Biphasic release propensity of mucin granules is supervised by TSPAN8

Agonist-mediated stimulated pathway of mucin and insulin release is biphasic in which a rapid fusion of pre-docked granules is followed by slow docking and fusion of granules from the reserve pool. The sustained neurotransmitter release also necessitates docking of vesicles from a reserve pool. We present here a surprising finding that plasma membrane-located tetraspanin-8 (Tspan-8) sequesters syntaxin-2 (Stx2) to control external agonist-dependent mucin release. Tspan-8 specifically affects fusion of granules in reserve during the second phase of stimulated mucin release. The Tspan-8 and Stx2 complex does not contain VAMP-8 and Munc18, which are required for fusion of mucin granules. We suggest that by sequestering Stx2, Tspan-8 prevents docking granules in the reserve pool. In the absence of Tspan-8, granules in reserve pool are free to dock to Stx2 and their fusion doubles the quantities of mucins secreted. Tspan-8 thus emerges as the long-sought component that controls biphasic mucin release. We suggest a similar mechanism likely controls biphasic insulin and sustained neurotransmitter release.