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    A. Masoud Sadaghiani.
    Store-operated calcium (SOC) entry and channel play a central role in regulating intracellular calcium concentrations in a variety of cell types. SOC is critical for many physiological processes, most notably activation of the immune system, where its lack of function is known to cause severe combined immunodeficiency (SCID) in human patients. In lymphocytes, where SOC has been extensively studied, it has been shown that SOC is mediated by the calcium channel Orai that is activated by its direct binding to STIM, a calcium sensor localized in the endoplasmic reticulum. While it was previously thought that SOC serves an important role only in immune and non-excitable cells, it is now clear that SOC and the proteins that regulate its function are ubiquitously expressed in variety of tissues, including muscle and the nervous system, and serve a diverse set of biological functions. More recently, SOC has been shown to act in a several pathological processes, ranging from muscular dystrophy to cancer, underscoring the significance of gaining a better understanding of its mechanism of action. Here we set out to develop pharmacological blockers of SOC, in order to gain insights into its molecular mechanism and physiological role. Such blockers could allow for acute inhibition of SOC, allowing for a temporal control that is essential for mechanistic studies. If successfully developed, such reagents could also be of therapeutic use as immunosuppressants or anti thrombotic agents in human patients. We designed a novel methodology for generating SOC blockers based on the identification and targeting of minimal functional domains (MFDs) of STIM and Orai. Using this approach, we identified small molecule blockers that can inhibit SOC at high nanomolar concentrations and can also block T cell activation in vitro and in vivo. These studies not only provide an important set of tools for better understanding STIM and Orai function, but also identify compounds that could potentially be developed into therapeutic agents for the treatment of pathological conditions such as autoimmune disease.
    Digital Access   2012