TY - JOUR
T1 - Extracellular domains of α-neurexins participate in regulating synaptic transmission by selectively affecting N- and P/Q-type Ca2+ channels
AU - Zhang, Weiqi
AU - Rohlmann, Astrid
AU - Sargsyan, Vardanush
AU - Aramuni, Gayane
AU - Hammer, Robert E
AU - Südhof, Thomas C.
AU - Missler, Markus
PY - 2005/4/27
Y1 - 2005/4/27
N2 - 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 Ca 2+ channels, constituting an essential role at synapses that critically involves the extracellular domains of neurexins.
AB - 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 Ca 2+ channels, constituting an essential role at synapses that critically involves the extracellular domains of neurexins.
KW - Brainstem
KW - Calcium channels
KW - Cell adhesion
KW - Synapse
KW - Transgenic mouse
KW - Transmission
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U2 - 10.1523/JNEUROSCI.0497-05.2005
DO - 10.1523/JNEUROSCI.0497-05.2005
M3 - Article
C2 - 15858059
AN - SCOPUS:18244407522
SN - 0270-6474
VL - 25
SP - 4330
EP - 4342
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 17
ER -