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¹ Islet Cell Exocytosis, Department of Clinical Sciences in Malmo, Clinical Research Centre (CRC), Building 91, Floor 11, Lund University, Ing. 72 UMAS, SE-20502 Malmö, Sweden
² Department of Medical Chemistry and Molecular Pharmacology, Purdue University, Indiana, USA
³ OCDEM, University of Oxford, Old Road Campus, Oxford OX3 7 LJ, United Kingdom

(Requests for offprints should be addressed to L Eliasson; Email: Lena.Eliasson{at}med.lu.se)

SNARE-proteins (soluble NSF-attachment protein receptor) are important for Ca²⁺-dependent exocytosis. We have used capacitance measurements and confocal imaging to dissect the role of synaptosomal protein of 25 kDa (SNAP-25) and syntaxin 1 in rapid exocytosis in insulin-secreting pancreatic ß-cells. Following immunoneutralization of syntaxin 1 and SNAP-25, exocytosis was strongly reduced and associated with a marked reduction in the size of the readily releasable pool (RRP) by 65% and 86% in the presence of the anti-SNAP-25 and anti-syntaxin 1 antibodies respectively. The size of the immediately releasable pool (IRP), a subset of RRP in close association with the voltage-dependent Ca²⁺-channels, was reduced to an equal extent. The reduction in IRP correlated with slowed release kinetics and the time constant () increased from a control value of 16 to 36 ms and 51 ms after inclusion of anti-SNAP-25 and anti-syntaxin 1 antibodies respectively in the pipette solution. We further show that SNAP-25 and syntaxin 1 aggregate in clusters along the plasma membrane. The size of these clusters was estimated to be ~300 nm and every ß-cell contained ~400 SNAP-25/syntaxin 1 clusters. Whereas the inhibitory action of the anti-syntaxin 1 antibody on exocytosis could be attributed almost entirely to suppression of the voltage-dependent Ca²⁺-current (–40%), the effect of the anti-SNAP-25 antibody was not mediated by decreased Ca²⁺-entry and is more likely due to a direct interference with the exocytotic machinery. Our data are consistent with the concept that both syntaxin 1 and SNAP-25 are required for rapid exocytosis in ß-cells.

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