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Melanocortin activity

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https://www.readbyqxmd.com/read/28094871/divergence-of-camp-signaling-pathways-mediating-augmented-nucleotide-excision-repair-and-pigment-induction-in-melanocytes
#1
Erin M Wolf Horrell, Stuart G Jarrett, Katharine M Carter, John A D'Orazio
Loss-of-function melanocortin 1 receptor (MC1R) polymorphisms are common in UV-sensitive fair-skinned individuals and are associated with blunted cAMP second messenger signaling and higher lifetime risk of melanoma because of diminished ability of melanocytes to cope with UV damage. cAMP signaling positions melanocytes to resist UV injury by up-regulating synthesis of UV-blocking eumelanin pigment and by enhancing the repair of UV-induced DNA damage. cAMP enhances melanocyte nucleotide excision repair (NER), the genome maintenance pathway responsible for the removal of mutagenic UV photolesions, through cAMP-activated protein kinase (protein kinase A)-mediated phosphorylation of the ataxia telangiectasia mutated and Rad3 related (ATR) protein on the S435 residue...
January 17, 2017: Experimental Dermatology
https://www.readbyqxmd.com/read/28093215/melanocortin-4-receptor-constitutive-activity-inhibits-l-type-voltage-gated-calcium-channels-in-neurons
#2
F Agosti, S Cordisco Gonzalez, V Martinez Damonte, M J Tolosa, N Di Siervi, H B Schioth, C Davio, M Perello, J Raingo
The melanocortin 4 receptor (MC4R) is a G protein-coupled receptor (GPCR) that is expressed in several brain nuclei playing a crucial role in the regulation of energy balance controlling the homeostasis of the organism. It displays both agonist-evoked and constitutive activity, and moreover, it can couple to different G proteins. Most of the research on MC4R has been focused on agonist-induced activity, while the molecular and cellular basis of MC4R constitutive activity remains scarcely studied. We have previously shown that neuronal N-type voltage-gated calcium channels (CaV2...
January 13, 2017: Neuroscience
https://www.readbyqxmd.com/read/28081251/physical-activity-and-sedentary-behaviors-modify-the-association-between-melanocortin-4-receptor-gene-variant-and-obesity-in-chinese-children-and-adolescents
#3
Jie-Yun Song, Qi-Ying Song, Shuo Wang, Jun Ma, Hai-Jun Wang
Effects of MC4R variants in previous Chinese population studies were inconsistent. Gene-environment interactions might influence the effect of MC4R variants on obesity, which was still unclear. We performed the study to clarify the association of variants near MC4R gene with obesity-related phenotypes and gene-environment interactions in Chinese children and adolescents. Two common variants (rs12970134 and rs17782313) near MC4R were genotyped in 2179 children and adolescents aged 7-18 years in Beijing of China...
2017: PloS One
https://www.readbyqxmd.com/read/28073831/deletion-of-protein-kinase-c-lambda-in-pomc-neurons-predisposes-to-diet-induced-obesity
#4
Mauricio D Dorfman, Jordan E Krull, Jarrad M Scarlett, Stephan J Guyenet, Mini P Sajan, Vincent Damian, Hong T Nguyen, Michael Leitges, Gregory J Morton, Robert V Farese, Michael W Schwartz, Joshua P Thaler
Effectors of the phosphoinositide 3-kinase (PI3K) signal transduction pathway contribute to the hypothalamic regulation of energy and glucose homeostasis in divergent ways. Here we show that CNS action of the PI3K signaling intermediate atypical protein kinase C (aPKC) constrains food intake, weight gain, and glucose intolerance in both rats and mice. Pharmacologic inhibition of CNS aPKC activity acutely increases food intake and worsens glucose tolerance in chow-fed rodents and causes excess weight gain during high fat diet (HFD) feeding...
January 10, 2017: Diabetes
https://www.readbyqxmd.com/read/28063031/pharmacokinetics-and-pharmacodynamics-of-afamelanotide-and-its-clinical-use-in-treating-dermatologic-disorders
#5
REVIEW
Elisabeth I Minder, Jasmin Barman-Aksoezen, Xiaoye Schneider-Yin
Afamelanotide, the first α-melanocyte-stimulating hormone (MSH) analogue, synthesized in 1980, was broadly investigated in all aspects of pigmentation because its activity and stability were higher than the natural hormone. Afamelanotide binds to the melanocortin-1 receptor (MC1R), and MC1R signaling increases melanin synthesis, induces antioxidant activities, enhances DNA repair processes and modulates inflammation. The loss-of-function variants of the MC1R present in fair-skinned Caucasians are less effectively activated by the natural hormone...
January 6, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28051332/activation-of-the-central-melanocortin-system-chronically-reduces-body-mass-without-the-necessity-of-long-term-caloric-restriction
#6
I Côté, Y Sakarya, N Kirichenko, D Morgan, C S Carter, N Tümer, P J Scarpace
Melanotan II (MTII) is a potent appetite suppressor that rapidly reduces body mass. Given the rapid loss of anorexic response upon chronic MTII treatment, most investigations have focused on the initial physiological adaptations. However, other evidence supports MTII as a long-term modulator of energy balance that remains to be established. Therefore, we examined the chronic effects of MTII on energy homeostasis. MTII (high or low dose) or artificial cerebrospinal fluid (aCSF) was infused into the lateral ventricle of the brain of 6-month-old F344BN rats (6-7/group) over 40 days...
October 19, 2016: Canadian Journal of Physiology and Pharmacology
https://www.readbyqxmd.com/read/28048872/we-fg-bra-10-radiodosimetry-of-a-novel-alpha-particle-therapy-targeted-to-uveal-melanoma-absorbed-dose-to-organs-in-mice
#7
Christopher J Tichacek, Narges K Tafreshi, Mikalai M Budzevich, Epifanio Ruiz, Thaddeus J Wadas, Mark L McLaughlin, Eduardo G Moros, David L Morse
PURPOSE: The melanocortin-1 receptor (MC1R) is expressed in 94% of uveal melanomas and is described as an ideal target for this untreatable disease. MC1RL is a high affinity MC1R specific peptidomimetic ligand that can serve as a scaffold for therapeutic conjugates such as alpha particle emitting isotopes. The purpose of this study was to assess normal tissue distribution and risk as a result of using the DOTA chelator conjugated to MC1RL to deliver (225) Ac: MC1RL-DOTA-(225) Ac. METHODS: 17 non-tumor bearing BALB/c mice were intravenously injected with the novel MC1RL-DOTA-(225) Ac radiopharmaceutical with an average initial administered activity of 2...
June 2016: Medical Physics
https://www.readbyqxmd.com/read/28045525/a-macrocyclic-agouti-related-protein-nle-4-dphe-7-%C3%AE-melanocyte-stimulating-hormone-chimeric-scaffold-produces-subnanomolar-melanocortin-receptor-ligands
#8
Mark D Ericson, Katie T Freeman, Sathya M Schnell, Carrie Haskell-Luevano
The melanocortin system consists of five receptor subtypes, endogenous agonists, and naturally occurring antagonists. These receptors and ligands have been implicated in numerous biological pathways including processes linked to obesity and food intake. Herein, a truncation structure-activity relationship study of chimeric agouti-related protein (AGRP)/[Nle4,DPhe7]α-melanocyte stimulating hormone (NDP-MSH) ligands is reported. The tetrapeptide His-DPhe-Arg-Trp or tripeptide DPhe-Arg-Trp replaced the Arg-Phe-Phe sequence in the AGRP active loop derivative c[Pro-Arg-Phe-Phe-Xxx-Ala-Phe-DPro], where Xxx was the native Asn of AGRP or a diaminopropionic (Dap) acid residue previously shown to increase antagonist potency at the mMC4R...
January 17, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28028605/neuropeptide-systems-and-new-treatments-for-nicotine-addiction
#9
REVIEW
Adriaan W Bruijnzeel
RATIONALE: The mildly euphoric and cognitive enhancing effects of nicotine play a role in the initiation of smoking, while dysphoria and anxiety associated with smoking cessation contribute to relapse. After the acute withdrawal phase, smoking cues, a few cigarettes (i.e., lapse), and stressors can cause relapse. Human and animal studies have shown that neuropeptides play a critical role in nicotine addiction. OBJECTIVES: The goal of this paper is to describe the role of neuropeptide systems in the initiation of nicotine intake, nicotine withdrawal, and the reinstatement of extinguished nicotine seeking...
December 28, 2016: Psychopharmacology
https://www.readbyqxmd.com/read/28009464/effect-of-melanotan-ii-on-brain-fos-immunoreactivity-and-oxytocin-neuronal-activity-and-secretion-in-rats
#10
Luis Paiva, Nancy Sabatier, Gareth Leng, Mike Ludwig
Melanocortins stimulate the central oxytocin systems which are involved in regulating social behaviours. Alterations in central oxytocin have been linked to neurological disorders such as autism, and melanocortins have been proposed for therapeutic treatment. Here, we investigated how systemic administration of melanotan-II (MT-II), a melanocortin agonist, affects oxytocin neuronal activity and secretion in rats. Our results show that intravenous (i.v.), but not intranasal, administration of MT-II markedly induced Fos expression in magnocellular neurones of the supraoptic (SON) and paraventricular nuclei (PVN) of the hypothalamus, and this response was attenuated by prior intracerebroventricular (i...
December 23, 2016: Journal of Neuroendocrinology
https://www.readbyqxmd.com/read/28006784/long-term-energy-deficit-in-mice-causes-long-lasting-hypothalamic-alterations-after-recovery
#11
Mathieu Méquinion, Ophélia Le Thuc, Sara Zgheib, David Alexandre, Nicolas Chartrel, Carole Rovère, Pierre Hardouin, Odile Viltart, Christophe Chauveau
Although short-term effects on fasting or energy deficit on hypothalamic neuropeptide circuitries are now better understood, the effects of long-term energy deficit and refeeding remain to be elucidated. We showed that after a long-term energy deficit mice exhibited persistent hypoleptinemia following the refeeding period despite restoration of fat mass, ovarian activity and feeding behavior. We aimed to examine the hypothalamic adaptations after 10 weeks of energy deficit and after 10 further weeks of nutritional recovery...
December 23, 2016: Neuroendocrinology
https://www.readbyqxmd.com/read/27997171/pyrimidine-based-inhibitors-of-dynamin-i-gtpase-activity-competitive-inhibition-at-the-pleckstrin-homology-domain
#12
Luke R Odell, Mohammed K Abdel-Hamid, Timothy A Hill, Ngoc Chau, Kelly A Young, Fiona M Deane, Jennette A Sakoff, Sofia Andersson, James A Daniel, Phillip J Robinson, Adam McCluskey
The large GTPase dynamin mediates membrane fission during clathrin-mediated endocytosis (CME). The aminopyrimidine compounds were reported to disrupt dynamin localization to the plasma membrane via the PH domain and implicate this mechanism in the inhibition of CME. We have used a computational approach of binding site identification, docking, and interaction energy calculations to design and synthesize a new library of aminopyrimidine analogues targeting site-2 of the pleckstrin homology (PH) domain. The optimized analogues showed low micromolar inhibition against both dynamin I (IC50 = 10...
December 20, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27991864/gs%C3%AE-deficiency-in-the-dorsomedial-hypothalamus-underlies-obesity-associated-with-gs%C3%AE-mutations
#13
Min Chen, Yogendra B Shrestha, Brandon Podyma, Zhenzhong Cui, Benedetta Naglieri, Hui Sun, Thuy Ho, Eric A Wilson, Yong-Qi Li, Oksana Gavrilova, Lee S Weinstein
Gsα, encoded by Gnas, mediates hormone and neurotransmitter receptor-stimulated cAMP generation. Heterozygous Gsα-inactivating mutations lead to obesity in Albright hereditary osteodystrophy (AHO) patients, but only when the mutations occur on the maternal allele. This parent-of-origin effect is due to Gsα imprinting in the CNS, although the relevant CNS regions are unknown. We have now shown that mice with a Gnas gene deletion disrupting Gsα expression on the maternal allele, but not the paternal allele, in the dorsomedial nucleus of the hypothalamus (DMH) developed obesity and reduced energy expenditure without hyperphagia...
December 19, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27988176/anxiogenic-like-effects-of-fluoxetine-render-adult-male-rats-vulnerable-to-the-effects-of-a-novel-stress
#14
Francisca Gomez, Luis García-García
Fluoxetine (FLX) has paradoxical anxiogenic-like effects during the acute phase of treatment. In adolescent (35d-old) male rats, the stress-like effects induced by short-term (3d-4d) FLX treatment appear to involve up-regulation of paraventricular nucleus (PVN) arginine vasopressin (AVP) mRNA. However, studies on FLX-induced anxiety-like effects in adult rodents are inconclusive. Herein, we sought to study the response of adult male rats (60-65d-old) to a similar FLX treatment, also investigating how the stressful component, inherent to our experimental conditions, contributed to the responses...
December 14, 2016: Pharmacology, Biochemistry, and Behavior
https://www.readbyqxmd.com/read/27936173/insights-into-basal-signaling-regulation-oligomerization-and-structural-organization-of-the-human-g-protein-coupled-receptor-83
#15
Anne Müller, Julia Catherine Berkmann, Patrick Scheerer, Heike Biebermann, Gunnar Kleinau
The murine G-protein coupled receptor 83 (mGPR83) is expressed in the hypothalamus and was previously suggested to be involved in the regulation of metabolism. The neuropeptide PEN has been recently identified as a potent GPR83 ligand. Moreover, GPR83 constitutes functionally relevant hetero-oligomers with other G-protein coupled receptors (GPCR) such as the ghrelin receptor (GHSR) or GPR171. Previous deletion studies also revealed that the long N-terminal extracellular receptor domain (eNDo) of mGPR83 may act as an intra-molecular ligand, which participates in the regulation of basal signaling activity, which is a key feature of GPCR function...
2016: PloS One
https://www.readbyqxmd.com/read/27931246/increased-alternate-splicing-of-htr2c-in-a-mouse-model-for-prader-willi-syndrome-leads-disruption-of-5ht2c-receptor-mediated-appetite
#16
Alastair S Garfield, Jennifer R Davies, Luke K Burke, Hannah V Furby, Lawrence S Wilkinson, Lora K Heisler, Anthony R Isles
Alternate splicing of serotonin (5-hydroxytryptamine; 5-HT) 2C receptor (5-HT2CR) pre-RNA is negatively regulated by the small nucleolar RNA, Snord115, loss of which is observed in nearly all individuals with Prader-Willi Syndrome (PWS), a multigenic disorder characterised by hyperphagia and obesity. Given the role of the 5-HT2CR in the regulation of ingestive behaviour we investigated the pathophysiological implications of Snord115 deficiency on 5-HT2CR regulated appetite in a genotypically relevant PWS mouse model (PWS-IC)...
December 8, 2016: Molecular Brain
https://www.readbyqxmd.com/read/27916623/multiple-beneficial-effects-of-melanocortin-mc4-receptor-agonists-in-experimental-neurodegenerative-disorders-therapeutic-perspectives
#17
REVIEW
Daniela Giuliani, Alessandra Ottani, Laura Neri, Davide Zaffe, Paolo Grieco, Jerzy Jochem, Gian Maria Cavallini, Anna Catania, Salvatore Guarini
Melanocortin peptides induce neuroprotection in acute and chronic experimental neurodegenerative conditions. Melanocortins likewise counteract systemic responses to brain injuries. Furthermore, they promote neurogenesis by activating critical signaling pathways. Melanocortin-induced long-lasting improvement in synaptic activity and neurological performance, including learning and memory, sensory-motor orientation and coordinated limb use, has been consistently observed in experimental models of acute and chronic neurodegeneration...
December 1, 2016: Progress in Neurobiology
https://www.readbyqxmd.com/read/27916541/the-orphan-g-protein-coupled-receptor-gpr139-is-activated-by-the-peptides-adrenocorticotropic-hormone-acth-%C3%AE-and-%C3%AE-melanocyte-stimulating-hormone-%C3%AE-msh-and-%C3%AE-msh-and-the-conserved-core-motif-hfrw
#18
Anne Cathrine Nøhr, Mohamed A Shehata, Alexander S Hauser, Vignir Isberg, Jacek Mokrosinski, Kirsten B Andersen, I Sadaf Farooqi, Daniel Sejer Pedersen, David E Gloriam, Hans Bräuner-Osborne
GPR139 is an orphan G protein-coupled receptor that is expressed primarily in the brain. Not much is known regarding the function of GPR139. Recently we have shown that GPR139 is activated by the amino acids l-tryptophan and l-phenylalanine (EC50 values of 220 μM and 320 μM, respectively), as well as di-peptides comprised of aromatic amino acids. This led us to hypothesize that GPR139 may be activated by peptides. Sequence alignment of the binding cavities of all class A GPCRs, revealed that the binding pocket of the melanocortin 4 receptor is similar to that of GPR139...
January 2017: Neurochemistry International
https://www.readbyqxmd.com/read/27916394/hypoactive-sexual-desire-disorder-international-society-for-the-study-of-women-s-sexual-health-isswsh-expert-consensus-panel-review
#19
REVIEW
Irwin Goldstein, Noel N Kim, Anita H Clayton, Leonard R DeRogatis, Annamaria Giraldi, Sharon J Parish, James Pfaus, James A Simon, Sheryl A Kingsberg, Cindy Meston, Stephen M Stahl, Kim Wallen, Roisin Worsley
The objective of the International Society for the Study of Women's Sexual Health expert consensus panel was to develop a concise, clinically relevant, evidence-based review of the epidemiology, physiology, pathogenesis, diagnosis, and treatment of hypoactive sexual desire disorder (HSDD), a sexual dysfunction affecting approximately 10% of adult women. Etiologic factors include conditions or drugs that decrease brain dopamine, melanocortin, oxytocin, and norepinephrine levels and augment brain serotonin, endocannabinoid, prolactin, and opioid levels...
January 2017: Mayo Clinic Proceedings
https://www.readbyqxmd.com/read/27911598/type-3-deiodinase-role-on-central-thyroid-hormone-action-affects-the-leptin-melanocortin-system-and-circadian-activity
#20
Zhaofei Wu, M Elena Martinez, Donald L St Germain, Arturo Hernandez
The role of thyroid hormones (TH) in the central regulation of energy balance is increasingly appreciated. Mice lacking the type 3 deiodinase (DIO3), which inactivates TH, have decreased circulating TH levels relative to control mice due to defects in the hypothalamic-pituitary-thyroid axis. However, we have shown that the TH status of the adult Dio3(-/-) brain is opposite that of the serum, exhibiting enhanced levels of TH action. Since the brain, specially the hypothalamus, harbors important circuitries that regulate metabolism, we aimed to examine the energy balance phenotype of Dio3(-/-) mice and determine whether it is associated with hypothalamic abnormalities...
December 2, 2016: Endocrinology
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