The presenilins have been implicated in both AB formation and in apoptosis. Several studies suggest that COOH-termini of the presenilins are critical for these processes. We have made use of the yeast two-hybrid system to identify proteins that interact with the COOH-terminus of the presenilins. We have identified the novel calcium and presenilin-binding protein calsenilin as an interactor. Calsenilin is a member of the recovering family of calcium binding proteins that are typically myristoylated and can modulate the activity of G-protein coupled receptor kinases (GRKs). As a calcium binding protein, calsenilin may function as a calcium sensor and may be involved in calcium signaling. We have characterized the post-translational modification of calsenilin, its distribution, and its interaction with domains of the presenilins. We are currently studying the role of calsenilin in calcium signaling, in apoptosis and in AB formation. In addition, we are determining whether calsenilin interacts with other proteins including GRKs