We previously demonstrated that the Rab27 effector, granuphilin, is essential for the stable attachment of secretory granules to the plasma membrane (docking; Fig. 1). Granuphilin-null secretory cells lack stably docked granules but surprisingly exhibit enhanced secretory responses to stimuli (J. Cell Biol. 2005). This finding challenges the widely believed sequential model or the linear docking-priming-fusion model that stable docking is a necessary first step before a vesicle acquires fusion competence (priming). It may also contradict the general view that a readily releasable pool derives from a subset of stably docked secretory vesicles (Fig. 2). We are currently investigating the relationship between docking and fusion of secretory granules under total internal reflection fluorescence (TIRF) microscopy in living cells expressing multiple fluoresce-labeled proteins (Fig. 3).
Fig.1 Granuphilin-deficient beta cells show increased granule exocytosis despite the lack of stably docked granules
Gomi H et al., J Cell Biol (2005)
Fig.2 Sequential (linear) model vs. Parallel model
Burgoyne RD, Physiol Rev (2003)
• Stable docking is a necessary first step before a vesicle acquires fusion competence (priming).
• A subset of stably docked secretory vesicles is first released after stimulation and thus constitutes a readily releasable pool.
Izumi T et al., Diabetes Obes Metab (2007)
• Secretory vesicle docking is not a prerequisite or a ready state for fusion, but a temporal constraint to inhibit spontaneous fusion of incoming vesicles.
• Molecularly and/or morphologically undocked granules can fuse efficiently, even with skipping a stable docking step.
• All fusing vesicles do not necessarily follow the same linear docking-priming-fusion pathway: both docked and undocked vesicles readily fuse in parallel even in the early phase of stimulus-induced secretion.
Fig.3 Heterogeneous behaviors of insulin granules prior to fusion under TIRF microscopy
Kasai K et al., Traffic (2008)