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Pigmentation Revisited

By: Peter T. Pugliese, MD
Posted: February 26, 2009, from the March 2009 issue of Skin Inc. magazine.

page 5 of 12

Figure 6 displays the various stimulators of melanogenesis reacting with their specific receptors and producing a biological cascade to eventually result in the formation of cAMP, which stimulates tyrosinase formation in the nucleus. UV light stimulates melanin production, as do other inflammatory biochemicals. All of this requires very strict enzyme control; if any enzyme in the system is missing, melanin cannot be produced. Tyrosinase is the major enzyme required for the synthesis of melanin and most of the stimuli are directed to promoting the production of melanin. Tracing this key enzyme that produces melanin is essentially the story of melanocyte physiology. Melanin is actually made in the melanosomes and must be transferred to the keratinocyte to produce skin color. This process is the next topic.

The transfer of melanosomes from melanocytes to keratinocytes is unique in human biology—no other combination of cells transfers an organelle. Three steps are required to make this transfer.

Step 1: The formation of the dendrite. Dendrites are fingerlike projections of cells. The Langerhans cell and the melanocyte are the only two cells in the epidermis that have dendritic projections. Formation of the dendrite is quite an operation, involving many genes, two of which are the Rho and Rac genes, which are molecular switches.k The dendrite is essentially an extension of the material in the cytoplasm of the melanocyte (or any other dendritic cell). The purpose in forming a dendrite, of course, and in the case of the melanocyte, is to transport melanosomes. Microtubulesl must be assembled and many proteins made to achieve this action, and this is the role of the proteins Rho and Rac. The dendrite having been formed, the melansomes can now be moved.8, 9

Step 2: Melanosomes to the dendrite. Think of this process as a track on which a train runs. Cytoskeletal components known as microtubules form the surface on which the melanosomes are transported to the tip of the dendrite. The actual motive force is supplied by two other proteins called dynein, which transports the melanosomes to the end of the dendrite, and kynein, a motor protein that transports the melanosomes to the center of the cell. So in actuality, the melanosomes can move back and forth in the dendrite. The situation changes when the melanosomes are at the tip of the dendrite and are ready for transfer to the keratinocyte. At this point, they are ready to be transferred to the keratinocyte, but new players enter the field.10, 11

Step 3: Melanosomes to the keratinocyte. At the dendrite tip, a protein known as actin makes up fibers that are needed to transport the melanosomes further into new structures called filopodia, tiny thread-like tubes that are produced at the ends of the dendrite. Within these tiny structures, a protein known as RAB27A latches on to the melanosomes and then bind to a second protein called melanophilin. This whole complex then binds to Myosin Va, a transporter protein that then attaches the complex to actin in order to move it through the filopodia. You can see this structure in Figure 7. An awful lot of names to digest, I realize, but just understand that many steps are involved, and that if any one protein is not normal, pigmentation abnormalities will occur.12, 13, 14