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The Journal of Neuroscience, April 27, 2005, 25(17):4330-4342; doi:10.1523/JNEUROSCI.0497-05.2005

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

Weiqi Zhang,^1 * Astrid Rohlmann,^1 * Vardanush Sargsyan,¹ Gayane Aramuni,¹ Robert E. Hammer,^2,5 Thomas C. Südhof,^3,4,5 and Markus Missler^1,6

¹Center for Physiology and Pathophysiology, Georg-August University, D-37073 Göttingen, Germany, Departments of ²Biochemistry and ³Molecular Genetics, ⁴Center for Basic Neuroscience, and ⁵Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, and ⁶Department of Genetics and Molecular Neurobiology, Otto-von-Guericke-University, D-39106 Magdeburg, Germany

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, - and -neurexins, that are composed of distinct extracellular domains linked to identical intracellular sequences. Deletions of one, two, or all three -neurexins in mice recently demonstrated their essential role at synapses. In multiple -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 1 rescues the release and Ca²⁺-current phenotypes, whereas transgenic neurexin 1 has no effect, indicating the importance of the extracellular sequences for the function of neurexins. Because neurexin 1 rescued the knock-out phenotype independent of the -neurexin gene deleted, these data are consistent with a redundant function among different -neurexins. In both knock-out and transgenically rescued mice, -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 -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.

Key words: transgenic mouse; synapse; transmission; calcium channels; cell adhesion; brainstem

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Received Sep 8, 2004; revised March 7, 2005; accepted March 16, 2005.

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