scholarly journals Reduced MC4R signaling alters nociceptive thresholds associated with red hair

2021 ◽  
Vol 7 (14) ◽  
pp. eabd1310
Author(s):  
Kathleen C. Robinson ◽  
Lajos V. Kemény ◽  
Gillian L. Fell ◽  
Andrea L. Hermann ◽  
Jennifer Allouche ◽  
...  
Keyword(s):  
Central Area ◽  
Opioid Analgesics ◽  
Loss Of Function ◽  
Melanocortin 1 Receptor ◽  
Melanocyte Stimulating Hormone ◽  
Red Hair ◽  
Gray Area ◽  
Increased Sensitivity ◽  
Physiologic Role

Humans and mice with natural red hair have elevated basal pain thresholds and an increased sensitivity to opioid analgesics. We investigated the mechanisms responsible for higher nociceptive thresholds in red-haired mice resulting from a loss of melanocortin 1 receptor (MC1R) function and found that the increased thresholds are melanocyte dependent but melanin independent. MC1R loss of function decreases melanocytic proopiomelanocortin transcription and systemic melanocyte-stimulating hormone (MSH) levels in the plasma of red-haired (Mc1re/e) mice. Decreased peripheral α-MSH derepresses the central opioid tone mediated by the opioid receptor OPRM1, resulting in increased nociceptive thresholds. We identified MC4R as the MSH-responsive receptor that opposes OPRM1 signaling and the periaqueductal gray area in the brainstem as a central area of opioid/melanocortin antagonism. This work highlights the physiologic role of melanocytic MC1R and circulating melanocortins in the regulation of nociception and provides a mechanistic framework for altered opioid signaling and pain sensitivity in red-haired individuals.

scholarly journals Three novel mutations in ASIP associated with black fibre in alpacas (Vicugna pacos)

2011 ◽  
Vol 149 (4) ◽  
pp. 529-538 ◽  
Author(s):  
N. L. FEELEY ◽  
S. BOTTOMLEY ◽  
K. A. MUNYARD
Keyword(s):  
Amino Acids ◽  
Regulatory Region ◽  
Loss Of Function ◽  
Coding Region ◽  
Contributing Factors ◽  
Novel Mutations ◽  
Melanocortin 1 Receptor ◽  
Melanocyte Stimulating Hormone ◽  
Vicugna Pacos ◽  
Probable Loss

SUMMARYThe coding region of the alpaca Agouti signalling protein (ASIP) gene was sequenced. It was determined to be 402 nucleotides long and code for a protein that is 133 amino acids long. Eight mutations were identified in a sample of 15 alpaca, five in the coding region and three in the introns flanking the exons. In silico analysis showed that three of the five mutations in the coding sequence, c.325_381del57, c.292C>T and c.353G>A are probable loss-of-function mutations. The three mutations were strongly associated with black fibre colour, with 0·90 of black alpacas in the current study having two copies of one or another of the mutations. However, not all black animals displayed the putative ‘aa’ genotype, and almost half of the non-black animals did display that genotype. Contributing factors such as regulatory region mutations, interactions of ASIP with melanocortin-1 receptor (MC1R) and α-melanocyte stimulating hormone (α-MSH), the effect of dilution genes and subjective phenotype assignment are discussed. These mutations will allow alpaca breeders to select for or against black, but they do not explain all black phenotypes in this species.

scholarly journals The Role of Melanocortin 1 Receptor in Cutaneous Malignant Melanoma

2014 ◽  
Vol 16 (4) ◽  
pp. 421-428 ◽  
Author(s):  
Mary Beth Steck
Keyword(s):  
Malignant Melanoma ◽  
Mapk Pathway ◽  
The United States ◽  
Cutaneous Malignant Melanoma ◽  
Mitogen Activated Protein Kinase ◽  
Genomic Research ◽  
Melanocortin 1 Receptor ◽  
Red Hair ◽  
Increased Risk

Cutaneous malignant melanoma (CMM) is an epidemic cancer in the United States. Survival rates for invasive CMM have not increased in past decades despite numerous clinical trials and the effective use of various combinations of chemotherapy agents to treat other cancers. Recent research has investigated the role of melanocortin 1 receptor ( MC1R), a gene associated with red-hair phenotype in White individuals and with increased risk for developing CMM, in the mitogen-activated protein kinase (MAPK) pathway. This limited narrative review discusses the incidence, history, and risk factors for CMM. It explores familial CMM and provides a brief review of melanocyte development and melanogenesis. Histology of CMM and cytogenetic techniques used to identify CMM mutations is also discussed. The structure and function of MC1R is described, with particular attention to MC1R’s role in the MAPK pathway. Finally, the review touches on individualized therapy for CMM using genetic biomarkers and explores the promise of genomic research for finding effective treatments.

scholarly journals Pharmacological Characterization of Loss of Function Mutations of the Human Melanocortin 1 Receptor That Are Associated with Red Hair

2004 ◽  
Vol 123 (5) ◽  
pp. 917-923 ◽  
Author(s):  
Aneta Ringholm ◽  
Janis Klovins ◽  
Richard Rudzish ◽  
Sion Phillips ◽  
Jonathan L. Rees ◽  
...  
Keyword(s):  
Loss Of Function ◽  
Pharmacological Characterization ◽  
Melanocortin 1 Receptor ◽  
Red Hair

scholarly journals The melanocortin 1 receptor is the principal mediator of the effects of agouti signaling protein on mammalian melanocytes

2001 ◽  
Vol 114 (5) ◽  
pp. 1019-1024 ◽  
Author(s):  
Z.A. Abdel-Malek ◽  
M.C. Scott ◽  
M. Furumura ◽  
M.L. Lamoreux ◽  
M. Ollmann ◽  
...  
Keyword(s):  
Coat Color ◽  
Wild Type Mouse ◽  
Tyrosinase Activity ◽  
Loss Of Function ◽  
Wild Type ◽  
Melanocortin 1 Receptor ◽  
Signaling Protein ◽  
Melanocyte Stimulating Hormone ◽  
Related Proteins ◽  
Stimulating Hormone

The agouti gene codes for agouti signaling protein (ASP), which is temporally expressed in wild-type mouse follicular melanocytes where it induces pheomelanin synthesis. Studies using purified full-length agouti signaling protein has shown that it competes with (α)-melanocyte stimulating hormone for binding to the melanocortin 1 receptor. We have investigated whether ASP binds exclusively to the melanocortin 1 receptor expressed on mouse melanocytes in primary culture, or additionally activates a receptor that has not been identified yet. We have compared the responses of congenic mouse melanocytes derived from C57 BL/6J-E(+)/E(+), e/e, or E(so)/E(so) mice to (alpha)-MSH and/or ASP. E(+)/E(+) melanocytes express the wild-type melanocortin 1 receptor, e/e melanocytes express a loss-of-function mutation in the melanocortin 1 receptor that results in a yellow coat color, and E(so)/E(so) is a mutation that causes constitutive activation of the melanocortin 1 receptor and renders melanocytes unresponsive to (alpha)-melanocyte stimulating hormone. Mouse E(+)/E(+) melanocytes, but not e/e or E(so)/E(so) melanocytes, respond to agouti signaling protein with decreased basal tyrosinase activity, and reduction in levels of tyrosinase and tyrosinase-related proteins 1 and 2. Only in E(+)/E(+) melanocytes does agouti signaling protein abrogate the stimulatory effects of (alpha)-melanocyte stimulating hormone on cAMP formation and tyrosinase activity. These results indicate that a functional melanocortin 1 receptor is obligatory for the response of mammalian melanocytes to agouti signaling protein.

Loss of Function Mutations of the Human Melanocortin 1 Receptor Are Common and Are Associated with Red Hair

1999 ◽  
Vol 260 (2) ◽  
pp. 488-491 ◽  
Author(s):  
Helgi B. Schiöth ◽  
Siôn R. Phillips ◽  
Richard Rudzish ◽  
Mark A. Birch-Machin ◽  
Jarl E.S. Wikberg ◽  
...  
Keyword(s):  
Loss Of Function ◽  
Melanocortin 1 Receptor ◽  
Red Hair

Shall I Move My Right or My Left Hand?

2003 ◽  
Vol 17 (2) ◽  
pp. 69-86 ◽  
Author(s):  
Claudio Babiloni ◽  
Fabio Babiloni ◽  
Filippo Carducci ◽  
Febo Cincotti ◽  
Claudio Del Percio ◽  
...  
Keyword(s):  
Bimanual Coordination ◽  
Central Area ◽  
Eeg Analysis ◽  
Complementary Information ◽  
Left Hand ◽  
Mirror Movements ◽  
Related Potentials ◽  
Motor Acts ◽  
Abstract Event

Abstract Event-related desynchronization/synchronization (ERD/ERS) at alpha (10Hz), beta (20Hz), and gamma (40Hz) bands and movement-related potentials (MRPs) were investigated in right-handed subjects who were “free” to decide the side of unilateral finger movements (“fixed” side as a control). As a novelty, this “multi-modal” EEG analysis was combined with the evaluation of involuntary mirror movements, taken as an index of “bimanual competition.” A main issue was whether the decision regarding the hand to be moved (“free” movements) could modulate ERD/ERS or MRPs overlying sensorimotor cortical areas typically involved in bimanual tasks. Compared to “fixed” movements, “free” movements induced the following effects: (1) more involuntary mirror movements discarded from EEG analysis; (2) stronger vertex MRPs (right motor acts); (3) a positive correlation between these potentials and the number of involuntary mirror movements; (4) gamma ERS over central areas; and (5) preponderance of postmovement beta ERS over left central area (dominant hemisphere). These results suggest that ERD/ERS and MRPs provide complementary information on the cortical processes belonging to a lateralized motor act. In this context, the results on vertex MRPs would indicate a key role of supplementary/cingulate motor areas not only for bimanual coordination but also for the control of “bimanual competition” and involuntary mirror movements.

Shifting Concepts

2020 ◽  
Keyword(s):  
Experimental Philosophy ◽  
Central Area ◽  
Linguistic Meaning ◽  
Human Cognition ◽  
Important Work ◽  
Linguistic Communication ◽  
New Perspective ◽  
Semantic Properties ◽  
Conceptual Variation

Concepts stand at the centre of human cognition. We use concepts in categorizing objects and events in the world, in reasoning and action, and in social interaction. It is therefore not surprising that the study of concepts constitutes a central area of research in philosophy and psychology. Since the 1970s, psychologists have carried out intriguing experiments testing the role of concepts in categorizing and reasoning, and have found a great deal of variation in categorization behaviour across individuals and cultures. During the same period, philosophers of language and mind did important work on the semantic properties of concepts, and on how concepts are related to linguistic meaning and linguistic communication. An important motivation behind this was the idea that concepts must be shared, across individuals and cultures. However, there was little interaction between these two research programs until recently. With the dawn of experimental philosophy, the proposal that the experimental data from psychology lacks relevance to semantics is increasingly difficult to defend. Moreover, in the last decade, philosophers have approached questions about the tension between conceptual variation and shared concepts in communication from a new perspective: that of ameliorating concepts for theoretical or for social and political purposes. The volume brings together leading psychologists and philosophers working on concepts who come from these different research traditions.

scholarly journals An R2R3-type myeloblastosis transcription factor MYB103 is involved in phosphorus remobilization

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Fangwei Yu ◽  
Shenyun Wang ◽  
Wei Zhang ◽  
Hong Wang ◽  
Li Yu ◽  
...  
Keyword(s):  
Cell Wall ◽  
Transcription Factor ◽  
Abiotic Stresses ◽  
Myb Transcription Factor ◽  
Ethylene Signaling ◽  
Biotic And Abiotic Stresses ◽  
P Deficiency ◽  
P Concentration ◽  
Increased Sensitivity

Abstract The members of myeloblastosis transcription factor (MYB TF) family are involved in the regulation of biotic and abiotic stresses in plants. However, the role of MYB TF in phosphorus remobilization remains largely unexplored. In the present study, we show that an R2R3 type MYB transcription factor, MYB103, is involved in phosphorus (P) remobilization. MYB103 was remarkably induced by P deficiency in cabbage (Brassica oleracea var. capitata L.). As cabbage lacks the proper mutant for elucidating the mechanism of MYB103 in P deficiency, another member of the crucifer family, Arabidopsis thaliana was chosen for further study. The transcript of its homologue AtMYB103 was also elevated in response to P deficiency in A. thaliana, while disruption of AtMYB103 (myb103) exhibited increased sensitivity to P deficiency, accompanied with decreased tissue biomass and soluble P concentration. Furthermore, AtMYB103 was involved in the P reutilization from cell wall, as less P was released from the cell wall in myb103 than in wildtype, coinciding with the reduction of ethylene production. Taken together, our results uncover an important role of MYB103 in the P remobilization, presumably through ethylene signaling.

scholarly journals A family harboring an MLKL loss of function variant implicates impaired necroptosis in diabetes

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Joanne M. Hildebrand ◽  
Bernice Lo ◽  
Sara Tomei ◽  
Valentina Mattei ◽  
Samuel N. Young ◽  
...  
Keyword(s):  
Potential Role ◽  
Autosomal Dominant ◽  
Inflammatory Diseases ◽  
Diabetic Patients ◽  
Incomplete Penetrance ◽  
Loss Of Function ◽  
Healthy Sibling ◽  
Dominant Disease ◽  
Terminal Effector

AbstractMaturity-onset diabetes of the young, MODY, is an autosomal dominant disease with incomplete penetrance. In a family with multiple generations of diabetes and several early onset diabetic siblings, we found the previously reported P33T PDX1 damaging mutation. Interestingly, this substitution was also present in a healthy sibling. In contrast, a second very rare heterozygous damaging mutation in the necroptosis terminal effector, MLKL, was found exclusively in the diabetic family members. Aberrant cell death by necroptosis is a cause of inflammatory diseases and has been widely implicated in human pathologies, but has not yet been attributed functions in diabetes. Here, we report that the MLKL substitution observed in diabetic patients, G316D, results in diminished phosphorylation by its upstream activator, the RIPK3 kinase, and no capacity to reconstitute necroptosis in two distinct MLKL−/− human cell lines. This MLKL mutation may act as a modifier to the P33T PDX1 mutation, and points to a potential role of impairment of necroptosis in diabetes. Our findings highlight the importance of family studies in unraveling MODY’s incomplete penetrance, and provide further support for the involvement of dysregulated necroptosis in human disease.

scholarly journals Non-productive angiogenesis disassembles Aß plaque-associated blood vessels

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Maria I. Alvarez-Vergara ◽  
Alicia E. Rosales-Nieves ◽  
Rosana March-Diaz ◽  
Guiomar Rodriguez-Perinan ◽  
Nieves Lara-Ureña ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Vessels ◽  
Molecular Signature ◽  
Loss Of Function ◽  
Local Loss ◽  
Microglial Phagocytosis ◽  
Vascular Phenotype ◽  
Cerebral Microvasculature ◽  
Vascular Component

AbstractThe human Alzheimer’s disease (AD) brain accumulates angiogenic markers but paradoxically, the cerebral microvasculature is reduced around Aß plaques. Here we demonstrate that angiogenesis is started near Aß plaques in both AD mouse models and human AD samples. However, endothelial cells express the molecular signature of non-productive angiogenesis (NPA) and accumulate, around Aß plaques, a tip cell marker and IB4 reactive vascular anomalies with reduced NOTCH activity. Notably, NPA induction by endothelial loss of presenilin, whose mutations cause familial AD and which activity has been shown to decrease with age, produced a similar vascular phenotype in the absence of Aß pathology. We also show that Aß plaque-associated NPA locally disassembles blood vessels, leaving behind vascular scars, and that microglial phagocytosis contributes to the local loss of endothelial cells. These results define the role of NPA and microglia in local blood vessel disassembly and highlight the vascular component of presenilin loss of function in AD.

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