title: Compensatory contribution of Cav2.3 channels to acetylcholine release at the neuromuscular junction of tottering mice.
abstract: Tottering (Tg) mice carry the mutation P601L in their Cacna1a encoded Cav2.1 channels. Transmitter release at the wild-type neuromuscular junction (NMJ) is almost exclusively mediated by Cav2.1 channels, and we used this model synapse to study synaptic consequences of the Tg mutation. With electrophysiology, and using subtype-specific Cav2 channel-blocking toxins, we assessed a possible compensatory contribution of non-Cav2.1 channels to evoked acetylcholine (ACh) release at Tg NMJs. Release was reduced by approximately 75% by the Cav2.1 channel blocker omega-agatoxin-IVA, which was less than the approximately 95% reduction observed in wild-type. Release at Tg NMJs, but not at wild-type synapses, was reduced by approximately 15% by SNX-482, a Cav2.3 channel blocker. No Cav2.2 channel involvement was found. Probably, there is a small reduction in functional presynaptic Cav2.1 channels at Tg NMJs, which is compensated for by Cav2.3 channels. The remaining Cav2.1 channels are likely to convey enlarged Ca2+ flux, because evoked ACh release at Tg NMJs, at low extracellular Ca2+ concentration, was approximately sixfold higher than at wild-type NMJs. This is the first report of compensatory expression of non-Cav2.1 channels at NMJs of mice with a single amino acid change in Cav2.1.
authors.affiliation: Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Simon
authors.initials: S
authors.lastname: Kaja
authors.forename: Rob C G
authors.initials: RC
authors.lastname: Van de Ven
authors.forename: Michel D
authors.initials: MD
authors.lastname: Ferrari
authors.forename: Rune R
authors.initials: RR
authors.lastname: Frants
authors.forename: Arn M J M
authors.initials: AM
authors.lastname: Van den Maagdenberg
authors.forename: Jaap J
authors.initials: JJ
authors.lastname: Plomp
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000032:analysis / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020864:Calcium Channels, N-Type / Q000032:analysis / Q000502:physiology; D020865:Calcium Channels, P-Type / Q000235:genetics* / Q000502:physiology; D020907:Calcium Channels, Q-Type / Q000235:genetics* / Q000502:physiology; D020908:Calcium Channels, R-Type / Q000502:physiology*; D027682:Cation Transport Proteins / Q000502:physiology*; D004594:Electrophysiology; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D009469:Neuromuscular Junction / Q000737:chemistry / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013111:Spider Venoms / Q000494:pharmacology; D013569:Synapses / Q000502:physiology; D020867:omega-Agatoxin IVA / Q000494:pharmacology
chemical_list: D000109:Acetylcholine; D002118:Calcium; D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D020908:Calcium Channels, R-Type; D027682:Cation Transport Proteins; D013111:Spider Venoms; D020867:omega-Agatoxin IVA; C500963:Cacna1b protein, mouse; C498916:Cacna1e protein, mouse; C115521:SNX 482