Brief Report

Intracellular Ca²⁺ and Ca²⁺/Calmodulin-dependent Kinase II Mediate Acute Potentiation of Neurotransmitter Release by Neurotrophin-3

Correspondence to: Bai Lu, Unit on Synapse Development and Plasticity, National Institute of Child Health and Human Development, National Institutes of Health, Building 49, Rm. 6A80, 49 Convent Dr., MSC4480, Bethesda, MD 20892-4480. Tel:(301) 435-2970 Fax:(301) 480-3526 E-mail:lub{at}codon.nih.gov.

Neurotrophins have been shown to acutely modulate synaptic transmission in a variety of systems, but the underlying signaling mechanisms remain unclear. 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 neurotrophic factor (BDNF), which requires Ca²⁺ influx for its acute effect, NT3 rapidly enhances spontaneous transmitter release at the developing NMJ even when Ca²⁺ influx is completely blocked, suggesting that the NT3 effect is independent of extracellular Ca²⁺. Depletion of intracellular Ca²⁺ stores, or blockade of inositol 1, 4, 5-trisphosphate (IP3) or ryanodine receptors, prevents the NT3-induced synaptic potentiation. Blockade of IP3 receptors can not prevent BDNF-induced potentiation, suggesting that BDNF and NT3 use different mechanisms to potentiate transmitter release. Inhibition of Ca²⁺/calmodulin-dependent kinase II (CaMKII) completely blocks the acute effect of NT3. Furthermore, the NT3-induced potentiation requires a continuous activation of CaMKII, because application of the CaMKII inhibitor KN62 reverses the previously established NT3 effect. Thus, NT3 potentiates neurotransmitter secretion by stimulating Ca²⁺ release from intracellular stores through IP3 and/or ryanodine receptors, leading to an activation of CaMKII.

Key Words: ryanodine receptors, inositol 1, 4,, 5-trisphosphate receptors, acetylcholine, neuromuscular junction, synaptic transmission

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