Molecular Basis of Insulin-stimulated GLUT4 Vesicle Trafficking

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Among all the diverse actions of insulin, one of the most critical and intensively studied is its regulation of glucose homeostasis. In the postabsorptive state, insulin action in muscle and adipose tissue results in increased glucose uptake from the circulation, thereby maintaining plasma euglycemia and preventing hyperglycemia (1Klip A. Tsakiridis T. Marette A. Ortiz P.A. FASEB J. 1994; 8: 43-53Crossref PubMed Scopus (285) Google Scholar, 2Olson A.L. Pessin J.E. Annu. Rev. Nutr. 1996; 16: 235-256Crossref PubMed Scopus (388) Google Scholar, 3Kahn B.B. Cell. 1998; 92: 593-596Abstract Full Text Full Text PDF PubMed Scopus (374) Google Scholar). Defects in this pathway result in insulin resistance, a condition in which excessive concentrations of insulin are required to reduce blood glucose levels and often precede the development of frank Type II diabetes (3Kahn B.B. Cell. 1998; 92: 593-596Abstract Full Text Full Text PDF PubMed Scopus (374) Google Scholar, 4Saltiel A.R. Olefsky J.M. Diabetes. 1996; 45: 1661-1669Crossref PubMed Scopus (0) Google Scholar). Although it has been appreciated for almost two decades that this major action of insulin results from a redistribution of glucose transporter proteins from intracellular storage sites to the plasma membrane (5Suzuki K. Kono T. Proc. Natl. Acad. Sci. U. S. A. 1980; 77: 2542-2545Crossref PubMed Scopus (770) Google Scholar,6Cushman S.W. Wardzala L.J. J. Biol. Chem. 1980; 255: 4758-4762Abstract Full Text PDF PubMed Google Scholar), the cellular mechanisms responsible for these trafficking events and the defects associated with insulin resistance have remained largely enigmatic. We now know that facilitative glucose uptake occurs through a family of highly related integral membrane proteins that share significant sequence similarity. Although several lines of evidence suggest the presence of additional glucose transporters, to date only four members of this gene family have been described and documented to function as authentic glucose transporters. For example, although GLUT5 was originally thought to be a glucose transporter it was subsequently identified as a facilitative fructose transporter (7Burant C.F. Takeda J. Brot-Laroche E. Bell G.I. Davidson N.O. J. Biol. Chem. 1992; 267: 14523-14526Abstract Full Text PDF PubMed Google Scholar). Of the four established glucose transporter isoforms, the following GLUT4 is highly expressed in adipose tissue and striated muscle with significantly lower levels of the GLUT1 isoform (see accompanying minireview by Charron et al. (8Charron M.J. Katz E.B. Olson A.L. J. Biol. Chem. 1999; 274: 3253-3256Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar)). In the basal state, GLUT4 cycles slowly between the plasma membrane and one or more intracellular compartments, with the vast majority of the transporter residing in vesicular compartments within the cell interior (9Rea S. James D.E. Diabetes. 1997; 46: 1667-1677Crossref PubMed Google Scholar, 10Kandror K.V. Pilch P.F. Am. J. Physiol. 1996; 271: E1-E14Crossref PubMed Google Scholar). Activation of the insulin receptor triggers a large increase in the rate of GLUT4 vesicle exocytosis and a smaller decrease in the rate of internalization by endocytosis (11Satoh S. Nishimura H. Clark A.E. Kozka I.J. Vannucci S.J. Simpson I.A. Quon M.J. Cushman S.W. Holman G.D. J. Biol. Chem. 1993; 268: 17820-17829Abstract Full Text PDF PubMed Google Scholar, 12Jhun B.H. Rampal A.L. Liu H. Lachaal M. Jung C.Y. J. Biol. Chem. 1992; 268: 17710-17715Abstract Full Text PDF Google Scholar, 13Yang J. Holman G.D. J. Biol. Chem. 1993; 268: 4600-4603Abstract Full Text PDF PubMed Google Scholar, 14Czech M.P. Buxton J.M. J. Biol. Chem. 1993; 268: 9187-9190Abstract Full Text PDF PubMed Google Scholar). The stimulation of exocytosis by insulin is probably the major step for GLUT4 translocation because complete inhibition of GLUT4 endocytosis only modestly increases plasma membrane-associated GLUT4 protein without affecting the extent of insulin-stimulated GLUT4 translocation (15Shibata H. Suzuki Y. Omata W. Tanaka S. Kojima I. J. Biol. Chem. 1995; 270: 11489-11495Crossref PubMed Scopus (45) Google Scholar, 16Kao A.W. Ceresa B.P. Santeler S.R. Pessin J.E. J. Biol. Chem. 1998; 273: 25450-25457Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar, 17Ceresa B.P. Kao A.W. Santeler S.R. Pessin J.E. Mol. Cell. Biol. 1998; 18: 3862-3870Crossref PubMed Scopus (199) Google Scholar). In contrast to GLUT4, GLUT1 is localized both to the plasma membrane and intracellular storage sites in the basal state but only displays a modest insulin-stimulated redistribution to the plasma membrane. Thus, the overall insulin-dependent shift in the cellular dynamics of GLUT4 vesicle trafficking results in a net increase of GLUT4 on the cell surface, thereby increasing the rate of glucose uptake. As detailed in the previous minireview by Czech and Corvera (18Czech M.P. Corvera S. J. Biol. Chem. 1999; 274: 1865-1868Abstract Full Text Full Text PDF PubMed Scopus (450) Google Scholar), it is unclear if a single or multiple overlapping pathways can lead to GLUT4 translocation. At present, substantial evidence has documented that the activation and/or appropriate targeting of the Type I phosphatidylinositol (PI) 1The abbreviations used are: PI, phosphatidylinositol; GTPγS, guanosine 5′-3-O-(thio)triphosphate; IRAP, insulin-responsive aminopeptidase; t-SNARE, target membrane SNAP receptor; v-SNARE, vesicle SNAP receptor; SNAP, soluble NSF (N-ethylmaleimide-sensitive factor) attachment protein. 3-kinase is necessary for insulin-stimulated GLUT4 translocation and glucose uptake (19Shepherd P.R. Siddle K. Nave B.T. Biochem. Soc. Trans. 1997; 25: 978-981Crossref PubMed Scopus (16) Google Scholar). However, the specific downstream targets for PI 3-kinase have remained questionable with evidence both for and against protein kinase B, also known as Akt (20Cong L.N. Chen H. Li Y. Zhou L. McGibbon M.A. Taylor S.I. Quon M.J. Mol. Endocrinol. 1997; 11: 1881-1890Crossref PubMed Google Scholar, 21Kohn A.D. Summers S.A. Birnbaum M.J. Roth R.A. J. Biol. Chem. 1996; 271: 31372-31378Abstract Full Text Full Text PDF PubMed Scopus (1093) Google Scholar, 22Kitamura T. Ogawa W. Sakaue H. Hino Y. Kuroda S. Takata M. Matsumoto M. Maeda T. Konishi H. Kikkawa U. Kasuga M. Mol. Cell. Biol. 1998; 18: 3708-3717Crossref PubMed Scopus (296) Google Scholar). Alternatively, the atypical protein kinase C isoforms (protein kinase Cζ and λ) are downstream targets of PI 3-kinase and have also been implicated in the insulin stimulation of GLUT4 translocation (23Standaert M.L. Galloway L. Karnam P. Bandyopadhyay G. Moscat J. Farese R.V. J. Biol. Chem. 1997; 272: 30075-30082Crossref PubMed Scopus (408) Google Scholar, 24Bandyopadhyay G. Standaert M.L. Zhao L. Yu B. Avignon A. Galloway L. Karnam P. Moscat J. Farese R.V. J. Biol. Chem. 1997; 272: 2551-2558Crossref PubMed Scopus (276) Google Scholar, 81Kotani K. Ogawa W. Matsumoto M. Kitamura T. Sakaue H. Hino Y. Miyake K. Sano W. Akimoto K. Ohno S. Kasuga M. Mol. Cell. Biol. 1998; 18: 6971-6982Crossref PubMed Google Scholar). In addition to PI 3-kinase-dependent signal transduction pathways, several studies have demonstrated the presence of PI 3-kinase-independent mechanisms of GLUT4 translocation. For example, osmotic shock, GTPγS, and exercise/contraction in skeletal muscle induce GLUT4 translocation in the complete absence of PI 3-kinase activity (25Chen D. Elmendorf J.S. Olson A.L. Li X. Earp H.S. Pessin J.E. J. Biol. Chem. 1997; 272: 27401-27410Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar, 26Baldini G. Holman R. Charron M.J. Lodish H.F. J. Biol. Chem. 1991; 266: 4037-4040Abstract Full Text PDF PubMed Google Scholar, 27Elmendorf J.S. Chen D. Pessin J.E. J. Biol. Chem. 1998; 273: 13289-13296Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 28Yeh J.I. Gulve E.A. Rameh L. Birnbaum M.J. J. Biol. Chem. 1995; 270: 2107-2111Abstract Full Text Full Text PDF PubMed Scopus (306) Google Scholar). These treatments can result in increased AMP levels, and it has been suggested that activation of the AMP-dependent protein kinase stimulates glucose uptake (29Hayashi T. Hirshman M.F. Kurth E.J. Winder W.W. Goodyear L.J. Diabetes. 1998; 47: 1369-1373Crossref PubMed Scopus (707) Google Scholar). G protein-coupled receptors linked to Gq have also been observed to induce GLUT4 translocation (30Kishi K. Hayashi H. Wang L. Kamohara S. Tamaoka K. Shimizu T. Ushikubi F. Narumiya S. Ebina Y. J. Biol. Chem. 1996; 271: 26561-26568Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar). Future studies will be necessary to ascertain the specific roles and relationships between protein kinase B, protein kinase Cζ and λ, and/or other PI 3-kinase-dependent as well as independent signaling processes in GLUT4 translocation. In any case, whatever specific signal transduction pathway(s) are involved, they must directly impact on the GLUT4 intracellular storage sites and its subsequent trafficking to and fusion with the plasma membrane. It is well established that integral membrane proteins traffic to and from the plasma membrane through an endosomal recycling membrane system. Immunoelectron microscopy has demonstrated that the GLUT4 protein is predominantly localized in small vesicles and tubulovesicular structures, with relatively smaller amounts found in the trans-Golgi network, clathrin-coated vesicles, and endosomes (31Rodnick K.J. Slot J.W. Studelska D.R. Hanpeter D.E. Robinson L.J. Geuze H.J. James D.E. J. Biol. Chem. 1992; 267: 6278-6285Abstract Full Text PDF PubMed Google Scholar, 32Slot J.W. Geuze H.J. Gigengack S. Lienhard G.E. James D.E. J. Cell Biol. 1991; 113: 123-135Crossref PubMed Scopus (712) Google Scholar, 33Slot J.W. Geuze H.J. Gigengack S. James D.E. Lienhard G.E. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 7815-7819Crossref PubMed Scopus (352) Google Scholar, 34Wang W. Hansen P.A. Marshall B.A. Holloszy J.O. Mueckler M. J. Cell Biol. 1996; 135: 415-430Crossref PubMed Scopus (100) Google Scholar, 35Smith R.M. Charron M.J. Shah N. Lodish H.F. Jarett L. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 6893-6897Crossref PubMed Scopus (134) Google Scholar). Subcellular fractionation and immunoabsorption studies have indicated a substantial co-distribution of GLUT4 with markers of several intracellular membrane compartments including GLUT1 and the transferrin and the insulin-like growth factor-2/mannose 6-phosphate receptors (9Rea S. James D.E. Diabetes. 1997; 46: 1667-1677Crossref PubMed Google Scholar, 10Kandror K.V. Pilch P.F. Am. J. Physiol. 1996; 271: E1-E14Crossref PubMed Google Scholar). However, several studies have observed the presence of a separate subpopulation of GLUT4-containing vesicles different from the constitutively recycling endosomal system. For example, GLUT4-containing vesicles are enriched in the v-SNARE protein, VAMP2, but not the related VAMP3/cellubrevin isoform, which is present in the constitutively recycling endosome population (36Martin L.B. Shewan A. Millar C.A. Gould G.W. James D.E. J. Biol. Chem. 1998; 273: 1444-1452Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar, 37Martin S. Tellam J. Livingstone C. Slot J.W. Gould G.W. James D.E. J. Cell Biol. 1996; 134: 625-635Crossref PubMed Scopus (180) Google Scholar, 38Sevilla L. Tomas E. Munoz P. Guma A. Fischer Y. Thomas J. Ruiz-Montasell B. Testar X. Palacin M. Blasi J. Zorzano A. Endocrinology. 1997; 138: 3006-3015Crossref PubMed Google Scholar). The presence of distinct vesicle populations may also account for the ability of insulin to stimulate 2–4-fold plasma membrane increases of several recycling proteins (i.e. GLUT1, transferrin, and insulin-like growth factor-2/mannose 6-phosphate receptors), whereas plasma membrane GLUT4 content can increase 10–20-fold. Thus, it appears that this unique subpopulation of GLUT4-containing vesicles is primarily responsible for the majority of insulin-stimulated translocation. Irrespective of which vesicle population is insulin-responsive, there must be specific mechanisms in place to localize GLUT4 to its appropriate intracellular storage sites. To address this issue, several laboratories have examined the subcellular localization of GLUT4/GLUT1 and GLUT4/transferrin receptor chimeric proteins. Steady-state analysis of the C-terminal region of GLUT4 identified a dileucine motif (SLL) that when mutated resulted in the plasma membrane accumulation of GLUT4 (39Verhey K.J. Yeh J.I. Birnbaum M.J. J. Cell Biol. 1995; 130: 1071-1079Crossref PubMed Scopus (114) Google Scholar, 40Marsh B.J. Alm R.A. McIntosh S.R. James D.E. J. Cell Biol. 1995; 130: 1081-1091Crossref PubMed Scopus (76) Google Scholar, 41Haney P.M. Levy M.A. Strube M.S. Mueckler M. J. Cell Biol. 1995; 129: 641-658Crossref PubMed Scopus (86) Google Scholar, 42Czech M.P. Chawla A. Wook C.W. Buxton J. Armoni M. Tang W. Joly M. Corvera S. J. Cell Biol. 1993; 123: 127-135Crossref PubMed Scopus (70) Google Scholar). However, further mutational studies and kinetic analysis revealed that this motif was, in fact, required for efficient internalization (43Corvera S. Chawla A. Chakrabarti R. Joly M. Buxton J. Czech M.P. J. Cell Biol. 1994; 126: 979-989Crossref PubMed Scopus (103) Google Scholar, 44Garippa R.J. Johnson A. Park J. Petrush R.L. McGraw T.E. J. Biol. Chem. 1996; 271: 20660-20668Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar). Thus the apparent lack of intracellular sequestration in these mutants resulted from an accumulation of GLUT4 at the plasma membrane because of a reduction in the rate of endocytosis. Even though a contiguous GLUT4 amino acid sequence responsible for intracellular sequestration or retention has not yet been identified, kinetic and morphological data strongly suggest the presence of an intracellular targeting signal within the GLUT4 cytoplasmic C-terminal domain. There are two general models that can account for the insulin-stimulated translocation of these intracellular GLUT4-containing vesicles to the plasma membrane. Schematic representations of the retention and synaptic models of GLUT4 vesicle trafficking are illustrated in Figs. 1and 2. The retention model predicts that the specific sequences within GLUT4 or other co-localized vesicular proteins (see below) specifically target this vesicle population away from recycling endosomes (Fig. 1). Insulin stimulation allows these sequestered vesicles to enter the constitutive recycling endosome pathway and thereby results in default trafficking to the plasma membrane. This model is consistent with the predominant localization of GLUT4 to small vesicles and tubulovesicular structures adjacent to endosomes typically underlying the plasma membrane (32Slot J.W. Geuze H.J. Gigengack S. Lienhard G.E. James D.E. J. Cell Biol. 1991; 113: 123-135Crossref PubMed Scopus (712) Google Scholar, 34Wang W. Hansen P.A. Marshall B.A. Holloszy J.O. Mueckler M. J. Cell Biol. 1996; 135: 415-430Crossref PubMed Scopus (100) Google Scholar, 35Smith R.M. Charron M.J. Shah N. Lodish H.F. Jarett L. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 6893-6897Crossref PubMed Scopus (134) Google Scholar). In addition, expression of GLUT4 in neuroendocrine cells and fibroblast cell lines results in the localization of GLUT4 to secretory granules and to endosomes (42Czech M.P. Chawla A. Wook C.W. Buxton J. Armoni M. Tang W. Joly M. Corvera S. J. Cell Biol. 1993; 123: 127-135Crossref PubMed Scopus (70) Google Scholar, 45Haney P.M. Slot J.W. Piper R.C. James D.E. Mueckler M. J. Cell Biol. 1991; 114: 689-699Crossref PubMed Scopus (99) Google Scholar, 46Hudson A.W. Ruiz M. Birnbaum M.J. J. Cell Biol. 1992; 116: 785-797Crossref PubMed Scopus (78) Google Scholar, 47Hudson A.W. Fingar D.C. Seidner G.A. Griffiths G. Burke B. Birnbaum M.J. J. Cell Biol. 1993; 122: 579-588Crossref PubMed Scopus (53) Google Scholar). These data are consistent with the presence of specific GLUT4 intracellular sequestration sequences that can function in heterologous cell systems.Figure 2Schematic representation of the hypothesized synaptic model of GLUT4 vesicle trafficking. In this model GLUT4 vesicles are localized to both small synaptic-like vesicles as well as larger tubulovesicular compartments, both enriched for the v-SNARE protein VAMP2. Presumably the tubulovesicular structures are in equilibrium with the smaller vesicles. In either case, insulin stimulation results in the association of GLUT4-containing vesicles with the plasma membrane through the interaction of VAMP2 with the t-SNARE complex composed of syntaxin 4 and SNAP23. In addition, the modulator proteins Munc18c and Synip are thought to provide an inhibitory and stimulatory function, respectively. IR, insulin receptor.View Large Image Figure ViewerDownload (PPT) A functional regulatory property of the retention model can be proposed based upon the recent observation that expression of the GLUT4 C-terminal domain results in the translocation of the endogenous GLUT4 protein to the plasma membrane (48Lee W. Jung C.Y. J. Biol. Chem. 1997; 272: 21427-21431Crossref PubMed Scopus (25) Google Scholar). Similarly, the insulin-responsive aminopeptidase (IRAP), also known as vp165, to and GLUT4 vesicles K.V. Pilch P.F. Proc. Natl. Acad. Sci. U. S. A. 1994; PubMed Scopus Google Scholar, S.R. R. Lienhard G.E. J. Biol. Chem. 1995; 270: PubMed Scopus Google Scholar). The cytoplasmic domain of displays with the GLUT4 C and of the cytoplasmic domain of also results in plasma membrane translocation of GLUT4 M. C. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus (100) Google Scholar). This model also for the apparent of the GLUT4 C-terminal which more following insulin stimulation W. Hansen P.A. Marshall B.A. Holloszy J.O. Mueckler M. J. Cell Biol. 1996; 135: 415-430Crossref PubMed Scopus (100) Google Scholar, 35Smith R.M. Charron M.J. Shah N. Lodish H.F. Jarett L. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 6893-6897Crossref PubMed Scopus (134) Google Scholar). The of these data is that insulin-responsive cells a retention which is responsible for the intracellular sequestration of the GLUT4-containing vesicles. of this interaction by either insulin stimulation or through with an appropriate allows the GLUT4-containing vesicles to enter the recycling endosome thereby in plasma membrane translocation. Although several of the retention model are there are several lines of evidence with this a substantial of the GLUT4-containing vesicles appears to be away from recycling endosome to small synaptic vesicles. This the of GLUT4 with VAMP2 and the that a substantial of the GLUT4 protein distinct from the recycling of the transferrin receptor (36Martin L.B. Shewan A. Millar C.A. Gould G.W. James D.E. J. Biol. Chem. 1998; 273: 1444-1452Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar, 37Martin S. Tellam J. Livingstone C. Slot J.W. Gould G.W. James D.E. J. Cell Biol. 1996; 134: 625-635Crossref PubMed Scopus (180) Google Scholar). of the transferrin endosomes not insulin-stimulated GLUT4 translocation. These data that insulin-stimulated GLUT4 trafficking can independent of the recycling endosome at the endosome population by the transferrin In either case, it is to that both the retention and synaptic vesicle models are not For example, insulin induce the trafficking of multiple GLUT4 vesicle populations through different Alternatively, GLUT4 may be in synaptic-like vesicles that are sequestered because of GLUT4 and/or retention In contrast to GLUT4 substantial has been in of synaptic vesicle trafficking in the regulation of from the membrane N. Physiol. Rev. 1996; PubMed Scopus Google Scholar, 1997; PubMed Scopus Google Scholar, Y. Proc. Natl. Acad. Sci. U. S. A. 1997; PubMed Scopus Google Scholar). In this protein in the vesicle for vesicle with receptor at the target membrane for target between the t-SNARE and v-SNARE proteins in with the association of several proteins example, and are responsible for trafficking and of the complex required for membrane In the insulin-stimulated trafficking of GLUT4 vesicles has several in with the exocytosis pathway of synaptic vesicles, including the presence of vesicular proteins (Fig. As described the v-SNARE VAMP2 with GLUT4 vesicles based on several appears to be for insulin-stimulated GLUT4 translocation. Although there are specific that either syntaxin 4 or plasma membrane t-SNARE studies and/or have strongly implicated syntaxin 4 and as the t-SNARE proteins required for insulin-stimulated GLUT4 translocation A.L. Pessin J.E. Mol. Cell. Biol. 1997; PubMed Scopus Google Scholar, S. L.B. McIntosh S. T. G. James D.E. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar, A. Wang H.S. Liu L. A. Mol. Biol. Cell. 1996; PubMed Scopus (126) Google Scholar, B. A. Wang L. A. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar). In the of synaptic there are also several of and t-SNARE The of and with to plasma membrane in or reduce vesicle that these proteins are for and t-SNARE The isoform is predominantly expressed in it the association of and with syntaxin J. Proc. Natl. Acad. Sci. U. S. A. 1994; PubMed Scopus Google Scholar). In contrast to and Munc18c are expressed but only Munc18c syntaxin 4 McIntosh S. James D.E. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar, McIntosh S. D.R. C.W. James D.E. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). In to the of Munc18c to syntaxin 4 the of VAMP2, and increased expression of Munc18c insulin-stimulated GLUT4 translocation Y. M. T. H. S. H. Kasuga M. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar, D.C. Ceresa B.P. S. Elmendorf J.S. K. Pessin J.E. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). insulin the of Munc18c to syntaxin this that GLUT4 translocation is by Munc18c in the basal state and that insulin stimulation may result in a of the Munc18c have identified a protein that specifically to syntaxin 4 and is expressed in muscle and adipose S. M. B. P. K. J. S. Y. A. R. and J. E. for to the interaction of Synip with syntaxin 4 is by insulin, which also a of the 4 However, in contrast to expression of the Synip protein has on insulin-stimulated GLUT4 or translocation. expression of the C-terminal domain of Synip not an insulin-stimulated from syntaxin 4 but in a by both GLUT4 and translocation. These data suggest that although Munc18c may have an inhibitory Synip as a of insulin-stimulated GLUT4 translocation. Future studies will be necessary to the of these and the between 4 and 4 In addition to the of these proteins in GLUT4 the small protein also appears to an functional upon the between function and synaptic insulin-responsive found to several In was found to with the M. A. E. A. Y. J. Biol. Chem. 1993; 268: Full Text PDF PubMed Google Scholar). insulin stimulation resulted in a redistribution of the recent studies have also demonstrated that of a C-terminal expression of a C-terminal or expression of all result in an inhibition of insulin-stimulated GLUT4 translocation M. N. M. E. Y. Mol. Cell. Biol. 1996; 16: PubMed Scopus (99) Google Scholar, H. Omata W. Suzuki Y. Tanaka S. Kojima I. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar, S. I. Zorzano A. K. Biochem. J. 1997; PubMed Scopus Google Scholar). These data have been to that is an in the GLUT4 translocation the of GLUT4 is known the of plasma membrane GLUT4 analysis has indicated that insulin increases the rate of GLUT4 exocytosis with a decrease in the rate of endocytosis K.V. Pilch P.F. Am. J. Physiol. 1996; 271: E1-E14Crossref PubMed Google M.P. Annu. Rev. Nutr. 1995; PubMed Scopus Google Scholar, G.D. Cushman S.W. 1994; 16: PubMed Scopus Google Scholar). Although insulin-stimulated exocytosis activation of the PI inhibition of this activity has on the rate of endocytosis J. Kasuga M. Holman G.D. Biochem. J. 1996; PubMed Scopus Google Scholar). analysis has demonstrated that in the basal state, the small of plasma membrane-associated GLUT4 is almost found in (32Slot J.W. Geuze H.J. Gigengack S. Lienhard G.E. James D.E. J. Cell Biol. 1991; 113: 123-135Crossref PubMed Scopus (712) Google Scholar, 33Slot J.W. Geuze H.J. Gigengack S. James D.E. Lienhard G.E. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 7815-7819Crossref PubMed Scopus (352) Google Scholar, L.J. S. J. James D.E. J. Cell Biol. 1992; PubMed Scopus Google Scholar). However, following insulin stimulation only a of the plasma GLUT4 is found in whereas the majority of GLUT4 is in plasma membrane (32Slot J.W. Geuze H.J. Gigengack S. Lienhard G.E. James D.E. J. Cell Biol. 1991; 113: 123-135Crossref PubMed Scopus (712) Google Scholar, L.J. S. J. James D.E. J. Cell Biol. 1992; PubMed Scopus Google Scholar). Although the responsible for this observation is not the insulin-stimulated decrease in GLUT4 localization result from either of the targeting or specific of the GLUT4 protein. In any case, of by or of the has established a for endocytosis in GLUT4 internalization R.J. Johnson A. Park J. Petrush R.L. McGraw T.E. J. Biol. Chem. 1996; 271: 20660-20668Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, H. M.J. Simpson I.A. J. Biol. Chem. 1993; 268: Full Text PDF PubMed Google Scholar). implicated in vesicle is the (Fig. In addition to its highly a domain and a C-terminal region that and the and D.E. J. 1997; 16: PubMed Scopus (199) Google Scholar, R. T. M.A. Proc. Natl. Acad. Sci. U. S. A. 1997; PubMed Scopus Google Scholar). These can with several signaling including and P. 1997; PubMed Scopus Google Scholar, Annu. Rev. Biochem. 1997; PubMed Scopus Google Scholar). In this insulin has been observed to induce the association of a complex with and which in the rate of activity A. K. I. T. H. K. Kitamura Y. Y. T. N. Kasuga M. J. 1994; PubMed Scopus (76) Google Scholar, F. E. Endocrinology. 1998; PubMed Scopus Google Scholar). insulin has been to induce the of F. E. Endocrinology. 1998; PubMed Scopus Google Scholar). these data suggest that insulin may the rate of constitutively recycling cell proteins as GLUT4 through a with this expression of a GLUT4 endocytosis without affecting insulin-stimulated GLUT4 translocation A.W. Ceresa B.P. Santeler S.R. Pessin J.E. J. Biol. Chem. 1998; 273: 25450-25457Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar, 17Ceresa B.P. Kao A.W. Santeler S.R. Pessin J.E. Mol. Cell. Biol. 1998; 18: 3862-3870Crossref PubMed Scopus (199) Google Scholar, H. Cushman S.W. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). In addition, of a the sites GLUT4 endocytosis and results in the accumulation of GLUT4 at the cell A. S. L.J. D. P. A. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus (66) Google Scholar). These data provide evidence that the internalization of GLUT4 occurs through a clathrin-coated These the of function in GLUT4 endocytosis and suggest that the and/or of vesicles may be a target for the insulin regulation of GLUT4 endocytosis. the observation that insulin stimulates the translocation of glucose proteins from intracellular storage sites to the plasma have of the insulin signal transduction the regulation of glucose and relationships to glucose this four functional facilitative glucose transporter isoforms have been identified, and We now know that the GLUT4 isoform is primarily to insulin and for the if not of insulin-stimulated glucose in muscle and adipose tissue In the basal state, this transporter is between multiple intracellular membrane compartments, of which with the recycling endosome and which may be localized to unique vesicular Future studies are to the intracellular retention present in GLUT4, the by which GLUT4 is to these intracellular storage sites and the functional of these Although it is from this that the GLUT4 intracellular trafficking pathways to be a substantial is on the specific and t-SNARE proteins directly the major will the of the downstream signal transduction pathway that the and/or fusion of these GLUT4 vesicles with the plasma membrane. on all these is at an and the for the development of an and model that insulin action at the with the of glucose homeostasis.