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

• DOI: 10.1523/jneurosci.0497-05.2005
• Publication Date: 2005-04-27T19:52:58Z
• Authors: Weiqi Zhang; Astrid Rohlmann; Vardanush Sargsyan; Gayane Aramuni; Robert E. Hammer; Thomas C. Südhof; Markus Missler
• Keywords: 6-Cyano-7-nitroquinoxaline-2,3-dione; 0303 health sciences; Blotting, Western; Excitatory Postsynaptic Potentials; Dose-Response Relationship, Radiation; Mice, Transgenic; Nerve Tissue Proteins; Calcium Channels, P-Type; Calcium Channel Blockers; Electric Stimulation; Membrane Potentials; 3. Good health; Mice; 03 medical and health sciences; Calcium Channels, N-Type; Animals, Newborn; Animals; Immunoprecipitation; Calcium; Excitatory Amino Acid Antagonists; Horseradish Peroxidase; Brain Stem; Glycoproteins

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 Ca2+channels were impaired. It remained unclear, however, which neurexin variants actually influence exocytosis and Ca2+channels, which domain of neurexins is required for this function, and which Ca2+-channel subtypes are regulated. Here, we show by electrophysiological recordings that transgenic neurexin 1α rescues the release and Ca2+-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 Ca2+channels, but left L-type Ca2+channels unscathed. Our findings indicate that α-neurexins represent organizer molecules in neurotransmission that regulate N- and P/Q-type Ca2+channels, constituting an essential role at synapses that critically involves the extracellular domains of neurexins.