Transient Confinement of CaV2.1 Ca2+-Channel Splice Variants Shapes Synaptic Short-Term Plasticity

The precision and reliability of synaptic information transfer depend on the molecular organization of voltage-gated calcium channels (VGCCs) within the presynaptic membrane. Alternative splicing of exon 47 affects the C-terminal structure of VGCCs and their affinity to intracellular partners and synaptic vesicles (SVs). We show that hippocampal synapses expressing VGCCs either with exon 47 (Ca(V)2.1(+47)) or without (Ca(V)2.1(Delta 47)) differ in release probability and short-term plasticity. Tracking single channels revealed transient visits (similar to 100 ms) of presynaptic VGCCs in nanodomains (similar to 80 nm) that were controlled by neuronal network activity. Surprisingly, despite harboring prominent binding sites to scaffold proteins, CaV2.1(+47) persistently displayed higher mobility within nanodomains. Synaptic accumulation of Ca(V)2.1 was accomplished by optogenetic clustering, but only CaV2.1(+47) increased transmitter release and enhanced synaptic short-term depression. We propose that exon 47-related alternative splicing of Ca(V)2.1 channels controls synapse-specific release properties at the level of channel mobility-dependent coupling between VGCCs and SVs.