Redundancy of Cav2.1 channel accessory subunits in transmitter release at the mouse neuromuscular junction

Cav2.1 (P/Q-type) channels possess a voltage-sensitive pore-forming α1 subunit that can associate with the accessory subunits α2δ, β and γ. The primary role of Cav2.1 channels is to mediate transmitter release from nerve terminals both in the central and peripheral nervous system. Whole-cell voltage-clamp studies in in vitro expression systems have indicated that accessory channel subunits can have diverse modulatory effects on membrane expression and biophysical properties of Cav2.1 channels. However, there is only limited knowledge on whether similar modulation also occurs in the specific presynaptic environment in vivo and, hence, whether accessory subunits influence neurotransmitter release. Ducky, lethargic and stargazer are mutant mice that lack functional α2δ-2, β4 and γ2 accessory Cav channel subunits, respectively. The neuromuscular junction (NMJ) is a peripheral synapse, where transmitter release is governed exclusively by Cav2.1 channels, and which can be characterized electrophysiologically with relative experimental ease. In order to investigate a possible synaptic influence of accessory subunits in detail, we electrophysiologically measured acetylcholine (ACh) release at NMJs of these three mutants. Surprisingly, we did not find any changes compared to wild-type littermates, other than a small reduction (25%) of evoked ACh release at ducky NMJs. This effect is most likely due to the ∼ 40% reduced synapse size, associated with the reduced size of ducky mice, rather than resulting directly from reduced Cav2.1 channel function due to α2δ-2 absence. We conclude that α2δ-2, β4, and γ2 accessory subunits are redundant for the transmitter release-mediating function of presynaptic Cav2.1 channels at the mouse NMJ.