Biphasic release propensity of mucin granules is supervised by tetraspanin-8 by sequestering syntaxin-2

<strong>Agonist-mediated stimulated pathway of</strong><strong> mucin and insulin release are biphasic in which rapid fusion of pre-docked granules is followed by slow docking and fusion of granules from the reserve pool. Here, based on a cell-culture system, we show that plasma membrane-located tetraspanin-8 sequesters syntaxin-2 to control mucin release. Tetraspanin-8 </strong><strong>affects fusion of granules during the second phase of stimulated mucin release</strong><strong>. The tetraspanin-8/syntaxin-2 complex does not contain VAMP-8, which functions with syntaxin-2 to mediate granule fusion. We suggest that by sequestering syntaxin-2, tetraspanin-8 prevents docking of granules </strong><strong>from the reserve pool</strong><strong>. In the absence of tetraspanin-8, more syntaxin-2 is available for docking and fusion of granules and thus </strong><strong>doubles the </strong><strong>quantities of mucins secreted. This principle also applies to insulin release and we suggest a cell type specific Tetraspanin/Syntaxin combination is a general mechanism </strong><strong>regulating the</strong><strong> fusion of dense core granules.</strong>