Extracellular Domains of α-Neurexins Participate in Regulating Synaptic Transmission by Selectively Affecting N- and P/Q-Type Ca²⁺Channels

<jats:p>Neurexins constitute a large family of highly variable cell-surface molecules that may function in synaptic transmission and/or synapse formation. Each of the three known neurexin genes encodes two major neurexin variants, α- and β-neurexins, that are composed of distinct extracellular domains linked to identical intracellular sequences. Deletions of one, two, or all three α-neurexins in mice recently demonstrated their essential role at synapses. In multiple α-neurexin knock-outs, neurotransmitter release from excitatory and inhibitory synapses was severely reduced, primarily probably because voltage-dependent Ca<jats:sup>2+</jats:sup>channels were impaired. It remained unclear, however, which neurexin variants actually influence exocytosis and Ca<jats:sup>2+</jats:sup>channels, which domain of neurexins is required for this function, and which Ca<jats:sup>2+</jats:sup>-channel subtypes are regulated. Here, we show by electrophysiological recordings that transgenic neurexin 1α rescues the release and Ca<jats:sup>2+</jats:sup>-current phenotypes, whereas transgenic neurexin 1β has no effect, indicating the importance of the extracellular sequences for the function of neurexins. Because neurexin 1α rescued the knock-out phenotype independent of the α-neurexin gene deleted, these data are consistent with a redundant function among different α-neurexins. In both knock-out and transgenically rescued mice, α-neurexins selectively affected the component of neurotransmitter release that depended on activation of N- and P/Q-type Ca<jats:sup>2+</jats:sup>channels, but left L-type Ca<jats:sup>2+</jats:sup>channels unscathed. Our findings indicate that α-neurexins represent organizer molecules in neurotransmission that regulate N- and P/Q-type Ca<jats:sup>2+</jats:sup>channels, constituting an essential role at synapses that critically involves the extracellular domains of neurexins.</jats:p>