Interplay between Rab27a effectors in pancreatic β-cells

Figure 1 Small GTPase GTP/GDP cycle. Small GTPases localize in the cytosol as a GDP-bound form under unstimulated conditions. Cell stimulation recruits GDP-bound small GTPases to the vicinity of the plasma membrane and converts these proteins to the GTP-bound form through GEF activity. The GTP-bound form interacts with its specific effectors and thereby transduces signals. GAPs promote the intrinsic GTPase activity of small GTPases and induce conversion of the GTP- to the GDP-bound form. GDIs form a complex with GDP-bound small GTPases and induce their intracellular redistribution from the plasma membrane to the cytosol. GEFs: Guanine nucleotide exchange factors; GAPs: GTPase-activating proteins; GDIs: GDP-dissociation inhibitors.

Figure 2 Schematic model of GTP-bound Rab27a function in pancreatic β-cells. Insulin-containing granules transported in the cytoplasm attach to the inner surface of the cell membrane (docking). The contents of both docked and undocked granules are eventually released following elevation of intracellular Ca²⁺ levels. GTP-bound Rab27a regulates insulin secretion by modulating the granule transport and docking steps via its effector proteins. Residents are granules that are pre-docked to the plasma membrane before fusion. Passengers are granules that fused without stably docking. Visitors are granules that remain near the plasma membrane for some time before fusion.

Figure 3 Interplay between Rab27a, coronin 3 and IQGAP1. GDP-bound Rab27a simultaneously binds coronin 3 and IQGAP1, resulting in the formation of a trimeric complex. WD: Five WD40 repeats; CHD: Calponin homology domain; NTR: N-terminal repeats; IQR: IQ repeats; GRD: RasGAP related domain; CT: Carboxy terminus of IQGAP1.

Figure 4 Schematic model of GDP-bound Rab27a function in pancreatic β-cells. Endocytosis is a complex process that involves cargo sorting, membrane invagination, vesicle scission and vesicle targeting. GDP-bound Rab27a modulates F-actin assembly and regulates the retrograde transport of the internalized secretory membrane, at the stage after scission from the plasma membrane. Scission is indicated by the dynamin step.

Figure 5 Rab27a GTP/GDP cycling synchronizes with the recycling of secretory membrane. In the basal state, GTP-bound Rab27a controls insulin secretion at pre-exocytotic stages via its GTP-specific effectors. Glucose stimulation causes insulin exocytosis. Glucose stimulation also converts Rab27a from its GTP- to its GDP-bound form. GDP-bound Rab27a interacts with IQGAP1, recruits coronin 3, and controls endocytosis of the secretory granule membrane. GAPs: GTPase-activating proteins.