Intracellular Ca(2+) and Ca(2+)/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 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 Ca(2+) influx for its acute effect, NT3 rapidly enhances spontaneous transmitter release at the developing NMJ even when Ca(2+) influx is completely blocked, suggesting that the NT3 effect is independent of extracellular Ca(2+). Depletion of intracellular Ca(2+) 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 Ca(2+)/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 Ca(2+) release from intracellular stores through IP3 and/or ryanodine receptors, leading to an activation of CaMKII.
He
X
X
Unit on Synapse Development and Plasticity, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
Yang
F
F
Xie
Z
Z
Lu
B
B
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002352:Carrier Proteins; D002478:Cells, Cultured; D018920:Coculture Techniques; D004553:Electric Conductivity; D004789:Enzyme Activation; D053496:Inositol 1,4,5-Trisphosphate Receptors; D047908:Intracellular Signaling Peptides and Proteins; D009469:Neuromuscular Junction / Q000502:physiology; D018377:Neurotransmitter Agents / Q000378:metabolism*; D020933:Neurotrophin 3 / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D017729:Presynaptic Terminals / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology*; D014981:Xenopus
D019208:Brain-Derived Neurotrophic Factor; C114422:CAMK2N2 protein, human; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002352:Carrier Proteins; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D047908:Intracellular Signaling Peptides and Proteins; D018377:Neurotransmitter Agents; D020933:Neurotrophin 3; D018160:Receptors, Cytoplasmic and Nuclear; D019837:Ryanodine Receptor Calcium Release Channel; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002118:Calcium