A transgenic mouse model of the slow-channel syndrome.
To investigate the effect of acetylcholine receptor (AChR) mutations on neuromuscular transmission and to develop a model for the human neuromuscular disease, the slow-channel syndrome, we generated transgenic mice with abnormal AChRs using a delta subunit with a mutation in the ion channel domain. In three transgenic lines, nerve-evoked end-plate currents and spontaneous miniature end-plate currents (MEPCs) had prolonged decay phases and MEPC amplitudes were reduced by 33%. Single nerve stimuli elicited repetitive compound muscle action potentials in vivo. Transgenic mice were abnormally sensitive to the neuromuscular blocker, curare. These observations demonstrate that we can predictably alter AChR function, synaptic responses, and muscle fiber excitation in vivo by overexpressing subunits containing well-defined mutations. Furthermore these data support the hypothesis that the electrophysiological findings in the neuromuscular disorder, the slow-channel syndrome, are due to mutant AChRs.
Gomez
C M
CM
Department of Neurology, University of Minnesota, Minneapolis, USA.
Bhattacharyya
B B
BB
Charnet
P
P
Day
J W
JW
Labarca
C
C
Wollmann
R L
RL
Lambert
E H
EH
D000818:Animals; D003472:Curare / Q000494:pharmacology; D004195:Disease Models, Animal; D004576:Electromyography; D005260:Female; D015870:Gene Expression; D006801:Humans; D007473:Ion Channels / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009045:Motor Endplate / Q000503:physiopathology; D009154:Mutation; D009468:Neuromuscular Diseases / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D011950:Receptors, Cholinergic / Q000235:genetics*; D009435:Synaptic Transmission / Q000187:drug effects; D014982:Xenopus laevis
D007473:Ion Channels; D011950:Receptors, Cholinergic; D003472:Curare