Inhibition of quantal release from motor nerve by wortmannin.

1. The effects of wortmannin, an inhibitor of phosphatidylinositol (PI) kinases and myosin light chain kinase, on the quantal release of neurotransmitter from mouse phrenic nerve were investigated. 2. Wortmannin (10 - 100 microM) initially enhanced, thereafter progressively depressed spontaneous quantal discharge (miniature endplate potential, mepp). The mean amplitude and the amplitude distribution of mepp were not altered. 3. The compound inhibited and prevented the intensive quantal release evoked by high KC1 solution as well as the mepp burst induced by alpha-latrotoxin, a polypeptide toxin that possesses Ca2+-independent synaptic action to trigger quantal release. The inhibitory actions of wortmannin were partially reversible. 4. Wortmannin depressed the amplitude of endplate potentials (epps) and increased the coefficient of variance of epps. The profile of epps in response to high frequency nerve stimulation exhibited fluctuations between run-down and run-up. The phenomenon is thus different from the consistency of run-up characteristic as the motor nerve Ca2+ channel is blocked by omega-agatoxin IVA. 5. LY294002, another inhibitor of PI 3-kinase, raised mepp frequency without causing late phase suppressions. The compound did not inhibit KC1-, alpha-latrotoxin- or nerve stimulation-evoked quantal release. 6. The results suggest that wortmannin could depress quantal release beyond the step of Ca2+ channel blockade, probably by interfering with the exocytotic cascade.