Quinidine normalizes the open duration of slow-channel mutants of the acetylcholine receptor.
Quinidine is a long-lived open-channel blocker of the wild-type endplate acetylcholine receptor (AChR). To test the hypothesis that quinidine can normalize the prolonged channel opening events of slow-channel mutants of human AChR, we expressed wild-type AChR and five well characterized slow-channel mutants of AChR in HEK 293 cells and monitored the effects of quinidine on acetylcholine-induced channel currents. Quinidine shortens the longest component of channel opening burst (tau3b) of both wild-type and mutant AChRs in a concentration-dependent manner, and 5 microM quinidine reduces tau3b of the mutant AChRs to that of wild-type AChRs in the absence of quinidine. Because this concentration of quinidine is attainable in clinical practice, the findings predict a therapeutic effect for quinidine in the slow-channel congenital myasthenic syndrome.
Fukudome
T
T
Muscle Research Laboratory and Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
Ohno
K
K
Brengman
J M
JM
Engel
A G
AG
D018680:Cholinergic Antagonists / Q000494:pharmacology*; D006801:Humans; D016014:Linear Models; D016015:Logistic Models; D008564:Membrane Potentials / Q000187:drug effects; D009154:Mutation; D018408:Patch-Clamp Techniques; D011802:Quinidine / Q000494:pharmacology*; D011950:Receptors, Cholinergic / Q000235:genetics*
D018680:Cholinergic Antagonists; D011950:Receptors, Cholinergic; D011802:Quinidine