Docked granules (within dotted lines) are less frequent in β-cells lacking granuphilin (bottom).

A docking state at the plasma membrane is not a prerequisite for vesicle secretion, according to findings on page 99. Gomi et al. find that docking actually impedes vesicle release during regulated secretion.The secretion of vesicles such as insulin granules must be tightly regulated to prevent unwanted insulin escape. A pool of granules that can be seen attached (or docked) at the plasma membrane seem to be poised for this regulated release, e.g., upon glucose sensing. But the new findings show that glucose-stimulated insulin secretion is even stronger when these docked vesicles are missing.

Gomi et al. first identified the molecule that docks granules as a Rab GTPase effector called granuphilin. In mice lacking granuphilin, the pool of docked granules was missing from pancreatic β-cells. Yet even more insulin was secreted in response to glucose stimulation than from wild-type β-cells.

Granuphilin might restrict secretion by interfering with the membrane fusion machinery. The restoration of docking in knock-out β-cells required the ability of granuphilin to bind, with the help of active Rabs, to a plasma membrane SNARE called syntaxin. The authors found that granuphilin stabilized a fusion-incompetent syntaxin complex. Syntaxin activation, and thus regulated secretion, might be promoted by signals downstream of glucose that inactivate the Rab and release granuphilin.