Researchers Unravel ProteinAAsASs Secrets
Neuroscientist Peter Koulen, PhD, at UNT Health Science Center, has spent years studying one specific protein to decipher its role within cells. As a result, he has defined how this protein is linked to a common genetic kidney disorder, identified a new class of proteins, and pointed the way to new theories on other diseases.
The first step in his research was identifying the location of the protein, an ion channel protein named Polycystin-2, in cells. Proteins are produced within cells, and most ion channel proteins then move to the cell surface. But this protein acts differently.
â??Measured at the molecular level, other individual ion channel proteins that are found at the same location inside cells as Polycystin-2, have very low activity, but at the cellular level, they are much more active,â? said Dr. Koulen, an assistant professor of pharmacology and neuroscience. â??The discrepancy was hard to explain with the current thinking about their role. A new hypothesis had to be developed and tested.â?After three years, he confirmed that Polycystin-2 forms a new class within a group of proteins known as intracellular calcium release channels.
These types of proteins are critical to nerve, muscle or epithelial cells that rely on changes in the calcium concentration inside cells to signal them to act. They work together to form regulated gates that allow ions to pass through the membranes of the cell, changing the composition of ions within the cell and triggering many different cell functions.
As an extension of his work, Dr. Koulen joined researchers from Yale University School of Medicine and the University of Heidelberg in Germany to study the proteinâ??s role in autosomal dominant polycystic kidney disease (ADPKD), a common genetic disorder. They knew the protein was encoded by the gene PKD-2 and that the disease was linked to a genetic mutation of the protein, but they wanted to define specifically how Polycystin-2 functions in an effort to identify the cause of ADPKD and possible treatments.
In the March issue of the international journal Nature Cell Biology, the multinational research team showed that Polycystin-2 causes calcium to be released in the kidneyâ??s epithelial cells. They were able to explain that Polycystin-2 acts in concert with other intracellular calcium release channels and might be responsible for the discrepancy between their low activity observed at the single channel level and their high activity at the cellular level. In addition, they show that the genetic defect in ADPKD results in the loss of this calcium-signaling mechanism.
If Polycystin-2 mutates, it affects the highly specialized and complex epithelial cells by making them revert to a simpler stage and lose their ability to perform. These cells form protective linings around various parts of the body, including the heart, kidney and brain.
The resulting damage first strikes the kidneys. The epithelial cells there can no longer function and the lining they form may develop cysts, or fluid-filled pouches. As a person ages, these cysts grow and their kidneys begin to fail.
â??ADPKD affects more than one in 1,000 newborn babies,â? said Dr. Koulen. â??When patients are young, the damage is mild and often remains undetected, but many of them suffer renal failure as adults and require kidney transplants.â?
People who have inherited ADPKD often do not notice anything unusual until they are 30 to 40 years old. The first noticeable symptoms may include high blood pressure, back or side pain, an increase in the size of the abdomen, blood in the urine and frequent bladder or kidney infections.
Today, ultrasound is the most reliable, inexpensive and non-invasive way to diagnose ADPKD once cysts develop. An individual at risk cannot yet be diagnosed before symptoms appear; however, family members of people with ADPKD can undergo special blood tests, called gene linkage analysis, to find out if they also carry the mutated gene and are at risk for the disease.
The finding may open the doors to new theories on other diseases, screening tests and therapies. For example, a person with ADPKD may have other health problems that could be related to this protein mutation. According to the National Kidney Foundation, which provided initial funding for Dr. Koulenâ??s research, ADPKD cysts are found primarily in the kidney but can also affect other organs, including the liver, pancreas, spleen and ovaries. Such â??outpouchingsâ? may occur in the walls of the large intestine and in the walls of blood vessels in the brain, where they may cause aneurysms and strokes. They may also be found in the abdominal wall, causing hernias. In addition, the valves of the heart may be affected, becoming floppy and resulting in heart failure in some patients.
â??If this protein is unable to function, it may impact the nervous system, the brain, and other vital organs,â? Dr. Koulen said. â??We are now working on ways to identify other health problems that could be traced to this mutation.â? Polycystin-2 could also provide a new target for the development of novel drugs to influence the calcium concentration inside cells, thus affecting their ability to function.
â??If we can find a way to control the gate formed by this channel protein, we could possibly shut down the signals that tell a cancerous cell to grow or a brain cell to die,â? Dr. Koulen explained. â??To date there are limited numbers of useful drugs available that target intracellular channels, and they often affect many cell types, leading to undesired side effects. Novel drugs targeting Polycystin-2 with minimal side effects could be relevant for a variety of diseases.â?
Dr. Koulen is continuing his research at the health science center with funding from Texasâ?? Advanced Research Program.
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