The phosphoinositide signaling cycle in myelin requires cooperative interaction with the axon

Previous studies on the origin of myelin phosphoinositides involved in sign aling mechanisms indicated axon to myelin transfer of phosphatidylinositol followed by myelin-localized incorporation of axon-derived phosphate groups into phosphatidylinositol 4-monophosphate and phosphatidylinositol 4,5-bis phosphate. This is in agreement with other studies showing the presence of phosphorylating activity in myelin that converts phosphatidylinositol into the mono-and diphospho derivatives. It was also found that the second messe nger, inositol 1,4,5-trisphosphate, is hydrolyzed to inositol 1,4-bisphosph ate by a myelin-localized enzyme. The present study was undertaken to deter mine the locus of the remaining reactions leading to formation of free inos itol and completion of the cycle by resynthesis of phosphatidylinositol. Th e latter reaction was found to occur preferentially in isolated axons, and to a limited extent if at all in myelin. On the other hand, hydrolytic reac tions which sequentially convert inositol 1,4,5-trisphosphate to inositol 1 ,4-bisphosphate, inositol 1-phosphate, and free inositol were found to occu r more prominently in myelin. Thus, restoration of phosphoinositides follow ing signal-induced breakdown of PIP2 in myelin is seen as requiring metabol ic interplay between myelin and axon.