Quinacrine (mepacrine) action at frog end-plate

Area of Science:

• Neuroscience
• Pharmacology
• Molecular Biology

Background:

• Neuromuscular junctions utilize acetylcholine receptors for signal transmission.
• Quinacrine is an antimalarial drug with potential interactions at the neuromuscular junction.
• Understanding drug interactions at the end-plate is crucial for pharmacology.

Purpose of the Study:

• To investigate the effects of quinacrine on neuromuscular end-plate currents and responses.
• To elucidate the mechanism of quinacrine's action at the voltage-clamped frog end-plate.
• To determine if quinacrine acts as an open channel blocker.

Main Methods:

• Electrophysiological recordings of end-plate currents (e.p.c.s.) and miniature end-plate currents (m.e.p.c.s.) in voltage-clamped frog muscles.
• Ionophoretic application of agonists (carbachol, acetylcholine) to assess receptor responses.
• Dose-dependent and use-dependent application of quinacrine to study channel block kinetics.

Main Results:

• Quinacrine (2 µM) attenuated carbachol responses and, at higher concentrations, abolished m.e.p.c.s.
• Quinacrine's depressant effect varied with pH, suggesting activity as an acridinium ion.
• A use-dependent block of end-plate channels was observed, with decay kinetics dependent on agonist, concentration, and membrane potential.
• Quinacrine reduced e.p.c./m.e.p.c. amplitude and increased decay rates, consistent with open channel blockade.
• The unblocking rate constant was voltage-dependent.

Conclusions:

• Quinacrine primarily acts as a slow, voltage-dependent blocker of open end-plate channels.
• Additional effects on acetylcholinesterase and channel gating may also occur.
• The findings support an open channel blocking model for quinacrine's action at the neuromuscular junction.