscore the significance of Melanocortins and MC1R in regulating human pigmentation. We demonstrated that human melanocytes respond to alpha-Melanocortin (alpha-MSH) or ACTH with increased proliferation and melanogenesis, and to agouti signaling protein by abrogation of these effects. alpha-MSH and ACTH were equipotent and more potent than beta-MSH, and gamma-MSH was the least potent in activating the MC1R and stimulating melanogenesis and proliferation of human melanocytes. We characterized the MC1R genotype in a panel of human melanocyte cultures and identified three cultures that were homozygous for Arg160Trp, heterozygous for Arg151Cys and Asp294His, and heterozygous for Arg160Trp and Asp294His substitutions, respectively. Those cultures failed to respond to alpha-MSH with increase in cAMP levels, tyrosinase activity, or proliferation and had an exaggerated response to the cytotoxic effect of ultraviolet (UV) radiation. These loss-of-function mutations have been associated with red hair phenotype and increased risk for skin cancer. Melanocytes homozygous for Val29Met substitution in MC1R responded normally to alpha-MSH and UVB, suggesting that this variant is a polymorphism. We observed that alpha-MSH promotes human melanocyte survival by inhibiting the UV-induced apoptosis independently of melanin synthesis. This effect was absent in human melanocytes with loss of function MC1R mutations. We predict that the survival effect of alpha-MSH is caused by reduction of UV-induced DNA damage and contributes to the prevention of melanoma.
Lisa E. Diamond - One of the best experts on this subject based on the ideXlab platform.
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original research women s sexual health an effect on the subjective sexual response in premenopausal women with sexual arousal disorder by bremelanotide pt 141 a Melanocortin receptor agonist
The Journal of Sexual Medicine, 2006Co-Authors: Lisa E. Diamond, Raymond C. Rosen, Julia R. Heiman, Michael A. Perelman, Dennis Earle, Ronald HarningAbstract:ABSTRACT Introduction Melanocortins affect multiple physiological responses, including sexual behaviors. Bremelanotide is a synthetic peptide Melanocortin analog of α‐melanocyte‐stimulating hormone that is an agonist at Melanocortin receptors MC3R and MC4R. Aim To evaluate a single intranasal dose of bremelanotide for potential effects on physiological and subjective measurements of sexual arousal and desire in premenopausal women with sexual arousal disorder. Main Outcome Measures Change in vaginal pulse amplitude during neutral and erotic videos after treatment with bremelanotide or placebo and subjects’ perceptions of physiological and sexual response within 24 hours of treatment with bremelanotide or placebo. Methods Eighteen premenopausal women with a primary diagnosis of female sexual arousal disorder were randomly assigned to receive a single intranasal dose of 20 mg bremelanotide or matching placebo in a double‐blind manner during the first in‐clinic treatment session, and the alternate medication during the second in‐clinic treatment session. During each session, subjects viewed a 20‐minute neutral video followed by a 20‐minute sexually explicit video. Vaginal photoplethysmography was used to monitor vaginal vasocongestion and questionnaires were used to evaluate perceptions of sexual response within the following 24‐hour period. Results More women reported moderate or high sexual desire following bremelanotide treatment vs. placebo ( P = 0.0114), and a trend toward more positive responses regarding feelings of genital arousal occurred after bremelanotide compared with placebo ( P = 0.0833). Among women who attempted sexual intercourse within 24 hours after treatment, significantly more were satisfied with their level of sexual arousal following bremelanotide, compared with placebo ( P = 0.0256). Vaginal vasocongestion did not change significantly while viewing erotic videos following bremelanotide administration compared with placebo. Conclusion This preliminary evaluation suggests the potential for bremelanotide to positively affect desire and arousal in women with female sexual arousal disorder and indicates that bremelanotide is a promising candidate for further evaluation in an at‐home study. Diamond LE, Earle DC, Heiman JR, Rosen RC, Perelman MA, and Harning R. An effect on the subjective sexual response in premenopausal women with sexual arousal disorder by bremelanotide (PT‐141), a Melanocortin receptor agonist. J Sex Med 2006;3:628–638.
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original research women s sexual healthoriginal research women s sexual health an effect on the subjective sexual response in premenopausal women with sexual arousal disorder by bremelanotide pt 141 a Melanocortin receptor agonist
The Journal of Sexual Medicine, 2006Co-Authors: Lisa E. Diamond, Raymond C. Rosen, Julia R. Heiman, Michael A. Perelman, Dennis Earle, Ronald HarningAbstract:Introduction Melanocortins affect multiple physiological responses, including sexual behaviors. Bremelanotide is a synthetic peptide Melanocortin analog of α‐melanocyte‐stimulating hormone that is an agonist at Melanocortin receptors MC3R and MC4R.
