Melittin enhances excitatory amino acid release and AMPA-stimulated ⁴⁵Ca²⁺ influx in cultured neurons

Melittin, a potent activator of phospholipase A₂, enhanced both spontaneous and depolarization-induced release of d-[³H]aspartate in primary cultures of cerebellar granule cells. The action of melittin was concentration-dependent (EC₅₀value = 300 ng/ml) did not require the presence of extracellular Ca²⁺. Melittin also stimulated the release of glutamate and aspartate, in addition to other endogenous amino acids (taurine, alanine and γ-aminobutyric acid). These effects were accompanied by an enhanced influx of ⁴⁵Ca²⁺, which was in part mediated by the activation of excitatory amino acid receptors by endogenous agonists. Low concentrations of melittin (50 ng/ml) potentiated the efficacy of AMPA in stimulating ⁴⁵Ca²⁺ influx without affecting stimulation by kainate or by glutamate added in the absence of extracellular Mg²⁺ (a condition that favors the activation of NMDA receptors). These results indicate that activation of phospholipase A₂ evokes both an enhanced glutamate release and an increased sensitivity of AMPA receptors, two events that may support synaptic facilitation and LTP formation.