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Vol. 15, Issue 12, 5565-5573, December 2004

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Insulin and Hypertonicity Recruit GLUT4 to the Plasma Membrane of Muscle Cells by Using N-Ethylmaleimide-sensitive Factor-dependent SNARE Mechanisms but Different v-SNAREs: Role of TI-VAMP

Varinder K. Randhawa ^* , Farah S.L. Thong ^*, Dawn Y. Lim ^* , Dailin Li ^*, Rami R. Garg ^*, Rachel Rudge , Thierry Galli , Assaf Rudich ^*, and Amira Klip ^*  

^* Programme in Cell Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada; Department of Biochemistry, University of Toronto, Toronto, Ontario M5G 1AS, Canada; and Membrane Traffic and Neuronal Plasticity, Institut National de la Santé et de la Recherche Médicale U536, Institut du Fer-à-Moulin, 75005 Paris, France

Submitted March 29, 2004; Revised August 20, 2004; Accepted September 27, 2004
Monitoring Editor: Guido Guidotti

Insulin and hypertonicity each increase the content of GLUT4 glucose transporters at the surface of muscle cells. Insulin enhances GLUT4 exocytosis without diminishing its endocytosis. The insulin but not the hypertonicity response is reduced by tetanus neurotoxin, which cleaves vesicle-associated membrane protein (VAMP)2 and VAMP3, and is rescued upon introducing tetanus neurotoxin-resistant VAMP2. Here, we show that hypertonicity enhances GLUT4 recycling, compounding its previously shown ability to reduce GLUT4 endocytosis. To examine whether the canonical soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) mechanism is required for the plasma membrane fusion of the tetanus neurotoxin-insensitive GLUT4 vesicles, L6 myoblasts stably expressing myc-tagged GLUT4 (GLUT4myc) were transiently transfected with dominant negative N-ethylmaleimide-sensitive factor (NSF) (DN-NSF) or small-interfering RNA to tetanus neurotoxin-insensitive VAMP (TI-VAMP siRNA). Both strategies markedly reduced the basal level of surface GLUT4myc and the surface gain of GLUT4myc in response to hypertonicity. The insulin effect was abolished by DN-NSF, but only partly reduced by TI-VAMP siRNA. We propose that insulin and hypertonicity recruit GLUT4myc from partly overlapping, but distinct sources defined by VAMP2 and TI-VAMP, respectively.

Abbreviations used: DN, dominant negative; eGFP, enhanced green fluorescent protein; GLUT, glucose transporter; GLUT1myc, GLUT1 protein with an exofacial myc epitope; GLUT4myc, GLUT4 protein with an exofacial myc epitope; L6-GLUT1myc, L6 myoblasts stably expressing GLUT1myc protein; L6-GLUT4myc, L6 myoblasts stably expressing GLUT4myc protein; PI 3-kinase, phosphatidylinositol 3-kinase; NSF, N-ethylmaleimide-sensitive factor; siRNA, small interfering RNA; SNAP, synaptosome-associated protein; SNARE, soluble N-ethylmaleimide-sensitive factor attachment protein receptor; t-SNARE, target membrane SNARE; v-SNARE, vesicle SNARE; TeNT, tetanus neurotoxin light chain; TI-VAMP, TeNT-insensitive VAMP; VAMP, vesicle-associated membrane protein; VW, toxin-resistant/insensitive; WT, wild type.

Corresponding author. E-mail address: amira{at}sickkids.ca.

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