PKC-dependent phosphorylation of Munc18a at Ser313 in activated RBL-2H3 cells

Adhikari, Pratikshya; Xu, Hao

doi:10.1007/s00011-017-1097-4

Cited by 8 publications

(4 citation statements)

References 9 publications

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“…As a result, the affinity of STXBP1 for syntaxin 1A was reduced, and the outcome was a change in exocytosis kinetics . Similar observations were reported in other cell systems (Adhikari, & Xu, 2018). We compare the interaction energies of STXBP1-syntaxin 1A for the WT and R39dup…”

Section: Mutation Effect On the Phosphorylation Of Stxbp1supporting

confidence: 74%

De novo STXBP1 mutation in a child with developmental delay and spasticity reveals a major structural alteration in the interface with syntaxin 1A

Banne

Falik‐Zaccai

Brielle

et al. 2020

American J of Med Genetics Pt B

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STXBP1, also known as Munc‐18, is a master regulator of neurotransmitter release and synaptic function in the human brain through its direct interaction with syntaxin 1A. STXBP1 binds syntaxin 1A is an inactive conformational state. STXBP1 decreases its binding affinity to syntaxin upon phosphorylation, enabling syntaxin 1A to engage in the SNARE complex, leading to neurotransmitter release. STXBP1‐related disorders are well characterized by encephalopathy with epilepsy, and a diverse range of neurological and neurodevelopmental conditions. Through exome sequencing of a child with developmental delay, hypotonia, and spasticity, we found a novel de novo insertion mutation of three nucleotides in the STXBP1 coding region, resulting in an additional arginine after position 39 (R39dup). Inconclusive results from state‐of‐the‐art variant prediction tools mandated a structure‐based approach using molecular dynamics (MD) simulations of the STXBP1–syntaxin 1A complex. Comparison of the interaction interfaces of the wild‐type and the R39dup complexes revealed a reduced interaction surface area in the mutant, leading to destabilization of the protein complex. Moreover, the decrease in affinity toward syntaxin 1A is similar for the phosphorylated STXBP1 and the R39dup. We applied the same MD methodology to seven additional previously reported STXBP1 mutations and reveal that the stability of the STXBP1–syntaxin 1A interface correlates with the reported clinical phenotypes. This study provides a direct link between the outcome of a novel variant in STXBP1 and protein structure and dynamics. The structural change upon mutation drives an alteration in synaptic function.

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Section: Mutation Effect On the Phosphorylation Of Stxbp1supporting

confidence: 74%

De novo STXBP1 mutation in a child with developmental delay and spasticity reveals a major structural alteration in the interface with syntaxin 1A

Banne

Falik‐Zaccai

Brielle

et al. 2020

American J of Med Genetics Pt B

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“…HO-1 is one of the key downstream genes induced by Nrf2 signaling pathway with important antioxidant and cytoprotective effects via a reduction in intracellular levels of the prooxidant Heme and by the increased production of cytoprotective levels of carbon monoxide (CO) and biliverdin (BV) [ 63 ]. Not surprisingly, we noted a significant dose- and time-dependent induction of HO-1 expression in response to ECT Cd exposure.…”

Section: Discussionmentioning

confidence: 99%

Zinc protects against cadmium-induced toxicity in neonatal murine engineered cardiac tissues via metallothionein-dependent and independent mechanisms

Zhen

et al. 2019

Acta Pharmacol Sin

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Cadmium (Cd) is a nonessential heavy metal and a prevalent environmental toxin that has been shown to induce significant cardiomyocyte apoptosis in neonatal murine engineered cardiac tissues (ECTs). In contrast, zinc (Zn) is a potent metallothionein (MT) inducer, which plays an important role in protection against Cd toxicity. In this study, we investigated the protective effects of Zn against Cd toxicity in ECTs and explore the underlying mechanisms. ECTs were constructed from neonatal ventricular cells of wild-type (WT) mice and mice with global MT gene deletion (MT-KO). In WT-ECTs, Cd (5−20 μM) caused a dose-dependent toxicity that was detected within 8 h evidenced by suppressed beating, apoptosis, and LDH release; Zn (50−200 μM) dose-dependently induced MT expression in ECTs without causing ECT toxicity; co-treatment of ECT with Zn (50 µM) prevented Cd-induced toxicity. In MT-KO ECTs, Cd toxicity was enhanced; but unexpectedly, cotreatment with Zn provided partial protection against Cd toxicity. Furthermore, Cd, but not Zn, significantly activated Nrf2 and its downstream targets, including HO-1; inhibition of HO-1 by a specific HO-1 inhibitor, ZnPP (10 µM), significantly increased Cd-induced toxicity, but did not inhibit Zn protection against Cd injury, suggesting that Nrf2-mediated HO-1 activation was not required for Zn protective effect. Finally, the ability of Zn to reduce Cd uptake provided an additional MT-independent mechanism for reducing Cd toxicity. Thus, Zn exerts protective effects against Cd toxicity for murine ECTs that are partially MT-mediated. Further studies are required to translate these findings towards clinical trials.

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“…The main caveats with these studies, some with opposite findings, are that the interference with expression or function of Stx was only partial, few tested Stx3 and -4 in the same experimental paradigms, none dissected the effects on compound exocytosis, and most relied on cell lines. We found that interfering with expression of synaptotagmin-2 (41) and Munc18-1 (42,43) in RBL-2H3 cells had different effects on exocytosis than their elimination in mature MCs (19,22). Thus, we chose to interrogate the impact of complete removal of Stx3 and Stx4 on single-vesicle and compound exocytosis in fully developed MCs.…”

Section: Mast Cells (Mcs) Participate In Allergy Inflammation and Dmentioning

confidence: 99%

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

Sánchez

Gonzalez

Moreno

et al. 2019

Journal of Biological Chemistry

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PKC-dependent phosphorylation of Munc18a at Ser313 in activated RBL-2H3 cells

Cited by 8 publications

References 9 publications

De novo STXBP1 mutation in a child with developmental delay and spasticity reveals a major structural alteration in the interface with syntaxin 1A

De novo STXBP1 mutation in a child with developmental delay and spasticity reveals a major structural alteration in the interface with syntaxin 1A

Zinc protects against cadmium-induced toxicity in neonatal murine engineered cardiac tissues via metallothionein-dependent and independent mechanisms

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

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