Voltage dependence of agonist effectiveness at the frog neuromuscular junction: resolution of a paradox.

1. End‐plate currents produced by nerve‐released acetylcholine and iontophoretically applied acetylcholine and carbachol have been recorded from voltage‐clamped frog cutaneous pectoris neuromuscular junctions made visible with Nomarski differential interference contrast optics. 2. The effectiveness of agonists ‐ that is, the end‐plate conductance change produced by a given dose‐has been determined as a function of post‐junctional membrane potential. 3. As the post‐junctional membrane potential is made more negative, nerve‐released acetylcholine becomes less effective whereas iontophoretically‐applied agonists become more effective. 4. This voltage dependence of agonist effectiveness is mediated neither by end‐plate current iontophoresis of agonist into the cleft nor through electric field effects on the esterase. 5. Influences of membrane potential on the opening and closing of end‐plate channel gates can account quantitatively for the voltage‐dependent effectiveness of both nerve‐released and iontophoretically applied agonist.