Identification of a Novel Signaling Molecule and Elucidation of Its Cellular Functions

—Development of an Interface between Neuroscience and Oral Health Science—

Abstract

The investigation of chemically synthesized inositol 1,4,5-trisphosphate [Ins (1,4,5)P₃] analogs has led to the isolation of a novel protein with a molecular size of 130 kDa, characterized as a molecule with a domain organization similar to phospholipase C (PLC)-δ1 but lacking enzymatic activity. Two isoforms of the molecule were subsequently identified, the molecule has 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 first examined. Yeast two-hybrid screening of a brain cDNA library identified GABARAP (GABA_A receptor-associated protein) and PP1 (protein phosphatase 1), which led us to examine the possible neurological involvement of PRIP, particularly in GABA_A receptor signaling. PRIP-1 and -2 double knock-out (DKO) mice were analyzed for GABA_A receptor function with special reference to the action of benzodiazepines whose target is the γ subunit of the receptors; sensitivity to benzodiazepine was reduced, as assessed by biochemical, electrophysiological, and behavioral analyses of DKO mice, suggesting the dysfunction of γ2 subunit-containing GABA_A receptors. The mesencephalic trigeminal nucleus, which mediates perceptions from periodontal mechanoreceptors and jaw-closer muscle spindles, receives many synaptic inputs, including those from GABA_A receptors, indicating that PRIP might indirectly be involved in rhythmical jaw movement. In the present article, we summarize our current research and the functional significance of PRIP.