Translocation between membranes and cytosol of p42(IP4), a specific inositol 1,3,4,5-tetrakisphosphate/phosphatidylinositol 3,4,5-trisphosphate-receptor protein from brain, is induced by inositol 1,3,4,5-tetrakisphosphate and regulated by a membrane-associated 5-phosphatase

The highly conserved 42-kDa protein, p42(IP4) was identified recently from porcine brain. It has also been identified similarly in bovine, rat and hum an brain as a protein with two pleckstrin homology domains that binds Ins(1 ,3,4,5)P-4 and PtdIns(3,4,5)P-3 with high affinity and selectivity. The bra in-specific p42(IP4) occurs both as membrane-associated and cytosolic prote in. Here, we investigate whether p42(IP4) can be translocated from membrane s by ligand interaction, p42(IP4) is released from cerebellar membranes by incubation with Ins(1,3,4,5)P-4. This dissociation is concentration-depende nt (> 100 nM), occurs within a few minutes and and is ligand-specific. p42( IP4) specifically associates with PtdIns(3,4,5)P-3-containing lipid vesicle s and can dissociate from these vesicles by addition of Ins(1,3,4,5)P-4. p4 2(IP4) is only transiently translocated from the membranes as Ins(1,3,4,5)P -4 can be degraded by a membrane-associated 5-phosphatase to Ins(1,3,4)P-3. Then, p42(IP4) re-binds to the membranes from which it can be re-released by re-addition of Ins(1,3,4,5)P-4. Thus, Ins(1,3,4,5)P-4 specifically induc es the dissociation from membranes of a PtdIns(3,4,5)P-3 binding protein th at can reversibly re-associate with the membranes. Quantitative analysis of the inositol phosphates in rat brain tissue revealed a concentration of In s(1,3,4,5)P-4 comparable to that required for p42(IP4) translocation. Thus, in vivo p42(IP4) might interact with membranes in a ligand-controlled mann er and be involved in physiological processes induced by the two second mes sengers Ins(1,3,4,5)P-4 and PtdIns(3,4,5)P-3.