PRIP, a novel Ins(1,4,5)P₃ binding protein, functional significance in Ca²⁺ signaling and extension to neuroscience and beyond

Investigation of chemically synthesized inositol 1,4,5-trisphosphate [Ins(1,4,5)P₃] analogs has led to the isolation of a novel binding protein with a molecular size of 130 kDa, characterized as a molecule with similar domain organization to phospholipase C-δ1 (PLC-δ1) but lacking the enzymatic activity. An isoform of the molecule was subsequently identified, and these molecules have been named PRIP (PLC-related, but catalytically inactive protein), with the two isoforms named PRIP-1 and -2. Regarding its ability to bind Ins(1,4,5)P₃ via the pleckstrin homology domain, the involvement of PRIP-1 in Ins(1,4,5)P₃-mediated Ca²⁺ signaling was examined using COS-1 cells overexpressing PRIP-1 and cultured neurons prepared from PRIP-1 knockout mice. Yeast two hybrid screening of a brain cDNA library using a unique N-terminus as bait identified GABARAP (GABA_A receptor associated protein) and PP1 (protein phosphatase 1), which led us to examine the possible involvement of PRIP in GABA_A receptor signaling. For this purpose PRIP knock-out mice were analyzed for GABA_A receptor function in relation to the action of benzodiazepines from the electrophysiological and behavioral aspects. During the course of these experiments we found that PRIP also binds to the β-subunit of GABA_A receptors and PP2A (protein phosphtase 2A). Here, we summarize how PRIP is involved in Ins(1,4,5)P3-mediated Ca²⁺ signaling and GABA_A receptor signaling based on the characteristics of binding molecules.