Human melanocytes expressing MC1R variant alleles show impaired activation of multiple signaling pathways
2007
Abstract
Variant alleles of the human MC1R gene are strongly associated with red hair color, fair skin and poor tanning ability (RHC-trait). Recently, we demonstrated that melanocytes harboring RHC alleles have markedly reduced surface expression and/or impaired G-protein coupling of the corresponding receptor protein. The consequences of such a deficit on MC1R-mediated signaling pathways have now been quantitatively evaluated utilizing strains of primary melanocytes homozygous for RHC-variant alleles, comparing responses to wild-type strains.
The ability of melanocortin peptides to increase transcription of cAMP-dependent pigmentation genes, including MITF and SLC45A2, was abrogated in melanocytes with RHC-associated variant alleles, an effect that may contribute to the RHC phenotype. Activation of the c-Fos transcription factor gene was also severely compromised, a finding of new potential roles of MC1R.
We also confirmed p38 signaling as an MC1R-regulated pathway and identified a large synergistic interaction between UV irradiation and MC1R stimulation for the activation of p38. This synergism was impaired in melanocytes expressing RHC variants of MC1R which may be relevant for the poor tanning ability associated with individuals possessing these alleles.
"[b]Dr. Alam wrote] explained that the importance of being a redhead may have stemmed from the biologically materialistic position concept, which is the conscious choice of mate based upon appearance, status, or other similar perceptions. Overall, this may have affected human evolution. Conceptually, the phenotype of red hair was like that of a peacock’s tail. In the way of attracting mates, these features were considered to be beautiful and at the time, red hair was also quite a rare feature, hence the reason why it was considered to be such a desirable trait. "
Of all the races on this earth, the Celtic are extremely well known for having one of the most captivating hair colors known to man, red. From mysterious and alluring, to fiery and powerful, this hair color captures the attention of people all over the world. Until about a decade ago, it was unknown know what exactly caused red hair color to emerge into our society however, this did not keep us from wondering why. From the artwork of Michelangelo, to the present day media attention of redheaded British Royalty, red hair color always had a significant position in our society. Thanks to the work of distinguished scientists, we know that the physical manifestation of this hair color is because of a mutation in a gene on chromosome sixteen, and not having originated from the Neanderthals.*
Generally, hair color is determined by a substance called melanin. This is produced by melanocytes, a group of specialized cells near the hair bulb. There are two types of melanin, eumelanin and red/yellow light melanin, and the ratios of these pigments are what determine hair color. Brown to black hair color is produced by a high amount of eumelanin pigment and a little amount of phaeomelanin. Red hair color is produced by a high amount of phaeomelanin, and a little amount of eumelanin pigment, while blond hair is produced by little amounts of both pigments.
There are two genes responsible for the production of hair color, the melanocortin-1 receptor gene (MC1R gene) and the pro-opimelanocortin gene (POMC gene). The MC1R gene is located on chromosome 16, the long arm, section 24, subsection 3, and it provides instructions for creating a gene product, the receptor for the alpha-melanocyte-stimulating produces peptide products yielding powerful hormones, namely ?-MSH. MSH is produced in the pituitary gland of the brain and binds to an extra-cellular melanocortin-1 receptor which is located in the plasma membrane. By the binding of this hormone to the outside of the receptor, the receptor becomes activated and its result shows up in the melanocytes particularly developed after trauma. Although the MC1R is one of 5 possible receptors, the MC1R is the main receptor for ?-MSH associated with skin color.
The melanocortin-1 receptor belongs to a class of protein receptors known as the G-protein-coupled receptors (GPCRs). These receptors make up the largest and most diverse families of proteins. They are located on the plasma membrane and communicate between the external and internal environments of the cell. Each receptor is activated by the binding of its specific ligand to the receptor’s active site. This causes the protein to become activated and release some specific components inside the cell for the activation of a specific cellular mechanism. According to the Journal of Cell Science, scientists claim Depending on the type of G protein to which the receptor is coupled, a variety of downstream signaling pathways can be activated…. This family of proteins is so incredibly diverse because each receptor has to stay independent in order to prevent conflicting signals with other receptors.
It is believed that the redheads were selected against in Africa because of the high levels of UV radiation, therefore causing a genetic drift to occur toward Europe. In recent genetic lab research, lead authors state that, In the cases of both Neanderthals and modern Europeans, the gene mutation that caused fairer complexions spread only after the respective populations migrated from Africa. From this genetic drift, countries such as Scotland and Ireland are known for the highest percentages of redheads in Europe.*
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