Syntaxin 3, but not syntaxin 4, is required for mast cell–regulated exocytosis, where it plays a primary role mediating compound exocytosis

Sánchez, Elizabeth; Gonzalez, Erika A.; Moreno, David S.; Cardenas, Rodolfo A.; Ramos, Marco A.; Dávalos, Alfredo J.; Manllo, John; Rodarte, Alejandro I.; Petrova, Youlia; Moreira, Daniel C.; Chavez, Miguel A.; Tortoriello, Alejandro; Lara, Adolfo; Gutierrez, Berenice A.; Burns, Alan R.; Heidelberger, Ruth; Adachi, Roberto

doi:10.1074/jbc.ra118.005532

Cited by 28 publications

(33 citation statements)

References 71 publications

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“…Generation of forebrain-specific syntaxin-3 cKO mice. Since global knockout of syntaxin-3 in mice leads to embryonic lethality 19 , we generated pyramidal neuron specific KO of syntaxin-3. We used syntaxin-3 flox mice that were previously successfully utilized in generating a mast cell specific syntaxin-3 cKO 19 .…”

Section: Resultsmentioning

confidence: 99%

“…Since global knockout of syntaxin-3 in mice leads to embryonic lethality 19 , we generated pyramidal neuron specific KO of syntaxin-3. We used syntaxin-3 flox mice that were previously successfully utilized in generating a mast cell specific syntaxin-3 cKO 19 . To eliminate syntaxin-3 expression from CA1 pyramidal neurons, we crossed syntaxin-3 flox/flox mice with mice expressing CaMK2a-Cre (Jacksons Lab) where Cre expression is distinctively strong in CA1 pyramidal neurons of the hippocampus 20,21 .…”

Section: Resultsmentioning

confidence: 99%

“…1a). Previously, the use of gene trapping in this manner had successfully eliminated the expression of syntaxin-3 in mast cells which resulted in significant impairment of exocytosis 19 .…”

Section: Resultsmentioning

confidence: 99%

“…Syntaxin-3 is an essential protein for survival in mice and is ubiquitously expressed throughout the organism, especially the brain 36 . A recent study using mast cell specific syntaxin-3 KO mice indicated an essential role of this protein in mast cell exocytosis 19 . However, our results suggest that its deletion in CA3 neurons does not impair the release of glutamate (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Generation of forebrain-specific syntaxin-3 KO mice. Syntaxin-3 flox/flox mice were previously created using embryonic stem (ES) cells from EUCOMM (clone EUCE320f12) 19 . We purchased C57BL/6 mice with CaMK2a-Cre 20 from the Jackson Laboratory and generated forebrain-specific syntaxin-3 KO mice.…”

Section: Methodsmentioning

confidence: 99%

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Syntaxin-3 is dispensable for basal neurotransmission and synaptic plasticity in postsynaptic hippocampal CA1 neurons

Shi

Harada

et al. 2020

Sci Rep

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Recent evidence suggests that SNARE fusion machinery play critical roles in postsynaptic neurotransmitter receptor trafficking, which is essential for synaptic plasticity. However, the key SNAREs involved remain highly controversial; syntaxin-3 and syntaxin-4 are leading candidates for the syntaxin isoform underlying postsynaptic plasticity. In a previous study, we showed that pyramidalneuron specific conditional knockout (cKO) of syntaxin-4 significantly reduces basal transmission, synaptic plasticity and impairs postsynaptic receptor trafficking. However, this does not exclude a role for syntaxin-3 in such processes. Here, we generated and analyzed syntaxin-3 cKO mice. Extracellular field recordings in hippocampal slices showed that syntaxin-3 cKO did not exhibit significant changes in CA1 basal neurotransmission or in paired-pulse ratios. Importantly, there were no observed differences during LTP in comparison to control mice. Syntaxin-3 cKO mice performed similarly as the controls in spatial and contextual learning tasks. Consistent with the minimal effects of syntaxin-3 cKO, syntaxin-3 mRNA level was very low in hippocampal and cortex pyramidal neurons, but strongly expressed in the corpus callosum and caudate axon fibers. Together, our data suggest that syntaxin-3 is dispensable for hippocampal basal neurotransmission and synaptic plasticity, and further supports the notion that syntaxin-4 is the major isoform mediating these processes.Synaptic transmission is essential for neuronal communication in the brain. During synaptic transmission, presynaptic neurons release neurotransmitters that bind to their respective receptors on the postsynaptic membrane. Ionotropic glutamate receptors (AMPARs and NMDARs) and GABA receptors on the postsynaptic membrane undergo receptor recycling. Receptor recycling is an essential process in synaptic plasticity such as long-term potentiation (LTP). LTP is a cellular correlate for higher-level cognitive functions of learning and memory 1-5 and requires rapid modifications in the quantity and composition of postsynaptic glutamate receptors 4,6,7 . Despite its importance, the underlying mechanisms of postsynaptic membrane receptor trafficking still remain unclear.Postsynaptic receptor trafficking employs a unique soluble NSF-attachment protein receptor (SNARE) complex that mediates the attachment and fusion of vesicles containing postsynaptic receptors to target membranes. The SNARE complex is composed of one vesicle membrane protein (v-SNARE; synaptobrevin) and two target membrane proteins (t-SNAREs; syntaxin and SNAP-25 isoforms) 8 . Botulinum neurotoxin B (BoNT/B) proteolyzes synaptobrevin-2 and when injected into CA1 pyramidal cells, blocks LTP induction 9 . This suggests that this open Scientific RepoRtS | (2020) 10:709 | https://doi.org/10.1038/s41598-019-57388-6www.nature.com/scientificreports www.nature.com/scientificreports/ v-SNARE is imperative for AMPAR delivery to the postsynaptic membrane during LTP. However, the particular isoforms of t-SNAREs involved in postsyna...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…1a). Previously, the use of gene trapping in this manner had successfully eliminated the expression of syntaxin-3 in mast cells which resulted in significant impairment of exocytosis 19 .…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Syntaxin-3 is dispensable for basal neurotransmission and synaptic plasticity in postsynaptic hippocampal CA1 neurons

Shi

Harada

et al. 2020

Sci Rep

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Increased STX3 transcript and protein levels were associated with poor prognosis in two independent cohorts of esophageal squamous cell carcinoma patients

Shinozuka,

Kanda,

Sato

et al. 2023

Cancer Medicine

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BackgroundSome conventional prognostic biomarkers for esophageal squamous cell carcinoma (ESCC) have the disadvantage that they have only been investigated at the level of either mRNA or protein levels or only in individual cohorts. Associations between Syntaxin 3 (STX3) expression and malignancy have been reported in several tumor types but not in ESCC. Here, we investigated the levels of both STX3 mRNA and protein, and its prognostic potential in two independent cohorts of patients with ESCC.MethodsSTX3 mRNA levels were examined in surgical specimens by quantitative PCR in a cohort that included 176 ESCC patients. STX3 protein levels were investigated in surgically resected ESCC tissues by immunohistochemistry using tissue microarrays in a different cohort of 177 ESCC patients. Correlations were analyzed between the expression of STX3 mRNA and protein with clinicopathological factors and long‐term prognosis.ResultsQuantitative PCR indicated a significant association between high level of STX3 mRNA expression and lymph node involvement, pathological stage, and poor overall survival. The multivariate analysis demonstrated that high STX3 mRNA expression was independently associated with poor overall survival outcomes. Immunohistochemistry revealed that STX3 protein expression in ESCC tissues and high STX3 protein expression were also significantly correlated with unfavorable overall survival.ConclusionsOverexpression of STX3 mRNA and protein may serve as potential prognostic biomarkers for ESCC patients.

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Methiothepin downregulates SNAP‐23 and inhibits degranulation of rat basophilic leukemia cells and mouse bone marrow‐derived mast cells

Kondo,

Suzuki,

Matsumura

et al. 2023

Eur J Immunol

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In the present study, we found that methiothepin (a non‐selective 5‐hydroxytryptamine (5‐HT) receptor antagonist) inhibited antigen‐induced degranulation in rat basophilic leukemia cells and mouse bone marrow‐derived mast cells. Although antigen stimulation induces release of histamine and serotonin (5‐HT) by exocytosis and mast cells express several types of 5‐HT receptor, the detailed role of these receptors remains unclear. Here, pretreatment of cells with methiothepin attenuated increased intracellular Ca2+ concentration, phosphorylated critical upstream signaling components: SFKs, Syk, and PLCγ1, and suppressed TNF‐α secretion via inhibition of Akt and ERK phosphorylation. Furthermore, it inhibited PMA/ionomycin‐induced degranulation; this finding suggested that methiothepin affected downstream signaling. IκB kinase β (IKKβ) phosphorylates synaptosomal associated protein 23 (SNAP23), which regulates the fusion events of the secretory granule/plasma membrane after mast cell activation, resulting in degranulation. We showed that methiothepin blocked PMA/ionomycin‐induced phosphorylation of SNAP23 by inhibiting its interaction with IKKβ. Together with the results of selective 5‐HT antagonists, it is suggested that methiothepin inhibits mast cell degranulation by downregulating upstream signaling pathways and exocytotic fusion machinery through mainly 5‐HT1A receptor. Our findings provide that 5‐HT antagonists may be used to relieve allergic reactions.This article is protected by copyright. All rights reserved

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Syntaxin 3, but not syntaxin 4, is required for mast cell–regulated exocytosis, where it plays a primary role mediating compound exocytosis

Cited by 28 publications

References 71 publications

Syntaxin-3 is dispensable for basal neurotransmission and synaptic plasticity in postsynaptic hippocampal CA1 neurons

Syntaxin-3 is dispensable for basal neurotransmission and synaptic plasticity in postsynaptic hippocampal CA1 neurons

Increased STX3 transcript and protein levels were associated with poor prognosis in two independent cohorts of esophageal squamous cell carcinoma patients

Methiothepin downregulates SNAP‐23 and inhibits degranulation of rat basophilic leukemia cells and mouse bone marrow‐derived mast cells

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