Researchers have developed a unique technology using light to remotely control the cell’s internal stores of calcium. This elusive breakthrough could regulate the body’s immune system, potentially heading off disease, and control the sensation of pain.
Calcium is not only important for our bone strength, but it plays a key role in processes that control gene expression in our immune cells, muscle contraction, electrical transmission in the nervous system, and many other body functions. Abnormal changes of calcium levels in our cells can wreak havoc on the immune system and lead to various illnesses. As a result, a complex control system called store-operated calcium entry has developed through the course of evolution.
Science has shown that two different proteins, STIM and Orai, are at work in this system. STIM senses when the cell’s internal store of calcium is empty and communicates the information to Orai. The Orai protein then opens a channel in the cell membrane for calcium to enter and replenish the stockpile. Yet, mutation can cause break downs, a challenge that has vexed scientists for many years.
“Since this is a highly complex system that generates different calcium signals in different types of cells and also works alongside other calcium entry mechanisms … it is often very hard to study the role of this cellular machinery,” explained Technion Professor Raz Palty of the Rappaport Faculty of Medicine, who conducted the work with former Technion research associates Ronald Udasin and Elia Zomot, and in collaboration with groups headed by Technion Professor Yuval Shaked and Professor Michael Kienzler of the University of Connecticut.
The technology, published in PNAS, is based on an approach called photopharmacology — the activation of drugs that block calcium entry through Orai channels in the target tissue using light. Specifically, the researchers built a kind of “optical switch” that can be turned on and off to control when and where drugs introduced to the body are active. In this way, they regulate the level of calcium coming in through the Orai channel at a desired location and time. The study succeeded in modulating calcium entry in T lymphocytes, thereby regulating the production of cytokines. Managing cytokines is so crucial to the functioning of the immune system, that an uncontrolled and elevated release of the pro-inflammatory proteins can lead to advanced symptoms of COVID-19.
In a series of related experiments, researchers at Hebrew University of Jerusalem also found that manipulating the Orai-STIM system could control the sensation of pain. The scientists hope that these follow-up studies will provide a deeper understanding of the regulation mechanisms and broaden the clinical applications of their technology.