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Calcium is one of the most regulated minerals in the human body. That may be because so many important cellular processes rely on calcium ions: cell growth, neural signaling, muscle contraction, bone formation and fertilization, to name just a few. In fact, it is crucial that a low yet steady concentration of calcium ions be maintained within cells: There is growing evidence that disturbances in intracellular calcium levels may result in serious cellular dysfunction. For example, an excessive amount of calcium in nerve cells causes them to die, leading to neurodegenerative disease. Imbalances in calcium levels are also believed to be associated with various types of cancer as well as vascular and heart diseases.
Cells have evolved a unique “stocktaking” system to ensure their calcium supplies are tightly monitored and regulated. Prof. Eitan Reuveny of the Weizmann Institute’s Biological Chemistry Department has now discovered the role of a new protein that is involved in this process.
To make sure there is a plentiful supply of calcium on hand at all times – one that doesn’t jeopardize the carefully balanced concentration within the cell – calcium is stored in cellular “warehouses”: membrane-enclosed organelles known as mitochondria and the endoplasmic reticulum (ER). These immediately get restocked as soon as their supplies start to dwindle. How does the cell know exactly how much calcium to order? The process of acquiring more calcium is called store-operated calcium entry (SOCE), and up to now two players were known to be involved – STIM and Orai. STIM – a “stock-taker” protein – detects the depletion of calcium within the ER warehouses and makes its way to Orai – calcium-selective channels located in the cell’s plasma membrane – where it activates them to open. This results in an influx of calcium into the cell from the outside, which then gets taken up by the cellular warehouses.
What scientists didn't know was what regulates the closing of these channels, preventing the cellular warehouses from overfilling and spilling out into the cell. Now, Reuveny, together with Raz Palty, Adi Raveh, Ido Kaminsky and Ruth Meller, have identified a new protein that helps regulate SOCE activity, as they reported in the journal Cell. They found that once the Orai channels have opened, the new protein, SARAF, is employed to slowly inactivate STIM, causing the channels to start closing. This prevents the rapid overfilling of cells with calcium and keeps levels under control.
As expected, disabling SARAF activity led to calcium overspill and cell hyperactivity. The added observation that SARAF travels with STIM to the plasma membrane, where the Orai channels are located, provides further evidence that SARAF is involved in regulating STIM deactivation.
Although there is no direct evidence linking mutations in SARAF to human diseases, studies have recently identified SARAF as a biomarker that is associated with prostate cancer, Alzheimer’s disease and dilated cardiomyopathy – disease states that are accompanied by abnormal intracellular calcium levels.
Reuveny: “SARAF is expressed in cells all over the body, but their levels are especially high in the immune system and brain. We still don’t know exactly what it does there or how it works, so this is what we are endeavoring to find out next.”
SARAF tagged with green fluorescent protein. The fluorescent signals get stronger as SARAF moves closer to the plasma membrane.
Prof. Eitan Reuveny’s research is supported by the Nella and Leon Benoziyo Center for Neurological Diseases; the Yeda-Sela Center for Basic Research; and the Hugo and Valerie Ramniceanu Foundation. Prof. Reuveny is the incumbent of the Charles H. Hollenberg Professorial Chair.
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