Molecular mechanisms involved in secretory vesicle recruitment to the plasma membrane in β-cells

Glucose stimulates the release of insulin in part by activating the recruitment of secretory vesicles to the cell surface. While this movement is known to be microtubule-dependent, the molecular motors involved are undefined. Active kinesin was found to be essential for vesicle translocation in live β-cells, since microinjection of cDNA encoding dominant-negative KHC^mut (motor domain of kinesin heavy chain containing a Thr⁹³ → Asn point mutation) blocked vesicular movements. Moreover, expression of KHC^mut strongly inhibited the sustained, but not acute, stimulation of secretion by glucose. Thus, vesicles released during the first phase of insulin secretion exist largely within a translocation-independent pool. Kinesin-driven anterograde movement of vesicles is then necessary for the sustained (second phase) of insulin release. Kinesin may, therefore, represent a novel target for increases in intracellular ATP concentrations in response to elevated extracellular glucose and may be involved in the ATP-sensitive K⁺channel-independent stimulation of secretion by the sugar.