A syntaxin-related protein controls acetylcholine release by different mechanisms inAplysia

Smirnova, T.N.; Fossier, Philippe; Stinnakre, Jacques; Mallet, Jacques; Baux, Gérard

doi:10.1016/0306-4522(95)00134-5

Cited by 18 publications

(14 citation statements)

References 25 publications

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“…The net result of substrate occupation of the transporter would be to increase substrate translocation and thus reduce transmitter signaling. This negative regulation of signaling is consistent with that seen for the interaction of syntaxin 1A and certain calcium channels, where increased calcium levels lead to an increase in the affinity of the interaction (47); this interaction in turn reduces calcium channel function (6)(7)(8)(9)(10). Thus, via syntaxin 1A, both calcium channel and transmitter transporter substrates directly regulate their own permeation, providing an efficient mechanism by which to negatively regulate synaptic signaling.…”

Section: Discussionsupporting

confidence: 81%

Substrates regulate γ-aminobutyric acid transporters in a syntaxin 1A-dependent manner

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2002

Proc. Natl. Acad. Sci. U.S.A.

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Several ion channels and pumps are regulated by syntaxin 1A, a component of the synaptic vesicle docking and fusion apparatus. One such regulated protein is the rat brain ␥-aminobutyric acid (GABA) transporter GAT1. The N-terminal cytoplasmic domain of GAT1 directly interacts with syntaxin 1A; this interaction induces a decrease in the rate at which GABA and associated ions are transported. GAT1 function also is regulated by transporter substrates, raising the possibility that substrates mediate at least some of their effects by regulating the interaction between GAT1 and syntaxin 1A. In oocytes expressing GAT1 and syntaxin 1A, superfusion of transporter substrates increases the GAT1 transport rate. The substrate-induced rate change (i) is prevented by coapplication of GAT1 antagonists, (ii) does not occur in oocytes expressing GAT1 alone, and (iii) does not occur in oocytes expressing interactiondeficient syntaxin 1A mutants. In oocytes, and in hippocampal neurons that endogenously express both GAT1 and syntaxin 1A, substrate application results in a decrease in the fraction of syntaxin 1A that is bound to GAT1 on a time-scale comparable to the substrate-induced change in transport rates. These data suggest that substrate translocation regulates GAT1-syntaxin 1A interactions and provide a mechanism by which GABA transport can be increased during times of rising synaptic GABA concentrations. Syntaxin 1A was originally characterized as a component of the machinery involved in transmitter release (1, 2), and is a key player in vesicle trafficking and fusion (3, 4). Syntaxin 1A directly interacts and functionally regulates several excitability proteins, including Ca 2ϩ channels (5-10), cystic fibrosis Cl Ϫ channels (11, 12), K ϩ channels (13), and epithelial Na ϩ channels (14, 15). Mechanisms of the effects of syntaxin 1A include changes in protein trafficking and in channel properties such as gating. Syntaxin 1A also regulates Na ϩ and Cl Ϫ -dependent neurotransmitter transporters (16)(17)(18)(19). For example, glycine transporter trafficking is altered by syntaxin 1A coexpression (19). Syntaxin 1A alters not only trafficking of the rat brain ␥-aminobutyric acid (GABA) transporter GAT1 but also its rate of substrate translocation. The GAT1 N-terminal cytoplasmic tail binds the H3 domain of syntaxin 1A; the interaction causes a 4-fold decrease in substrate transport rates (18). These data suggest that protein-protein interactions regulate substrate translocation and identify a link between the machinery involved in transmitter release and uptake.Syntaxin 1A interactions are not the only mechanism by which GAT1 and other transporters are regulated (20, 21). For example, protein kinase C activation correlates with both decreases in GABA transport and decreases in surface GAT1 expression (17,22,23). Tyrosine phosphorylation of GAT1 increases GAT1 surface expression by decreasing the transporter internalization rate (24). Additionally, as with the transporters for serotonin (25), dopamine (26), and norepinephrine (27),...

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Section: Discussionsupporting

confidence: 81%

Substrates regulate γ-aminobutyric acid transporters in a syntaxin 1A-dependent manner

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2002

Proc. Natl. Acad. Sci. U.S.A.

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“…tion, potentially reducing transmitter release, and this inhibitory effect is relieved by other SNARE proteins and synaptotagmin (Bezprozvanny et al, 1995;Smirnova et al, 1995;Wiser et al, 1996;Sutton et al, 1999;Zhong et al, 1999;Bergsman and Tsien, 2000;Degtiar et al, 2000;Jarvis et al, 2000Jarvis et al, , 2002Zamponi, 2003). How would these apparently opposing actions affect synaptic transmission in vivo?…”

Section: Discussionmentioning

confidence: 99%

“…The decrease in transmitter release was interpreted to be attributable to dissociation of the Ca 2ϩ channel from the Ca 2ϩ sensor for transmitter release. Other experiments suggest that the interaction between syntaxin 1A and the synprint site enhances calcium channel inactivation (Bezprozvanny et al, 1995;Wiser et al, 1996;Degtiar et al, 2000;Bergsman and Tsien, 2000;Jarvis et al, 2000Jarvis et al, , 2002Smirnova et al, 1995;Sutton et al, 1999;Zhong et al, 1999;Zamponi, 2003). In particular, coexpression of syntaxin 1A with N-type Ca 2ϩ channels in Xenopus oocytes increases inactivation, but a mutant form of syntaxin 1A (A240V, V244A) binds to the channel without functional effect (Bezprozvanny et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Bidirectional Modulation of Transmitter Release by Calcium Channel/Syntaxin InteractionsIn Vivo

Keith¹,

Poage²,

Yokoyama³

et al. 2007

J. Neurosci.

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Protein interactions within the active zone of the nerve terminal are critical for regulation of transmitter release. The SNARE protein syntaxin 1A, primarily known for important interactions that control vesicle fusion, also interacts with presynaptic voltage-gated calcium channels. Based on recordings of calcium channel function in vitro, it has been hypothesized that syntaxin 1A-calcium channel interactions could alter calcium channel function at synapses. However, results at synapses in vitro suggest two potentially opposing roles: enhancement of neurotransmitter release by positioning docked vesicles near calcium channels and inhibition of calcium channel function by interaction with SNARE proteins. We have examined the possibility that these two effects of syntaxin can occur at synapses by studying the effects on transmitter release of manipulating syntaxin 1A-calcium channel interactions at Xenopus tadpole tail neuromuscular synapses in vivo. Introduction of synprint peptides, which competitively perturb syntaxin 1A-calcium channel interactions, decreased quantal content at these synapses and increased paired-pulse and tetanic facilitation. In contrast, injecting mRNA for mutant (A240V, V244A) syntaxin 1A, which reduces calcium channel modulation but not binding in vitro, increased quantal content and decreased paired-pulse and tetanic facilitation. Injection of wild-type syntaxin 1A mRNA had no effect. The opposing effects of synprint peptides and mutant syntaxin 1A provide in vivo support for the hypothesis that these interactions serve both to colocalize calcium channels with the release machinery and to modulate the functional state of the calcium channel. As such, these two effects of syntaxin on calcium channels modulate transmitter release in a bidirectional manner.

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“…In addition to serving an anchoring role, interactions between syntaxin and Ca 2ϩ channels may also cause inhibition of Ca 2ϩ channels in expression systems (6,(19)(20)(21)(22)(23) as well as in isolated nerve terminals (24). Syntaxin acts by promoting the slow inactivation of Ca 2ϩ channels (25).…”

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confidence: 99%

Molecular determinants of the functional interaction between syntaxin and N-type Ca ²⁺ channel gating

Bezprozvanny

Zhong

Scheller

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

103

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Syntaxin is a key presynaptic protein that binds to N-and P͞Q-type Ca 2؉ channels in biochemical studies and affects gating of these Ca 2؉ channels in expression systems and in synaptosomes. The present study was aimed at understanding the molecular basis of syntaxin modulation of N-type channel gating. Mutagenesis of either syntaxin 1A or the pore-forming ␣1B subunit of N-type Ca 2؉ channels was combined with functional assays of N-type channel gating in a Xenopus oocyte coexpression system and in biochemical binding experiments in vitro. Our analysis showed that the transmembrane region of syntaxin and a short region within the H3 helical cytoplasmic domain of syntaxin, containing residues Ala-240 and Val-244, appeared critical for the channel modulation but not for biochemical association with the ''synprint site'' in the II͞III loop of ␣1B. These results suggest that syntaxin and the ␣1B subunit engage in two kinds of interactions: an anchoring interaction via the II͞III loop synprint site and a modulatory interaction via another site located elsewhere in the channel sequence. The segment of syntaxin H3 found to be involved in the modulatory interaction would lie hidden within the four-helix structure of the SNARE complex, supporting the hypothesis that syntaxin's ability to regulate N-type Ca 2؉ channels would be enabled after SNARE complex disassembly after synaptic vesicle exocytosis.

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A syntaxin-related protein controls acetylcholine release by different mechanisms inAplysia

Cited by 18 publications

References 25 publications

Substrates regulate γ-aminobutyric acid transporters in a syntaxin 1A-dependent manner

Substrates regulate γ-aminobutyric acid transporters in a syntaxin 1A-dependent manner

Bidirectional Modulation of Transmitter Release by Calcium Channel/Syntaxin InteractionsIn Vivo

Molecular determinants of the functional interaction between syntaxin and N-type Ca ²⁺ channel gating

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A syntaxin-related protein controls acetylcholine release by different mechanisms inAplysia

Cited by 18 publications

References 25 publications

Substrates regulate γ-aminobutyric acid transporters in a syntaxin 1A-dependent manner

Substrates regulate γ-aminobutyric acid transporters in a syntaxin 1A-dependent manner

Bidirectional Modulation of Transmitter Release by Calcium Channel/Syntaxin InteractionsIn Vivo

Molecular determinants of the functional interaction between syntaxin and N-type Ca 2+ channel gating

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Molecular determinants of the functional interaction between syntaxin and N-type Ca ²⁺ channel gating