Verapamil, a Ca²⁺ channel blocker widely used in clinical practice, also affects the properties of frog and mouse muscle acetylcholine receptor (AChR), but its mechanism of action is incompletely understood.

We analysed the mechanism of action of verapamil on human wild type and mutant muscle AChRs harbouring in any subunit a valine-to-alanine mutation of 13' residue of the pore-lining M2 transmembrane segment. All mutations imparted slow-channel kinetics, and those in the eand bsubunits were identified in patients with congenital myasthenia

Recordings of unitary events in the cell-attached and outside-out configurations showed that verapamil reduces channel open probability, by prolonging the dwell time into the closed state for WT and all mutant AChR. The duration of channel openings decreased only for the eV265A-AChR, by shortening the longest exponential component of the open time distribution. These results indicate that verapamil invariabli enhances AChR desensitization, but acts as an open channel-blocker uniquely for the eV265A-AChR, emphasizing the major role played by this subunit in controlling the functional properties of human muscle AChR.