α-Neurexins couple Ca2+ channels to synaptic vesicle exocytosis

Synapses are specialized intercellular junctions in which cell adhesion molecules connect the presynaptic machinery for neurotransmitter release to the postsynaptic machinery for receptor signalling. Neurotransmitter release requires the presynaptic co-assembly of Ca 2+ channels with the secretory apparatus, but little is known about how synaptic components are organized. α-Neurexins, a family of >1,000 presynaptic cell-surface proteins encoded by three genes, link the pre- and postsynaptic compartments of synapses by binding extracellularly to postsynaptic cell adhesion molecules and intracellularly to presynaptic PDZ domain proteins. Using triple-knockout mice, we show that α-neurexins are not required for synapse formation, but are essential for Ca 2+ -triggered neurotransmitter release. Neurotransmitter release is impaired because synaptic Ca 2+ channel function is markedly reduced, although the number of cell-surface Ca 2+ channels appears normal. These data suggest that α-neurexins organize presynaptic terminals by functionally coupling Ca 2+ channels to the presynaptic machinery.