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The Journal of Neuroscience, June 15, 2000, 20(12):4368-4378

Syntaxin Modulation of Calcium Channels in Cortical Synaptosomes As Revealed by Botulinum Toxin C1

Jeremy B. Bergsman^{1, 2} and Richard W. Tsien²

¹ Neurosciences Program, and ² Department of Molecular and Cellular Physiology, Beckman Center, Stanford University School of Medicine, Stanford, California 94305

When the presynaptic membrane protein syntaxin is coexpressed in Xenopus oocytes with N- or P/Q-type Ca²⁺ channels, it promotes their inactivation (Bezprozvanny et al., 1995; Wiser et al., 1996, 1999; Degtiar et al., 2000) (I. B. Bezprozvanny, P. Zhong, R. H. Scheller, and R. W. Tsien, unpublished observations). These findings led to the hypothesis that syntaxin influences Ca²⁺ channel function in presynaptic endings, in a reversal of the conventional flow of information from Ca²⁺ channels to the release machinery. We examined this effect in isolated mammalian nerve terminals (synaptosomes). Botulinum neurotoxin type C1 (BoNtC1), which cleaves syntaxin, was applied to rat neocortical synaptosomes at concentrations that completely blocked neurotransmitter release. This treatment altered the pattern of Ca²⁺ entry monitored with fura-2. Whereas the initial Ca²⁺ rise induced by depolarization with K⁺-rich solution was unchanged, late Ca²⁺ entry was strongly augmented by syntaxin cleavage. Similar results were obtained when Ca²⁺ influx arose from repetitive firing induced by the K⁺-channel blocker 4-aminopyridine. Cleavage of vesicle-associated membrane protein with BoNtD or SNAP-25 with BoNtE failed to produce a significant change in Ca²⁺ entry. The BoNtC1-induced alteration in Ca²⁺ signaling was specific to voltage-gated Ca²⁺ channels, not Ca²⁺ extrusion or buffering, and it involved N-, P/Q- and R-type channels, the high voltage-activated channels most intimately associated with presynaptic release machinery. The modulatory effect of syntaxin was not immediately manifest when synaptosomes had been K⁺-predepolarized in the absence of external Ca²⁺, but developed with a delay after admission of Ca²⁺, suggesting that vesicular turnover may be necessary to make syntaxin available for its stabilizing effect on Ca²⁺ channel inactivation.

Key words: synaptosome; syntaxin; calcium channel; SNARE; synapse; synaptic vesicle; modulation; clostridium botulinum; toxin; neurotoxin; conotoxin; agatoxin; rat

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20124368-11$05.00/0

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