A Single Amino Acid Mutation in SNAP-25 Induces Anxiety-Related Behavior in Mouse

Kataoka, Masakazu; Yamamori, Saori; Suzuki, Eiji; Watanabe, Shigeru; Sato, Taku; Miyaoka, Hiroaki; Azuma, Sadahiro; Ikegami, Shiro; Kuwahara, Reiko; Suzuki-Migishima, Rika; Nakahara, Yohko; Nihonmatsu, Itsuko; Inokuchi, Kaoru; Katoh‐Fukui, Yuko; Yokoyama, Minesuke; Takahashi, Masami

doi:10.1371/journal.pone.0025158

Cited by 64 publications

(55 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…33 Still other studies indicate that prenatal replacement of the mature Snap25b isoform with Snap25a isoform results in developmental defects, seizures, and impaired short-term plasticity, while the introduction of the isoform change in adult mice results in severe learning impairment, morphologic changes in hippocampus, and altered neuropeptide expression. 34 Finally, in Drosophila melanogaster with a wild-type background, a heterozygous Arg206Ala (198 in vertebrates) mutation in Snap25b at a botulinum toxin A cleavage site curtails the MEPP frequency at the neuromuscular junction and is predicted to hinder contacts within rosettes of SNARE complexes that assemble to effect fusion of the synaptic vesicle with the presynaptic membrane. 35 SNAP25B has also been implicated in the pathogenesis of schizophrenia by studies showing altered transcript or protein levels in brain.…”

mentioning

confidence: 99%

Mutant SNAP25B causes myasthenia, cortical hyperexcitability, ataxia, and intellectual disability

et al. 2014

View full text Add to dashboard Cite

Objective: To identify and characterize the molecular basis of a syndrome associated with myasthenia, cortical hyperexcitability, cerebellar ataxia, and intellectual disability.Methods: We performed in vitro microelectrode studies of neuromuscular transmission, performed exome and Sanger sequencing, and analyzed functional consequences of the identified mutation in expression studies.Results: Neuromuscular transmission at patient endplates was compromised by reduced evoked quantal release. Exome sequencing identified a dominant de novo variant, p.Ile67Asn, in SNAP25B, a SNARE protein essential for exocytosis of synaptic vesicles from nerve terminals and of dense-core vesicles from endocrine cells. Ca 21 -triggered exocytosis is initiated when synaptobrevin attached to synaptic vesicles (v-SNARE) assembles with SNAP25B and syntaxin anchored in the presynaptic membrane (t-SNAREs) into an a-helical coiled-coil held together by hydrophobic interactions. Pathogenicity of the Ile67Asn mutation was confirmed by 2 measures. First, the Ca 21 triggered fusion of liposomes incorporating v-SNARE with liposomes containing t-SNAREs was hindered when t-SNAREs harbored the mutant SNAP25B moiety. Second, depolarization of bovine chromaffin cells transfected with mutant SNAP25B or with mutant plus wildtype SNAP25B markedly reduced depolarization-evoked exocytosis compared with wild-type transfected cells. Conclusion:Ile67Asn variant in SNAP25B is pathogenic because it inhibits synaptic vesicle exocytosis. We attribute the deleterious effects of the mutation to disruption of the hydrophobic a-helical coiled-coil structure of the SNARE complex by replacement of a highly hydrophobic isoleucine by a strongly hydrophilic asparagine. Neurology ® 2014;83:2247-2255 GLOSSARY AChR 5 acetylcholine receptor; cDNA 5 complementary DNA; CMS 5 congenital myasthenic syndrome; EP 5 endplate; MEPP 5 miniature endplate potential; SNAP25B 5 synaptosomal-associated protein, 25B; SNARE 5 soluble N-ethylmaleimide-sensitive factor attachment protein receptor; t-SNAREs 5 target membrane-attached SNAP25B and syntaxin; v-SNARE 5 synaptic vesicle-attached synaptobrevin.The SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins are core components of the synaptic vesicle fusion machinery. Synaptobrevin attached to the synaptic vesicles is referred to as a v-SNARE, and SNAP25 (synaptosomal-associated protein of 25 kD) and syntaxin attached to the target plasma membrane are designated as t-SNAREs.1 The assembled complex is a coiled-coil in which a-helices are held together by strong hydrophobic interactions. The complex is stabilized by complexin, a small soluble neuronal protein.2 In the resting state, Munc18 binds to a closed form of syntaxin and blocks formation of the SNARE complex but assists the SNARE complex to effect exocytosis in the active state. 3 SNAP25 also participates in endocytosis at hippocampal synapses 4 and negatively modulates the neuronal voltage-gated calcium channel during intense activity.5 Also, ...

show abstract

mentioning

confidence: 99%

Mutant SNAP25B causes myasthenia, cortical hyperexcitability, ataxia, and intellectual disability

et al. 2014

View full text Add to dashboard Cite

show abstract

“…The most compelling evidence for physiologically relevant phosphorylation-dependent control of SNAP-25 is that knock-in mice expressing a SNAP-25 mutant that cannot be phosphorylated display neurological defects including anxiety and epilepsy [131, 132]. SNAP-25 phosphorylation was first observed in vitro and was quickly shown to occur in response to PMA treatment in PC12 cells, correlating with enhanced exocytosis [109, 133].…”

Section: What Are the Local Exocytotic Protein Targets Of Pkc?mentioning

confidence: 99%

Regulation of insulin exocytosis by calcium-dependent protein kinase C in beta cells

Trexler

Taraska

2017

Cell Calcium

View full text Add to dashboard Cite

The control of insulin release from pancreatic beta cells helps ensure proper blood glucose levels, which is critical for human health. Protein kinase C has been shown to be one key control mechanism for this process. After glucose stimulation, calcium influx into beta cells triggers exocytosis of insulin-containing dense-core granules and activates protein kinase C via calcium-dependent phospholipase C-mediated generation of diacylglycerol. Activated protein kinase C potentiates insulin release by enhancing the calcium sensitivity of exocytosis, likely by affecting two main pathways that could be linked: 1) the reorganization of the cortical actin network, and 2) the direct phosphorylation of critical exocytotic proteins such as munc18, SNAP25, and synaptotagmin. Here, we review what is currently known about the molecular mechanisms of protein kinase C action on each of these pathways and how these effects relate to the control of insulin release by exocytosis. We identify remaining challenges in the field and suggest how these challenges might be addressed to advance our understanding of the regulation of insulin release in health and disease.

show abstract

“…Impaired phosphorylation of SNAP-25 reduces the SNAP-25-syntaxin protein-protein interaction (Nakata et al, 2012). These animals are anxious, may have seizures, as well as impaired dopamine and serotonin release in the amygdala (Kataoka et al, 2011). …”

Section: Introductionmentioning

confidence: 99%

Quantitative mass spectrometry reveals changes in SNAP-25 isoforms in schizophrenia

Barakauskas

Moradian

Barr

et al. 2016

Schizophrenia Research

View full text Add to dashboard Cite

SNAP-25 and syntaxin are presynaptic terminal SNARE proteins altered in amount and function in schizophrenia. In the ventral caudate, we observed 32% lower SNAP-25 and 26% lower syntaxin, but greater interaction between the two proteins using an in vitro assay. SNAP-25 has two isoforms, SNAP-25A and B, differing by only 9 amino acids, but with different effects on neurotransmission. A quantitative mass spectrometry assay was developed to measure total SNAP-25, and proportions of SNAP-25A and B. The assay had a good linear range (50- to 150-fold) and coefficient of variation (4.5%). We studied ventral caudate samples from patients with schizophrenia (n=15) previously reported to have lower total SNAP-25 than controls (n=13). We confirmed 27% lower total SNAP-25 in schizophrenia, and observed 31% lower SNAP-25A (P = 0.002) with 20% lower SNAP-25B amounts (P = 0.10). Lower SNAP-25A amount correlated with greater SNAP-25-syntaxin protein-protein interactions (r = -0.41, P = 0.03); the level of SNAP-25B did not. Administration of haloperidol or clozapine to rats did not mimic the changes found in schizophrenia. The findings suggest that lower levels of SNAP-25 in schizophrenia may represent a greater effect of the illness on the SNAP-25A isoform. This in turn could contribute to the greater interaction between SNAP25 and syntaxin, and possibly disturb neurotransmission in the illness.

show abstract

A Single Amino Acid Mutation in SNAP-25 Induces Anxiety-Related Behavior in Mouse

Cited by 64 publications

References 38 publications

Mutant SNAP25B causes myasthenia, cortical hyperexcitability, ataxia, and intellectual disability

Mutant SNAP25B causes myasthenia, cortical hyperexcitability, ataxia, and intellectual disability

Regulation of insulin exocytosis by calcium-dependent protein kinase C in beta cells

Quantitative mass spectrometry reveals changes in SNAP-25 isoforms in schizophrenia

Contact Info

Product

Resources

About