Regulation of Ca2+ channels by SNAP-25 via recruitment of syntaxin-1 from plasma membrane clusters
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- Regulation of Ca2+ channels by SNAP-25 via recruitment of syntaxin-1 from plasma membrane clusters
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Trine Lisberg Toft-Bertelsen, Iwona Ziomkiewicz, Sébastien Houy, Paulo César da Silva Pinheiro, Jakob B Sørensen
SNAP-25 regulates Ca(2+) channels, with potentially important consequences for diseases involving an aberrant SNAP-25 expression level. How this regulation is executed mechanistically remains unknown. We investigated this question in mouse adrenal chromaffin cells and found that SNAP-25 inhibits Ca(2+) currents, with the B-isoform being more potent than the A-isoform, but not when syntaxin-1 is cleaved by botulinum neurotoxin C. In contrast, syntaxin-1 inhibits Ca(2+) currents independently of SNAP-25. Further experiments using immunostaining showed that endogenous or exogenous SNAP-25 expression recruits syntaxin-1 from clusters on the plasma membrane, thereby increasing the immunoavailability of syntaxin-1 and leading indirectly to Ca(2+) current inhibition. Expression of Munc18-1, which recruits syntaxin-1 within the exocytotic pathway, does not modulate Ca(2+) channels, whereas overexpression of the syntaxin-binding protein Doc2B or ubMunc13-2 increases syntaxin-1 immunoavailability and concomitantly down-regulates Ca(2+) currents. Similar findings were obtained upon chemical cholesterol depletion, leading directly to syntaxin-1 cluster dispersal and Ca(2+) current inhibition. We conclude that clustering of syntaxin-1 allows the cell to maintain a high syntaxin-1 expression level without compromising Ca(2+) influx, and recruitment of syntaxin-1 from clusters by SNAP-25 expression makes it available for regulating Ca(2+) channels. This mechanism potentially allows the cell to regulate Ca(2+) influx by expanding or contracting syntaxin-1 clusters.
Originalsprog | Engelsk |
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Tidsskrift | Molecular Biology of the Cell |
Vol/bind | 27 |
Udgave nummer | 21 |
Sider (fra-til) | 3329-3341 |
Antal sider | 13 |
ISSN | 1059-1524 |
DOI | |
Status | Udgivet - 1 nov. 2016 |
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