LIPID-DEPENDENT MODULATION OF CA2-ENDINGS( AVAILABILITY IN ISOLATED MOSSY FIBER NERVE)

An enhancement of glutamate release from hippocampal neurons has been implicated in long-term potentiation, which is thought to be a cellula r correlate of learning and memory. This phenomenom appears to be invo lved the activation of protein kinase C and lipid second messengers ha ve been implicated in this process. The purpose of this study was ro e xamine how lipid-derived second messengers, which are known to potenti ate glutamate release, influence the accumulation of intraterminal fre e Ca2+, since exocytosis requires Ca2+ and a potentiation of Ca2+ accu mulation may provide a molecular mechanism for enhancing glutamate rel ease. The activation of protein kinase C with phorbol esters potentiat es the depolarization-evoked release of glutamate from messy fiber and other hippocampal nerve terminals. Here we show that the activation o f protein kinase C also enhances evoked presynaptic Ca2+ accumulation and this effect is attenuated by the protein kinase C inhibitor stauro sporine. In addition, the protein kinase C-dependent increase in evoke d Ca2+ accumulation was reduced by inhibitors of phospholipase A(2) an d voltage-sensitive Ca2+ channels, as well as by a lipoxygenase produc t of arachidonic acid metabolism. That some of the effects of protein kinase C activation were mediated through phospholipase A(2) was also indicated by the ability of staurosporine to reduce the Ca2+ accumulat ion induced by arachidonic acid or the phospholipase A(2) activator me littin. Similarly, the synergistic facilitation of evoked Ca2+ accumul ation induced by a combination of arachidonic acid and diacylglycerol analogs was attenuated by staurosporine. We suggest, therefore, that t he protein kinase C-dependent potentiation of evoked glutamate release is reflected by increases in presynaptic Ca2+ and that the lipid seco nd messengers play a central role in this enhancement of chemical tran smission processes.