Compensatory contribution of Cav2.3 channels to acetylcholine release at the neuromuscular junction of Tottering mice

Tottering (Tg) mice carry the mutation P601L in their Cacnala encoded Ca(v)2.1 channels. Transmitter release at the wild-type neuromuscular junction (NMJ) is almost exclusively mediated by Ca(v)2.1 channels, and we used this model synapse to study synaptic consequences of the Tg mutation. With electrophysiology, and using subtype-specific Ca(v)2 channel-blocking toxins, we assessed a possible compensatory contribution of non-Ca(v)2.1 channels to evoked acetylcholine (ACh) release at Tg NMJs. Release was reduced by similar to 75% by the Ca(v)2.1 channel blocker omega-agatoxin-IVA, which was less than the similar to 95% reduction observed in wild-type. Release at Tg NMJs, but not at wild-type synapses, was reduced by similar to 15% by SNX-482, a Ca(v)2.3 channel blocker. No Ca(v)2.2 channel involvement was found. Probably, there is a small reduction in functional presynaptic Ca(v)2.1 channels at Tg NMJs, which is compensated for by Ca(v)2.3 channels. The remaining Ca(v)2.1 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-Ca(v)2.1 channels at NMJs of mice with a single amino acid change in Ca(v)2.1.