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Typus
Verschleierung
Bearbeiter
Graf Isolan
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Untersuchte Arbeit:
Seite: 12, Zeilen: 9-33
Quelle: McCarthy and Elmendorf 2007
Seite(n): 374, 375, Zeilen: 374:left col. 38-41 - right col. 1-2.5-9.12ff; 375:left col. 8ff
In the basal state, GLUT4 cycles continuously between the plasma membrane and one or more intracellular compartments, with 90-95 percent of the transporter residing within the cell interior, tightly packaged into vesicles. The overall insulin-induced GLUT4 vesicle trafficking results in a >10-fold increase of GLUT4 protein at the cell surface (38). GLUT4 is found within large tubulo-vesicular structures in the perinuclear region of the cell and within small vesicles dispersed throughout the cytoplasm, also known as GLUT4 storage vesicles (GSVs) (39) (40). Perinuclear GLUT4 is likely localized in endosomes. GSVs on the other hand co-localize with insulin-responsive aminopeptidase (IRAP) and vesicle-associated membrane protein 2 (VAMP2). Upon insulin stimulation, it appears that GSVs are translocated to the cell surface, as there is an increase of GLUT4 at the plasma membrane that is proportional to the reduction in GLUT4-containing vesicles from the cytosolic compartment (41) (42), while the level of perinuclear GLUT4-containing vesicles remains relatively the same. Furthermore, total internal reflection fluorescence microscopy has revealed that in basal adipocytes, GLUT4-containing vesicles are located near the plasma membrane and are recruited to the cell surface with insulin stimulation (43) (Figure 2).

1.3.5 Role of insulin signalling in GLUT4 regulation

Activation of the insulin receptor triggers a cascade of phosphorylation events that ultimately promote GLUT4 vesicle exocytosis. The classical insulin signaling pathway (Figure 2) involves docking of the insulin receptor substrate (IRS) to the insulin receptor (IR), activation of phosphatidylinositol 3-kinase (PI3K) which leads to formation of plasma membrane phosphatidylinositol 3,4,5-trisphosphate (PI -P3), subsequent PI -P3-mediated activation of Akt and atypical protein kinase C (aPKC). Additionally, a PI3K-independent pathway involving c-Cbl, c-Cbl associated protein (CAP), and the GTPase TC10 may also regulate GLUT4 translocation. Insulin action is initiated when this peptide hormone binds to its receptor.


38. Malide,D, Ramm,G, Cushman,SW, Slot,JW: Immunoelectron microscopic evidence that GLUT4 translocation explains the stimulation of glucose transport in isolated rat white adipose cells. J.Cell Sci. 113 Pt 23:4203-4210, 2000

39. Kandror,KV, Pilch,PF: Compartmentalization of protein traffic in insulin-sensitive cells. Am.J.Physiol 271:E1-14, 1996

40. Rea,S, James,DE: Moving GLUT4: the biogenesis and trafficking of GLUT4 storage vesicles. Diabetes 46:1667-1677, 1997

41. Sehgal,SN, Baker,H, Vezina,C: Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization. J.Antibiot.(Tokyo) 28:727-732, 1975

42. Shi,J, Kandror,KV: Sortilin is essential and sufficient for the formation of Glut4 storage vesicles in 3T3-L1 adipocytes. Dev.Cell 9:99-108, 2005

43. Lizunov,VA, Matsumoto,H, Zimmerberg,J, Cushman,SW, Frolov,VA: Insulin stimulates the halting, tethering, and fusion of mobile GLUT4 vesicles in rat adipose cells. J.Cell Biol. 169:481-489, 2005

[Page 374]

In the basal state, GLUT4 cycles continuously between the plasma membrane and one or more intracellular compartments, with 90-95 per cent of the transporter residing within the cell interior, tightly packaged into vesicles3,4. [...] The overall insulin-dependent shift in the cellular dynamics of GLUT4 vesicle trafficking results in a >10-fold increase of GLUT4 protein at the cell surface7. [...]

GLUT4 is found within large tubulo-vesicular structures in the perinuclear region of the cell and within small vesicles dispersed throughout the cytoplasm, also known as GLUT4 storage vesicles (GSVs). Perinuclear GLUT4 is likely localized in endosomes and trans-Golgi network (TGN) structures, as evidence has shown that it co-localizes with endosomal and TGN markers, including transferrin receptor (TfR) and syntaxin 16, respectively9. GSVs on the other hand co-localize with insulin-responsive aminopeptidase (IRAP) and vesicle-associated membrane protein 2 (VAMP2). Upon insulin stimulation, it appears that GSVs are mobilized to the cell surface, as there is an increase of GLUT4 at the plasma membrane that is proportional to the reduction in GLUT4-containing vesicles from the cytosolic compartment10,11, while the level of perinuclear GLUT4-containing vesicles remains relatively unaffected10,12. Furthermore, total internal reflection fluorescence microscopy has revealed that in basal adipocytes, GLUT4-containing vesicles are located near the plasma membrane and are recruited to the cell surface with insulin stimulation13. [...]

[Page 375]

[...]

Insulin signaling systems regulating GLUT4

Activation of the insulin receptor triggers a cascade of phosphorylation events that ultimately promote GLUT4 vesicle exocytosis (Fig.). The classical insulin signaling pathway involves docking of the insulin receptor substrate (IRS) to the insulin receptor (IR), activation of phosphatidylinositol 3-kinase (PI3K) which leads to formation of plasma membrane phosphatidylinositol 3,4,5-trisphosphate (PI 3,4,5-P3), subsequent PI 3,4,5-P3-mediated activation of Akt and atypical protein kinase C (aPKC), and phosphorylation of AS160 (Akt substrate of 160 kDa) by Akt (Fig. A). Additionally, a PI3K-independent pathway involving c-Cbl, c-Cbl associated protein (CAP), and the GTPase TC10 may also regulate GLUT4 translocation (Fig. B), although this pathway appears to be exclusive to adipocytes. Here, we detail steps within both insulin signaling pathways.

IR and its substrates: Insulin action is initiated when this peptide hormone binds to its receptor.


3. Kandror KV, Pilch PF. Compartmentalization of protein traffic in insulin-sensitive cells. Am J Physiol 1996; 271 : E1-14.

4. Rea S, James DE. Moving GLUT4: the biogenesis and trafficking of GLUT4 storage vesicles. Diabetes 1997; 46 : 1667-77.

7. Malide D, Ramm G, Cushman SW, Slot JW. Immunoelectron microscopic evidence that GLUT4 translocation explains the stimulation of glucose transport in isolated rat white adipose cells. J Cell Sci 2000; 113 : 4203-10.

9. Larance M, Ramm G, Stockli J, van Dam EM, Winata S, Wasinger V, et al. Characterization of the role of the Rab GTPase-activating protein AS160 in insulin-regulated GLUT4 trafficking. J Biol Chem 2005; 280 : 37803-13.

10. Ramm G, Slot JW, James DE, Stoorvogel W. Insulin recruits GLUT4 from specialized VAMP2-carrying vesicles as well as from the dynamic endosomal/trans-Golgi network in rat adipocytes. Mol Biol Cell 2000; 11 : 4079-91.

11. Shi J, Kandror KV. Sortilin is essential and sufficient for the formation of Glut4 storage vesicles in 3T3-L1 adipocytes. Dev Cell 2005; 9 : 99-108.

12. Martin S, Millar CA, Lyttle CT, Meerloo T, Marsh BJ, Gould GW, et al. Effects of insulin on intracellular GLUT4 vesicles in adipocytes: evidence for a secretory mode of regulation. J Cell Sci 2000; 113 : 3427-38.

13. Lizunov VA, Matsumoto H, Zimmerberg J, Cushman SW, Frolov VA. Insulin stimulates the halting, tethering, and fusion of mobile GLUT4 vesicles in rat adipose cells. J Cell Biol 2005; 169 : 481-9.

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