Intracellular Ca2+ and Ca2+/calmodulin-dependent kinase II mediate acute potentiation of neurotransmitter release by neurotrophin-3

Neurotrophins have been shown to acutely modulate synaptic transmission in a variety of systems, but the underlying signaling mechanisms remain unclea r. Here we provide evidence for an unusual mechanism that mediates synaptic potentiation at the neuromuscular junction (NMJ) induced by neurotrophin-3 (NT3), using Xenopus nerve-muscle co-culture. Unlike brain-derived neurotr ophic factor (BDNF), which requires Ca2+ influx for its acute effect, NT3 r apidly enhances spontaneous transmitter release at the developing NMJ even when Ca2+ influx is completely blocked, suggesting that the NT3 effect is i ndependent of extracellular Ca2+. Depletion of intracellular Ca2+ stores, o r blockade of inositol 1,4,5-trisphosphate (IP3) or ryanodine receptors, pr events the NT3-induced synaptic potentiation. Blockade of IP3 receptors can not prevent BDNF-induced potentiation, suggesting that BDNF and NT3 use di fferent mechanisms to potentiate transmitter release. Inhibition of Ca2+/ca lmodulin-dependent kinase II (CaMKII) completely blocks the acute effect of NT3, Furthermore, the NT3-induced potentiation requires a continuous activ ation of CaMKII, because application of the CaMKII inhibitor KN62 reverses the previously established NT3 effect. Thus, NT3 potentiates neurotransmitt er secretion by stimulating Ca2+ release from intracellular stores through IP3 and/or ryanodine receptors, leading to an activation of CaMKII.