GLUT4

Solute carrier family 2 (facilitated glucose transporter), member 4

Effect of insulin on glucose uptake and metabolism. Insulin binds to its receptor (1) which in turn starts many protein activation cascades (2). These include: translocation of Glut-4 transporter to the plasma membrane and influx of glucose (3), glycogen synthesis (4), glycolysis (5) and fatty acid synthesis (6).
Identifiers
Symbols SLC2A4; GLUT4
External IDs OMIM: 138190 MGI: 95758 HomoloGene: 74381 GeneCards: SLC2A4 Gene
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 6517 20528
Ensembl ENSG00000181856 ENSMUSG00000018566
UniProt P14672 P14142
RefSeq (mRNA) NM_001042.2 NM_009204.2
RefSeq (protein) NP_001033.1 NP_033230.2
Location (UCSC) Chr 17:
7.19 – 7.19 Mb		 Chr 11:
69.76 – 69.76 Mb
PubMed search [1] [2]

Glucose transporter type 4, also known as GLUT4, is a protein that in humans is encoded by the GLUT4 gene. GLUT4 is the insulin-regulated glucose transporter found in adipose tissues and striated muscle (skeletal and cardiac) that is responsible for insulin-regulated glucose translocation into the cell. This protein is expressed primarily in muscle and fat cells, the major tissues in the body that respond to insulin. The first evidence for this distinct glucose transport protein was provided by David James in 1988.[1] The gene that encodes GLUT4 was cloned[2][3] and mapped in 1989.[4]

Contents

Tissue distribution

GLUT4 is primarily found in:

Regulation

Insulin

Under conditions of low insulin, GLUT4 is sequestered in intracellular vesicles in muscle and fat cells. Insulin induces a rapid increase in the uptake of glucose by inducing the translocation of GLUT4 from these vesicles to the plasma membrane. As the vesicles fuse with the plasma membrane, GLUT4 transporters are inserted and become available for transporting glucose, and glucose absorption increases.

Insulin binds to the insulin receptor in its dimeric form and activates the receptor's tyrosine-kinase domain. The receptor then phosphorylates and subsequently recruits Insulin Receptor Substrate or IRS-1, which in turn binds the enzyme PI-3 kinase through the binding of the enzyme's SH2 domain to the pTyr of IRS. PI-3 kinase converts the membrane lipid PIP2 to PIP3. PIP3 is specifically recognized by the PH domains of PKB (protein kinase B)or AKT, and also for PDK1 which, being localized together with PKB, can phosphorylate and activate PKB. Once phosphorylated, PKB is in its active form and phosphorylates TBC1D4, which inhibits the GAP domain or the GTPase-activating domain associated with TBC1D4, allowing for Rab protein to change from its GDP to GTP bound state. Inhibition of the GTPase-activating domain leaves proteins next in the cascade in their active form and stimulates GLUT4 to be expressed on the plasma membrane.

At the cell surface, GLUT4 permits the facilitated diffusion of circulating glucose down its concentration gradient into muscle and fat cells. Once within cells, glucose is rapidly phosphorylated by glucokinase in the liver and hexokinase in other tissues to form glucose-6-phosphate, which then enters glycolysis or is polymerized into glycogen. Glucose-6-phosphate cannot diffuse back out of cells, which also serves to maintain the concentration gradient for glucose to passively enter cells.[5]

Knockout mice that are heterogenous for GLUT4 develop insulin resistance in their muscles as well as diabetes.[6]

Contraction

Contraction also stimulates the cell to translocate GLUT4 receptors to the surface. This is especially true in cardiac muscle, where continuous contraction can be relied upon; but is observed to a lesser extent in skeletal muscle. [7]

Interactions

GLUT4 has been shown to interact with Death-associated protein 6.[8]

References

  1. ^ James DE, Brown R, Navarro J, Pilch PF (May 1988). "Insulin-regulatable tissues express a unique insulin-sensitive glucose transport protein". Nature 333 (6169): 183–5. doi:10.1038/333183a0. PMID 3285221. 
  2. ^ James DE, Strube M, Mueckler M (March 1989). "Molecular cloning and characterization of an insulin-regulatable glucose transporter". Nature 338 (6210): 83–7. doi:10.1038/338083a0. PMID 2645527. 
  3. ^ Birnbaum MJ (April 1989). "Identification of a novel gene encoding an insulin-responsive glucose transporter protein". Cell 57 (2): 305–15. doi:10.1016/0092-8674(89)90968-9. PMID 2649253. 
  4. ^ Bell GI, Murray JC, Nakamura Y, Kayano T, Eddy RL, Fan YS, Byers MG, Shows TB (August 1989). "Polymorphic human insulin-responsive glucose-transporter gene on chromosome 17p13". Diabetes 38 (8): 1072–5. doi:10.2337/diabetes.38.8.1072. PMID 2568955. 
  5. ^ Watson RT, Kanzaki M, Pessin JE (2004). "Regulated membrane trafficking of the insulin-responsive glucose transporter 4 in adipocytes". Endocr. Rev. 25 (2): 177–204. doi:10.1210/er.2003-0011. PMID 15082519. 
  6. ^ Stenbit AE, Tsao TS, Li J, Burcelin R, Geenen DL, Factor SM, Houseknecht K, Katz EB, Charron MJ (1997). "GLUT4 heterozygous knockout mice develop muscle insulin resistance and diabetes". NATURE MEDICINE 3 (10): 1096-1101. PMID 9334720. 
  7. ^ Lund S, Holman GD, Schmitz O, Pedersen O (1995). "Contraction stimulates translocation of glucose transporter GLUT4 in skeletal muscle through a mechanism distinct from that of insulin". Proc. Natl. Acad. Sci. U.S.A. 92 (13): 5817–21. doi:10.1073/pnas.92.13.5817. PMC 41592. PMID 7597034. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=41592. 
  8. ^ Lalioti VS, Vergarajauregui S, Pulido D, Sandoval IV (May 2002). "The insulin-sensitive glucose transporter, GLUT4, interacts physically with Daxx. Two proteins with capacity to bind Ubc9 and conjugated to SUMO1". J. Biol. Chem. 277 (22): 19783–91. doi:10.1074/jbc.M110294200. PMID 11842083. 

Further reading

External links