Characterization of acetylcholine release and the compensatory contribution of non-Ca(v)2.1 channels at motor nerve terminals of leaner Ca(v)2.1-mutant mice.
The severely ataxic and epileptic mouse leaner (Ln) carries a natural splice site mutation in Cacna1a, leading to a C-terminal truncation of the encoded Ca(v)2.1 alpha(1) protein. Ca(v)2.1 is a neuronal Ca(2+) channel, mediating neurotransmitter release at many central synapses and the peripheral neuromuscular junction (NMJ). With electrophysiological analyses we demonstrate severely reduced ( approximately 50%) neurotransmitter release at Ln NMJs. This equals the reduction at NMJs of Cacna1a null-mutant (Ca(v)2.1-KO) mice, which display a neurological phenotype remarkably similar to that of Ln mice. However, using selective Ca(v) channel blocking compounds we revealed a compensatory contribution profile of non-Ca(v)2.1 type channels at Ln NMJs that differs completely from that at Ca(v)2.1-KO NMJs. Our data indicate that the residual function and presence of Ln-mutated Ca(v)2.1 channels precludes presynaptic compensatory recruitment of Ca(v)1 and Ca(v)2.2 channels, and hampers that of Ca(v)2.3 channels. This is the first report directly showing at single synapses the deficits and plasticity in transmitter release resulting from the Ln mutation of Cacna1a.
Kaja
S
S
Department of Neurology, Leiden University Medical Centre, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
van de Ven
R C G
RC
Broos
L A M
LA
Frants
R R
RR
Ferrari
M D
MD
van den Maagdenberg
A M J M
AM
Plomp
J J
JJ
D000109:Acetylcholine / Q000378:metabolism*; D000222:Adaptation, Physiological / Q000235:genetics; D000818:Animals; D015220:Calcium Channels / Q000235:genetics*; D020864:Calcium Channels, N-Type / Q000235:genetics*; D020908:Calcium Channels, R-Type / Q000235:genetics; D027682:Cation Transport Proteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000294:innervation / Q000378:metabolism / Q000503:physiopathology; D009133:Muscular Atrophy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D009154:Mutation / Q000235:genetics; D009469:Neuromuscular Junction / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D021122:Protein Subunits / Q000235:genetics; D009435:Synaptic Transmission / Q000235:genetics*
D000109:Acetylcholine; D015220:Calcium Channels; D020864:Calcium Channels, N-Type; D020908:Calcium Channels, R-Type; D027682:Cation Transport Proteins; D021122:Protein Subunits; C500963:Cacna1b protein, mouse; C498916:Cacna1e protein, mouse