Low-frequency neuromuscular depression is a consequence of a reduction in nerve terminal Ca2+ currents at mammalian motor nerve endings

Eugene M. Silinsky*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


BACKGROUND: The decline in voluntary muscle contraction during low-frequency nerve stimulation is used clinically to assess the type and degree of neuromuscular block. The mechanism underlying this depression is unknown. METHODS: Simultaneous electrophysiological measurements of neurotransmitter release and prejunctional Ca2+ currents were made at mouse neuromuscular junctions to evaluate the hypothesis that decreases in nerve terminal Ca2+ currents are responsible for low-frequency depression. RESULTS: Under conditions generally used to measure Ca2+ currents at the neuromuscular junction, increasing the frequency of nerve stimulation briefly from 0.017 to 0.1-1 Hz caused a simultaneous reduction in the release of the neurotransmitter acetylcholine to 52.2 ± 4.4% of control and the Ca2+ current peak to 75.4 ± 2.0% of control (P < 0.001, n = 5 experiments for both measurements, mean ± SEM for all data). In conditions used for train-of-four monitoring (4 stimuli, 2 Hz), neurotransmitter release declined to 42.0 ± 1.0% of control and the Ca2+ current peak declined to 75.8 ± 3.3% of control between the first and fourth stimulus (P < 0.001, n = 7 experiments for both measurements). Depression in acetylcholine release during train-of-four protocols also occurred in the absence of neuromuscular-blocking drugs. DISCUSSION: The results demonstrate that neuromuscular depression during train-of-four monitoring is due to a decline in nerve terminal Ca2+ currents, hence reducing the release of acetylcholine. As similar processes may come into play at higher stimulation frequencies, agents that antagonize the decline in Ca currents could be used to treat conditions in which neuromuscular depression can be debilitating.

Original languageEnglish (US)
Pages (from-to)326-334
Number of pages9
Issue number2
StatePublished - Aug 2013

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine


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