Update on GLUT4 Vesicle Traffic: A Cornerstone of Insulin Action

KLIP, AMIRA; PAVAROTTI, MARTIN; BILAN, PHILIP J.; JALDÍN-FINCATI, JAVIER R.; FRENDO-CUMBO, SCOTT; BILAN, PHILIP J.; KLIP, AMIRA; PAVAROTTI, MARTIN; JALDÍN-FINCATI, JAVIER R.; FRENDO-CUMBO, SCOTT

TRENDS IN ENDOCRINOLOGY AND METABOLISM

ELSEVIER SCIENCE LONDON

Año: 2017 vol. 28 p. 597 - 611

1043-2760

Glucose transport is rate limiting for dietary glucose utilization by muscle and fat. The glucose transporter GLUT4 is dynamically sorted and retained intracellularly and redistributes to the plasma membrane (PM) by insulin-regulated vesicular traffic, or ?GLUT4 translocation?. Here we emphasize recent findings in GLUT4 translocation research. The application of total internal reflection fluorescence microscopy (TIRFM) has increased our understanding of insulin-regulated events beneath the PM, such as vesicle tethering and membrane fusion. We describe recent findings on Akt-targeted Rab GTPase-activating proteins (GAPs) (TBC1D1, TBC1D4, TBC1D13) and downstream Rab GTPases (Rab8a, Rab10, Rab13, Rab14, and their effectors) along with the input of Rac1 and actin filaments, molecular motors [myosinVa (MyoVa), myosin1c (Myo1c), myosinIIA (MyoIIA)], and membrane fusion regulators (syntaxin4, munc18c, Doc2b). Collectively these findings reveal novel events in insulin-regulated GLUT4 traffic. Insulin promotes GLUT4 redistribution from recycling endosomes and specialized intracellular compartments to the plasma membrane (PM). Signaling bifurcates downstream of phosphatidylinositol 3-kinase towards Akt and Rac. Akt signaling leads to activation of Rab10 in adipocytes and Rab8a and Rab13 in myoblasts. Rab10 acts at several steps in GLUT4 translocation, whereas Rab8a promotes GLUT4 exit from the perinuclear region and Rab13 promotes tethering of GLUT4 vesicles near the PM. Rac1 signaling induces cortical actin remodeling that tethers GLUT4 vesicles beneath the PM. Additional proteins may also fine-tune actin remodeling through tropomyosin3.1 and tropomodulin3 via Akt2 input. Insulin increases [Ca2+] beneath the PM, which may regulate the SNARE complex that mediates the final step of GLUT4 vesicle fusion with the PM.