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How melanin gives color to skin, hair and eyes

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.

If TPC2 lets too many ions escape, the inside of melanosomes becomes acidic, turning off production of melanin.

"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.

Within melanocytes are structures called melanosomes.

The P protein within melanosomes transports molecules in and out ion channels in order to maintain a neutral acidity balance.

Melanin is produced in the melanosome and protects our DNA from ultraviolet radiation.

A lack of melanin production is associated with albinism, a greater susceptibility to skin and eye cancer, as well as visual impairment.

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.

The OCA2 gene controls the production of P protein in melanocytes, the specialized cells that contain melanosomes where melanin is actually produced. Melanin not only colors our skin and hair, but also the light-sensitive retinal tissue at the back of our eyes affecting our vision.

In melanocytes, the P protein transports molecules into and out of melanosomes to reduce their acidity.

"Having more than one ion channel regulating the pH balance within the melanocyte cell compartment creates a complex regulatory mechanism. One that can be fine tuned to regulate pH [balance] under diverse conditions."

Elena Oancea PhD, Associate Professor, Molecular Pharmacology, Physiology and Biotechnology, Brown University, Providence, Rhode Island, USA.

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.

Using CRISPR-Cas9 gene editing, the team deleted the TPC2 gene and not only found they had abolished the ion current inflow, but could also add it back and restore ion current inflow.

They observed that cells with reduced TPC2 levels have more melanin, suggesting TPC2 is a negative regulator of pigmentation.

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.

Tyrosinase is a copper-containing enzyme in plant and animal tissues that catalyzes production of melanin and other pigments from tyrosine via oxidation. It can be observed as the blackening of a peeled or sliced potato when exposed to air.

Therefore, the new study found that TPC2 and OCA2 counterbalance each other.

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.

"Because TPC2 is a negative regulator of pigmentation, specific TPC2 blockers could be used to compensate for defects in pigmentation caused by an acidic melanosomal pH.

"Unfortunately, this is not simple. TPC2 channels also have important cell function in the lysosomes of non-pigment cells. Blocking TPC2 would not only increase pigmentation, but interfere with other vital functions mediated by the ion channel.

"Local delivery of
specific TPC2 blockers to melanocytes might be a way to circumvent this problem."

Elena Oancea PhD

With each study, the pigmentation picture gets colored in ... a little more.

Intracellular organelles mediate complex cellular functions that often require ion transport across their membranes. Melanosomes are organelles responsible for the synthesis of the major mammalian pigment melanin. Defects in melanin synthesis result in pigmentation defects, visual deficits, and increased susceptibility to skin and eye cancers. Although genes encoding putative melanosomal ion transporters have been identified as key regulators of melanin synthesis, melanosome ion transport and its contribution to pigmentation remain poorly understood. Here we identify two-pore channel 2 (TPC2) as the first reported melanosomal cation conductance by directly patch-clamping skin and eye melanosomes. TPC2 has been implicated in human pigmentation and melanoma, but the molecular mechanism mediating this function was entirely unknown. We demonstrate that the vesicular signaling lipid phosphatidylinositol bisphosphate PI(3,5)P2 modulates TPC2 activity to control melanosomal membrane potential, pH, and regulate pigmentation.

The National Institutes of Health (grants: T32GM077995, RO1AR066318) and the National Science Foundation supported the research.
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Jun 13, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   

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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