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Targeting central melanocortin receptors: a promising novel approach for treating alcohol abuse disorders.

Olney JJ, Navarro M, Thiele TE - Front Neurosci (2014)

Bottom Line: The MC3R and MC4R subtypes, the most abundant central MCRs, are widely expressed in brain regions known to modulate neurobiological responses to ethanol, including regions of the hypothalamus and extended amygdala.Agouti-related protein (AgRP), also produced in the arcuate nucleus, is secreted in terminals expressing MCRs and functions as an endogenous MCR antagonist.Ethanol consumption is associated with significant alterations in the expression levels of various MC peptides/protein, which suggests that ethanol-induced perturbations of MC/AgRP signaling may modulate excessive ethanol intake.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychology, University of North Carolina Chapel Hill, NC, USA.

ABSTRACT
The melanocortin (MC) peptides are produced centrally by propiomelanocortin (POMC) neurons within the arcuate nucleus of the hypothalamus and act through five seven-transmembrane G-protein coupled melanocortin receptor (MCR) subtypes. The MC3R and MC4R subtypes, the most abundant central MCRs, are widely expressed in brain regions known to modulate neurobiological responses to ethanol, including regions of the hypothalamus and extended amygdala. Agouti-related protein (AgRP), also produced in the arcuate nucleus, is secreted in terminals expressing MCRs and functions as an endogenous MCR antagonist. This review highlights recent genetic and pharmacological findings that have implicated roles for the MC and AgRP systems in modulating ethanol consumption. Ethanol consumption is associated with significant alterations in the expression levels of various MC peptides/protein, which suggests that ethanol-induced perturbations of MC/AgRP signaling may modulate excessive ethanol intake. Consistently, MCR agonists decrease, and AgRP increases, ethanol consumption in mice. MCR agonists fail to blunt ethanol intake in mutant mice lacking the MC4R, suggesting that the protective effects of MCR agonists are modulated by the MC4R. Interestingly, recent evidence reveals that MCR agonists are more effective at blunting binge-like ethanol intake in mutant mice lacking the MC3R, suggesting that the MC3R has opposing effects on the MC4R. Finally, mutant mice lacking AgRP exhibit blunted voluntary and binge-like ethanol drinking, consistent with pharmacological studies. Collectively, these preclinical observations provide compelling evidence that compounds that target the MC system may provide therapeutic value for treating alcohol abuse disorders and that the utilization of currently available MC-targeting compounds- such as those being used to treat eating disorders- may be used as effective treatments to this end.

No MeSH data available.


Related in: MedlinePlus

Melanocortin ligands and receptors. (A) Simplified model of posttranslational processing of POMC. Agonists that act at MCR1-5 are highlighted black. (B) These ligands exert their effects via five G-protein coupled receptors, differentially expressed throughout the body, with varying degrees of potency. ACTH, adrenocorticotropic hormone; CLIP, corticotrophin-like intermediate lobe peptide; CPE, carboxypeptidase E; JP, junctional peptide; LPH, lipotropic hormone; N-POC, N-pro-opiocortin; MC, melanocortin; MSH, melanocyte stimulating hormone; PC, prohormone convertase; POMC, proopiomelanocortin.
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Figure 1: Melanocortin ligands and receptors. (A) Simplified model of posttranslational processing of POMC. Agonists that act at MCR1-5 are highlighted black. (B) These ligands exert their effects via five G-protein coupled receptors, differentially expressed throughout the body, with varying degrees of potency. ACTH, adrenocorticotropic hormone; CLIP, corticotrophin-like intermediate lobe peptide; CPE, carboxypeptidase E; JP, junctional peptide; LPH, lipotropic hormone; N-POC, N-pro-opiocortin; MC, melanocortin; MSH, melanocyte stimulating hormone; PC, prohormone convertase; POMC, proopiomelanocortin.

Mentions: Post-translational processing of the prohormone, proopiomelanocortin (POMC), involves cleavage by two prohormone convertases, PC1/3 and PC2, that yield two different classes of peptides, melanocortins (MCs) and the opioid β-endorphin- hence the term pro-opio-melanocortin. Of the MC family, POMC cleavage leads to several peptides including: α-, β-, and γ-melanocyte stimulating hormone (MSH) as well as adrenocorticotrophic hormone (ACTH), which all share the same core amino acid sequence, His-Phe-Arg-Trp, that is required for the biological activity of these peptides. POMC is primarily expressed within the central nervous system (CNS) within the nucleus of the solitary tract (NST) of the brainstem, the arcuate nucleus of the hypothalamus (Arc), and the pituitary (Joseph et al., 1983; Hadley and Haskell-Luevano, 1999). Peripheral expression of POMC has also been observed in the skin, spleen, thyroid, and the gastrointestinal tract (Smith and Funder, 1988). The post-translational processing of POMC is tissue specific (Pritchard et al., 2002), which allows a multitude of peptides to be derived from a single prohormone (Figure 1).


Targeting central melanocortin receptors: a promising novel approach for treating alcohol abuse disorders.

Olney JJ, Navarro M, Thiele TE - Front Neurosci (2014)

Melanocortin ligands and receptors. (A) Simplified model of posttranslational processing of POMC. Agonists that act at MCR1-5 are highlighted black. (B) These ligands exert their effects via five G-protein coupled receptors, differentially expressed throughout the body, with varying degrees of potency. ACTH, adrenocorticotropic hormone; CLIP, corticotrophin-like intermediate lobe peptide; CPE, carboxypeptidase E; JP, junctional peptide; LPH, lipotropic hormone; N-POC, N-pro-opiocortin; MC, melanocortin; MSH, melanocyte stimulating hormone; PC, prohormone convertase; POMC, proopiomelanocortin.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4042890&req=5

Figure 1: Melanocortin ligands and receptors. (A) Simplified model of posttranslational processing of POMC. Agonists that act at MCR1-5 are highlighted black. (B) These ligands exert their effects via five G-protein coupled receptors, differentially expressed throughout the body, with varying degrees of potency. ACTH, adrenocorticotropic hormone; CLIP, corticotrophin-like intermediate lobe peptide; CPE, carboxypeptidase E; JP, junctional peptide; LPH, lipotropic hormone; N-POC, N-pro-opiocortin; MC, melanocortin; MSH, melanocyte stimulating hormone; PC, prohormone convertase; POMC, proopiomelanocortin.
Mentions: Post-translational processing of the prohormone, proopiomelanocortin (POMC), involves cleavage by two prohormone convertases, PC1/3 and PC2, that yield two different classes of peptides, melanocortins (MCs) and the opioid β-endorphin- hence the term pro-opio-melanocortin. Of the MC family, POMC cleavage leads to several peptides including: α-, β-, and γ-melanocyte stimulating hormone (MSH) as well as adrenocorticotrophic hormone (ACTH), which all share the same core amino acid sequence, His-Phe-Arg-Trp, that is required for the biological activity of these peptides. POMC is primarily expressed within the central nervous system (CNS) within the nucleus of the solitary tract (NST) of the brainstem, the arcuate nucleus of the hypothalamus (Arc), and the pituitary (Joseph et al., 1983; Hadley and Haskell-Luevano, 1999). Peripheral expression of POMC has also been observed in the skin, spleen, thyroid, and the gastrointestinal tract (Smith and Funder, 1988). The post-translational processing of POMC is tissue specific (Pritchard et al., 2002), which allows a multitude of peptides to be derived from a single prohormone (Figure 1).

Bottom Line: The MC3R and MC4R subtypes, the most abundant central MCRs, are widely expressed in brain regions known to modulate neurobiological responses to ethanol, including regions of the hypothalamus and extended amygdala.Agouti-related protein (AgRP), also produced in the arcuate nucleus, is secreted in terminals expressing MCRs and functions as an endogenous MCR antagonist.Ethanol consumption is associated with significant alterations in the expression levels of various MC peptides/protein, which suggests that ethanol-induced perturbations of MC/AgRP signaling may modulate excessive ethanol intake.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychology, University of North Carolina Chapel Hill, NC, USA.

ABSTRACT
The melanocortin (MC) peptides are produced centrally by propiomelanocortin (POMC) neurons within the arcuate nucleus of the hypothalamus and act through five seven-transmembrane G-protein coupled melanocortin receptor (MCR) subtypes. The MC3R and MC4R subtypes, the most abundant central MCRs, are widely expressed in brain regions known to modulate neurobiological responses to ethanol, including regions of the hypothalamus and extended amygdala. Agouti-related protein (AgRP), also produced in the arcuate nucleus, is secreted in terminals expressing MCRs and functions as an endogenous MCR antagonist. This review highlights recent genetic and pharmacological findings that have implicated roles for the MC and AgRP systems in modulating ethanol consumption. Ethanol consumption is associated with significant alterations in the expression levels of various MC peptides/protein, which suggests that ethanol-induced perturbations of MC/AgRP signaling may modulate excessive ethanol intake. Consistently, MCR agonists decrease, and AgRP increases, ethanol consumption in mice. MCR agonists fail to blunt ethanol intake in mutant mice lacking the MC4R, suggesting that the protective effects of MCR agonists are modulated by the MC4R. Interestingly, recent evidence reveals that MCR agonists are more effective at blunting binge-like ethanol intake in mutant mice lacking the MC3R, suggesting that the MC3R has opposing effects on the MC4R. Finally, mutant mice lacking AgRP exhibit blunted voluntary and binge-like ethanol drinking, consistent with pharmacological studies. Collectively, these preclinical observations provide compelling evidence that compounds that target the MC system may provide therapeutic value for treating alcohol abuse disorders and that the utilization of currently available MC-targeting compounds- such as those being used to treat eating disorders- may be used as effective treatments to this end.

No MeSH data available.


Related in: MedlinePlus