The Mechanism for Prejunctional Enhancement of Neuromuscular Transmission by Ethanol in the Mouse

Abstract

Ethanol has been shown to have both presynaptic and postsynaptic effects on synaptic transmission. However, the mechanisms by which ethanol affects evoked neurotransmitter release have not been studied at the mouse neuromuscular junction, a synapse at which binomial analysis of neurotransmitter release and measurements of prejunctional ionic currents can be made. Ethanol (400 mM) increased neurotransmitter release independently of both the cAMP and phorbol ester/Munc13 signaling pathways. Binomial analysis of neurotransmitter release revealed that ethanol increases the average probability of secretion without an effect on the immediately available store of the neurotransmitter. Application of ethanol also resulted in an inhibition of potassium currents in the motor nerve endings. These results suggest that the potentiating effects of ethanol on neurotransmitter release at the skeletal neuromuscular junction are mediated by an inhibition of the delayed rectifier potassium current, thus increasing both calcium entry into the nerve ending and the probability of neurotransmitter release. Identifying the mechanism through which ethanol enhances neurotransmitter release at the neuromuscular junction may be useful in determining the processes underlying the enhancement of neurotransmitter release at other synapses.

Excitation of Rat Cerebellar Golgi Cells by Ethanol: Further Characterization of the Mechanism

“…Our voltage-clamp studies further indicate that delayed rectifiers lack sensitivity to ethanol in GoCs. These findings are in general agreement with studies demonstrating that high concentrations of ethanol (>200 mM) are required to inhibit recombinant and native delayed rectifier-type K + channels (Anantharam et al, 1992, Searl and Silinsky, 2010). …”

“…Subthreshold Na + currents, active at voltages between -60 and –70 mV, were detected in rat GoCs and these likely contribute to the generation of the slow pacemaker depolarization preceding the spike threshold (Forti et al, 2006). Several studies have shown that ethanol acutely inhibits or has no effects on Na + channels but we are not aware of any studies on subthreshold Na + channels (Habuchi et al, 1995, Shiraishi and Harris, 2004, Klein et al, 2007, Xiao et al, 2008, Horishita and Harris, 2008, Searl and Silinsky, 2010). Evidence suggests that a specialized, non-inactivating subtype of Na + channels of unknown molecular characteristics mediates subthreshold currents (Taddese and Bean, 2002, Crill, 1996, Bean, 2007).…”

Antagonistic postsynaptic and presynaptic actions of cyclohexanol on neuromuscular synaptic transmission and function

“…Figure 11A shows representative perineurally recorded responses to intercostal nerve stimulation in control MPS solution and increasing concentrations of cyclohexanol (5-25 mM). As expected, the principal components of the waveform, after the stimulus artefact, comprised a brisk negative deflection -previously associated with inward Na + current at nodes of Ranvier -followed by a larger negative wave, associated with outward current generated by voltage-sensitive K + channels concentrated in presynaptic nerve terminals (Brigant & Mallart, 1982;Penner & Dreyer, 1986;Searl & Silinsky, 2010a). The axonal Na + current was evidently unaffected by cyclohexanol but the nerve terminal K + current was progressively reduced as cyclohexanol concentration was increased.…”

“…1984; Zuo et al. 2004; Searl & Silinsky, 2010 a , b ). Overall, aliphatic alcohols potentiate endplate responses at relatively low concentrations but inhibit them at higher concentrations (Cooper & Dretchen, 1975).…”