Differential Control of the Releasable Vesicle Pools by SNAP-25 Splice Variants and SNAP-23

Sørensen, Jakob B.; Nagy, Gábor; Varoqueaux, Frédérique; Nehring, Ralf B.; Brose, Nils; Wilson, Michael C.; Neher, Erwin

doi:10.1016/s0092-8674(03)00477-x

Cited by 324 publications

(396 citation statements)

References 42 publications

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“…We reported previously that the expression of the ubiquitous isoform SNAP-23 in Snap-25 null chromaffin cells supports some rescue of calcium-dependent exocytosis, but without a burst component (Sorensen et al, 2003b). Here, we first repeated this experiment with similar results, and then applied stronger stimulation into the Ͼ100 M range to investigate whether exocytosis in the presence of SNAP-23 might be shifted to higher [Ca 2ϩ ] i and therefore have gone undetected in previous studies.…”

Section: The Snap-25 Linker Domain Speeds Up Exocytosis Triggeringmentioning

confidence: 63%

“…Primary culture of mouse chromaffin cells was prepared and cultured as described previously (Sorensen et al, 2003b). SNAP-25a cysteine mutants and SNAP-25a/SNAP-23 chimeras were produced by polymerase chain reaction (PCR), and all constructs were verified by DNA sequencing.…”

Section: Cell Culture and Expression Constructsmentioning

confidence: 99%

“…Ca 2ϩ -triggered exocytosis from Snap-25 null mouse chromaffin cells is nearly abolished, but it can be rescued by viral expression of SNAP-25 isoforms (Sorensen et al, 2003b Here, we used this approach and fast electrophysiological techniques to address the role of the SNAP-25 linker domain in exocytosis. By mutating linker-cysteines in SNAP-25 and substituting the SNAP-23 linker for its SNAP-25 counterpart, we verify the function of cysteines in membrane targeting, and we show that the cysteine-containing part of the SNAP-25 and SNAP-23 linker is interchangeable.…”

Section: Introductionmentioning

confidence: 99%

“…However, other members of the family (SNAP-29, SNAP-46, Sec9, and SPO20) lack linker cysteines. It remains controversial whether palmitoylation is needed for the function of SNAP-25 in exocytosis, or only for membrane targeting, and it is unknown whether the linker plays any other, more active role in determining the special features that distinguish exocytosis from other membrane fusion reactions: calcium-triggering and a high rate of execution of the fusion process.Ca 2ϩ -triggered exocytosis from Snap-25 null mouse chromaffin cells is nearly abolished, but it can be rescued by viral expression of SNAP-25 isoforms (Sorensen et al, 2003b Here, we used this approach and fast electrophysiological techniques to address the role of the SNAP-25 linker domain in exocytosis. By mutating linker-cysteines in SNAP-25 and substituting the SNAP-23 linker for its SNAP-25 counterpart, we verify the function of cysteines in membrane targeting, and we show that the cysteine-containing part of the SNAP-25 and SNAP-23 linker is interchangeable.…”

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confidence: 99%

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The SNAP-25 Linker as an Adaptation Toward Fast Exocytosis

Nagy

Milošević

Mohrmann

et al. 2008

MBoC

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The assembly of four soluble N-ethylmaleimide-sensitive factor attachment protein receptor domains into a complex is essential for membrane fusion. In most cases, the four SNARE-domains are encoded by separate membrane-targeted proteins. However, in the exocytotic pathway, two SNARE-domains are present in one protein, connected by a flexible linker. The significance of this arrangement is unknown. We characterized the role of the linker in SNAP-25, a neuronal SNARE, by using overexpression techniques in synaptosomal-associated protein of 25 kDa (SNAP-25) null mouse chromaffin cells and fast electrophysiological techniques. We confirm that the palmitoylated linker-cysteines are important for membrane association. A SNAP-25 mutant without cysteines supported exocytosis, but the fusion rate was slowed down and the fusion pore duration prolonged. Using chimeric proteins between SNAP-25 and its ubiquitous homologue SNAP-23, we show that the cysteine-containing part of the linkers is interchangeable. However, a stretch of 10 hydrophobic and charged amino acids in the C-terminal half of the SNAP-25 linker is required for fast exocytosis and in its absence the calcium dependence of exocytosis is shifted toward higher concentrations. The SNAP-25 linker therefore might have evolved as an adaptation toward calcium triggering and a high rate of execution of the fusion process, those features that distinguish exocytosis from other membrane fusion pathways. INTRODUCTIONThe soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) are central to vesicular trafficking (Fasshauer, 2003;Jahn and Scheller, 2006;Rizo et al., 2006) and characterized by a stretch of 60 -70 amino acids, known as the SNARE motif (Terrian and White, 1997;Weimbs et al., 1997). The assembly of four SNARE domains into a coiled-coil bundle is a general mechanism in fusion of intracellular membrane compartments. The bundle is held together by layers of hydrophobic interaction, with the exception of the middle layer (layer "0"), which is formed by an arginine and three glutamines (Sutton et al., 1998). The SNARE domains can be subdivided into four homologous groups, named after their contribution to the zero layer: R, Qa, Qb, and Qc (Fasshauer et al., 1998b). SNARE assembly requires the participation of one domain from each group, resulting in a certain degree of specificity Scales et al., 2000a).In most cases, the four SNARE-domains are encoded by separate membrane-targeted proteins, but the SNAREs driving the fusion of vesicles with the plasma membrane (exocytosis) are special in that three proteins provide the four domains (Weimbs et al., 1998;Fukuda et al., 2000). One of the SNAREs in this pathway, exemplified by the best-known isoform synaptosomal-associated protein of 25 kDa (SNAP-25), seems to have been created by fusion of the Qb and Qc SNAREs. This arrangement necessitates a flexible linker, which runs back along the complex from the C-terminal end of the first (Qb) SNARE-domain and connects to the Nterminal end of the second SN...

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Section: The Snap-25 Linker Domain Speeds Up Exocytosis Triggeringmentioning

confidence: 63%

Section: Cell Culture and Expression Constructsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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The SNAP-25 Linker as an Adaptation Toward Fast Exocytosis

Nagy

Milošević

Mohrmann

et al. 2008

MBoC

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“…First, SNAP25 is a presynaptic plasma membrane protein essential for the triggering of vesicular fusion and neurotransmitter release. 12,13 Second, postmortem studies have shown modifica-tions of SNAP25 protein levels in some brain regions of bipolar patients. 14,15 Third, SNAP25 gene has been widely associated with attention-deficit hyperactivity disorder (ADHD), which is known to share genetic susceptibility with early-onset BD.…”

Section: Introductionmentioning

confidence: 99%

A SNAP25 promoter variant is associated with early-onset bipolar disorder and a high expression level in brain

et al. 2009

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Bipolar disorder (BD) is one of the most common and persistent psychiatric disorders. Earlyonset BD has been shown to be the most severe and familial form. We recently carried out a whole-genome linkage analysis on sibpairs affected by early-onset BD and showed that the 20p12 region was more frequently shared in our families than expected by chance. The synaptosomal-associated protein SNAP25 is a presynaptic plasma membrane protein essential for the triggering of vesicular fusion and neurotransmitter release, and for which abnormal protein levels have been reported in postmortem studies of bipolar patients. We hypothesised that variations in the gene encoding SNAP25, located on chromosome 20p12, might influence the susceptibility to early-onset BD. We screened SNAP25 for mutations and performed a case-control association study in 197 patients with early-onset BD, 202 patients with late-onset BD and 136 unaffected subjects. In addition, we analysed the expression level of the two SNAP25 isoforms in 60 brains. We showed that one variant, located in the promoter region, was associated with early-onset BD but not with the late-onset subgroup. In addition, individuals homozygous for this variant showed a significant higher SNAP25b expression level in prefrontal cortex. These results show that variations in SNAP25, associated with an increased gene expression level in prefrontal cortex, might predispose to early-onset BD. Further analyses of this gene, as well as analysis of genes encoding for the SNAP25 protein partners, are required to understand the impact of such molecular mechanisms in BD.

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Protein Mediated Membrane Fusion

Jahn

2006

Encyclopedia of Molecular Cell Biology and Molecular Medicine

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Differential Control of the Releasable Vesicle Pools by SNAP-25 Splice Variants and SNAP-23

Cited by 324 publications

References 42 publications

The SNAP-25 Linker as an Adaptation Toward Fast Exocytosis

The SNAP-25 Linker as an Adaptation Toward Fast Exocytosis

A SNAP25 promoter variant is associated with early-onset bipolar disorder and a high expression level in brain

Protein Mediated Membrane Fusion

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