Secretagogin Is a Redox-Responsive Ca2+ Sensor

Secretagogin (SCGN), a multifunctional, Ca2+ binding, regulatory protein, known to regulate insulin release, has recently been implicated in the control of stress-related corticotropin-releasing hormone (CRH) secretion. Localization of SCGN to multiple intracellular (such as cytosol, nucleus, and endoplasmic reticulum) and extracellular sites appears to provide multifunctional capabilities; however, the structural elements conferring such a widespread cellular distribution to SCGN remain unidentified. We report that the spatial and functional attributes of SCGN plausibly originate from the interplay between Ca2+ and its redox state. The mutation of selective Cys residues provides further insights into the origin and mode of redox responsiveness. In the reducing milieu, SCGN exhibits a higher affinity for Ca2+, and more stability than in the oxidizing environment, suggesting it is a redox-responsive Ca2+ sensor protein, which is further supported by its response to dithiothreitol (reducing stress) in MIN6 cells. Our data provide a biophysical and biochemical explanation for the diverse localization of SCGN in the cellular scenario and beyond the cell.