Neuromuscular transmission on the rebound.

Recent work at the zebrafish neuromuscular junction (NMJ) has shown that positively charged acetylcholine (ACh), at the high concentrations reached in the cleft during neuromuscular transmission, blocks acetylcholine receptors (AChRs) as soon as they open. Thus after two ACh molecules bind and open the channel, a third molecule enters and blocks the pore at a site resembling that for block by local anesthetics, suggesting that ACh is the endogenous anesthetic of the NMJ. Recovery from open channel block results in a rebound synaptic current only after ACh is cleared from the cleft. Kinetic modeling of other AChRs suggests that a rebound current is generated at all vertebrate NMJs, from fish to frogs to mammals. Open channel block prolongs the current at fast zebrafish NMJs in order to more effectively spread charge along the fibers, akin to multiple central synapses spread over dendrites. Together these findings indicate the need for a fundamental revision of current thinking about neuromuscular transmission at many levels, including channel structure, function and pharmacology.