Abnormal transmitter release at neuromuscular junctions of mice carrying the tottering alpha(1A) Ca(2+) channel mutation.
Neurotransmitter release at many synapses is regulated by P/Q-type Ca(2+) channels containing the alpha(1A) pore-forming subunit. Mutations in alpha(1A) cause cerebral disorders including familial hemiplegic migraine (FHM) and ataxia in humans. Tottering (tg) alpha(1A) mutant mice display ataxia and epilepsy. It is not known whether alpha(1A) mutations induce impairment of synaptic function, which could underlie the symptoms of these cerebral disorders. To assess whether alpha(1A) mutations influence neurotransmitter release, we studied P-type Ca(2+) channel-mediated acetylcholine (ACh) release at tg neuromuscular junctions (NMJs) with micro-electrode measurements of synaptic potentials. We found a Ca(2+)-, Mg(2+)- and K(+)-dependent increase of spontaneous ACh release at both homo- and heterozygote tg NMJs. Furthermore, there was increased run-down of high-rate evoked release at homozygous tg NMJs. In isotonic contraction experiments this led to block of synaptic transmission at lower concentrations of the ACh antagonist tubocurarine than were needed in wild-type muscles. Our results suggest that in tg motor nerve terminals there is increased influx of Ca(2+) under resting conditions. This study shows that functional consequences of alpha(1A) mutations causing cerebral disorders can be characterized at the NMJ.
Plomp
J J
JJ
Department of Physiology, Leiden University Medical Centre, Leiden, The Netherlands.
Vergouwe
M N
MN
Van den Maagdenberg
A M
AM
Ferrari
M D
MD
Frants
R R
RR
Molenaar
P C
PC
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D015220:Calcium Channels / Q000235:genetics*; D020864:Calcium Channels, N-Type / Q000235:genetics; D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D004594:Electrophysiology; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D008274:Magnesium / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009469:Neuromuscular Junction / Q000378:metabolism*; D010523:Peripheral Nervous System Diseases / Q000235:genetics / Q000503:physiopathology; D009435:Synaptic Transmission / Q000502:physiology*
D000109:Acetylcholine; D002118:Calcium; D015220:Calcium Channels; D020864:Calcium Channels, N-Type; D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D008274:Magnesium; D009419:Nerve Tissue Proteins