DANGER, a novel regulatory protein of inositol 1,4,5-trisphosphate-receptor activity

We report the cloning and characterization of DANGER, a novel protein which physiologically binds to inositol 1,4,5-trisphosphate receptors (IP ₃R). DANGER is a membrane-associated protein predicted to contain a partial MAB-21 domain. It is expressed in a wide variety of neuronal cell lineages where it localizes to membranes in the cell periphery together with IP₃R. DANGER interacts with IP₃R in vitro and co-immunoprecipitates with IP₃R from cellular preparations. DANGER robustly enhances Ca²⁺-mediated inhibition of IP₃R Ca ²⁺ release without affecting IP₃ binding in microsomal assays and inhibits gating in single-channel recordings of IP₃R. DANGER appears to allosterically modulate the sensitivity of IP₃R to Ca²⁺ inhibition, which likely alters IP₃R-mediated Ca ²⁺ dynamics in cells where DANGER and IP₃R are co-expressed.