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A year and a half ago, Brown University researchers found a molecular gas pedal that increases melanin production. Now they have found its brake. Understanding how color enters our eyes, skin and hair, helps explain albinism, or when color doesn't get produced at all.
The study in the Nature journal Scientific Reports shows that pigmentation is reduced by activity of a protein called TPC2, that channels the flow of positive sodium ions out of melanocytes. Melanocytes are compartments within cells that contain melanosomes where melanin is produced.
"We now know how TPC2 functions in melanosomes and can use this information to understand how melanosomes function under normal conditions, and how their function can be perturbed by mutations," adds corresponding author Elena Oancea PhD, an associate professor of molecular pharmacology, physiology and biotechnology at Brown University in Rhode Island.
For years, however, scientists had little insight into how pigmentation worked within the cell. But in late 2014, Elena Oancea's team discovered that melanosomes maintain internal acidity levels using an ion channel called OCA2 — short for oculocutaneous albinism type II.
Tracking down TPC2
Before the new study, the team only knew that the TPC2 gene had been generally associated with pigmentation. Two mutations within the gene were linked in 2008 to fair skin and light hair color in a study of northern Europeans.
But in the lab at Brown University, the team, which includes co-lead authors Nicholas Bellono and Illiana Escobar, was able to prove exactly how TPC2 works. The research involved two animal models, mice and frogs. Both mouse skin cells and frog eye cells, have larger melanosomes than human cells — allowing for easier measurement in experiments. Otherwise all the same proteins and mechanisms exist in mice and frogs as do in humans.
Taking electrical measurements from melanosomes, the team spotted a large inward flow of negative electrical current which corresponded with positive ions flowing out of melanosomes. The current was independent of regulation by OCA2, but did depend on a lipid (or fat) called PI(3,5)P2 found in the membrane surrounding the melanosome.
The current was consistent with what's typically produced by a TPC ion channel. When researchers blocked function of all TPC channels after adding the chemical verapamil to the cell culture, the electrical current stopped. Further testing supported that TPC2, and not TPC1, is found throughout the melanosome membrane.
From there they found that melanosomes with TPC2 were a bit more acidic than those without it. Therefore, TPC2 indeed directly competes with OCA2. Acidity affects the main enzyme that allows melanin synthesis, tyrosinase, and is only active in neutral acidity.
The pigment picture
Even after having made these new discoveries, the team is not finished studying how melanosomes work. Oancea speculates there may be more ion channels or other mechanisms involved in melanin production.
For people with albinism, one of the biggest questions is how to turn the newfound knowledge into viable treatment. TPC2 could be a target, but Oancea cautions it doesn't just function in melanosomes.
With each study, the pigmentation picture gets colored in ... a little more.
The National Institutes of Health (grants: T32GM077995, RO1AR066318) and the National Science Foundation supported the research.
A new study shows that pigmentation is reduced by activity of a protein called TPC2,
which normally channels the flow of positive sodium ions out of melanocytes —
the compartments within cells that produce melanin.
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