RAGE (receptor)

RAGE, the receptor for advanced glycation endproducts is a 35kD transmembrane receptor of the immunoglobulin super family which was first characterized in 1992 by Neeper "et al." [cite journal
author = Neeper, M; Schmidt, AM; Brett, J; Yan, SD; Wang, F; Pan, YC; Elliston, K; Stern, D; Shaw, A
title = Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins
journal=J.Biol.Chem.
volume=267
issue=21
year=1992
pages=14998–15004
pmid=1378843] .Its name comes from its ability to bind advanced glycation endproducts (AGE), a heterogeneous group of non-enzymatically altered proteins. Besides AGEs, RAGE is also able to bind other ligands and is thus often referred to as a pattern recognition receptor.

The interaction between RAGE and its ligands is thought to result in pro-inflammatory gene activation [cite journal
author=Bierhaus, A; Schiekofer, S; Schwaninger, M et al.
title=Diabetes-associated sustained activation of the transcription factor nuclear factor-kappaB
journal=Diabetes
volume=50
issue=12
year=2001
pages=2792–2808
pmid=11723063
doi=10.2337/diabetes.50.12.2792] . Due to an enhanced level of RAGE ligands in diabetes or other chronic disorders, this receptor is hypothesised to have a causative effect in a range of inflammatory diseases such as diabetic complications, Alzheimer's disease and even some tumors.

Isoforms of the RAGE protein, which lack the transmembrane and the signalling domain (commonly referred to as soluble RAGE or sRAGE) are hypothesized to counteract the detrimental action of the full-length receptor and are hoped to provide a means to develop a cure against RAGE-associated diseases.

Gene/polymorphisms

The [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=full_report&list_uids=177 human RAGE gene] lies within the major histocompatibility complex (MHC) class III region on chromosome 6 and comprises 11 exons interlaced by 10 introns. Total length of the gene is about 1400 base pairs (bp) including the promoter region, which partly overlaps with the PBX2 gene [cite journal
author=Hudson, BI; Stickland, MH; Futers, TS; Grant, PJ
title=Effects of novel polymorphisms in the RAGE gene on transcriptional regulation and their association with diabetic retinopathy
journal=Diabetes
volume=50
issue=6
year=2001
pages=1505–1511
pmid=11375354
doi=10.2337/diabetes.50.6.1505] . About 30 polymorphisms are known most of which are single nucleotide polymorphisms (SNP) [cite journal
author=Hudson, BI; Hofman, MA; Bucciarelli, L "et al."
title=Glycation and diabetes: The RAGE connection
journal=Current Science
volume=83
issue=12
year=2002
pages=1515–1521
url=http://www.ias.ac.in/currsci/dec252002/1515.pdf] .

RNA/alternative splicing

The primary transcript of the human RAGE gene (pre-mRNA) is thought to be alternatively spliced. So far about 6 isoforms including the full length transmembrane receptor have been found in different tissues such as lung, kidney, brain etc. Five of these 6 isoforms lack the transmembrane domain and are thus believed to be secreted from cells. Generally these isoforms are referred to as sRAGE (soluble RAGE) or esRAGE (endogenous secretory RAGE). One of the isoforms lacks the V-domain and is thus believed not to be able to bind RAGE ligands.

Structure

The full receptor consists of 5 domains: The cytosolic domain, which is responsible for signal transduction, the transmembrane domain which anchors the receptor in the cell membrane, the variable domain which binds the RAGE ligands and two constant domains.

RAGE ligands

RAGE is able to bind several ligands and therefore is referred to as a pattern-recognition receptor. Proteins which have so far been found to bind RAGE are:

*AGE
*HMGB1 (Amphoterin)
*S100b
*Amyloid-β-protein
*Mac-1

RAGE and disease

RAGE has been linked to several chronic diseases, which are thought to result from vascular damage. The pathogenesis is hypothesized to include ligand binding upon which RAGE signals activation of the nuclear factor kappa B (NF-κB). NF-κB controls several genes which are involved in inflammation. Interestingly, RAGE itself will also be up-regulated by NF-κB. Given a condition, where there is a large amount of RAGE ligands (e.g. AGE in diabetes or Amyloid-β-protein in Alzheimer's Disease) this establishes a positive feed-back cycle, which leads to chronic inflammation. This chronic condition is then believed to alter the micro- and macrovasculature in a fatal way which ends in organ damage or even organ failure. Diseases that have been linked to RAGE are:
*Atherosclerosis
*Peripheral vascular disease
*Myocardial infarction
*Congestive heart failure
*Diabetic retinopathy
*Diabetic neuropathy
*Diabetic nephropathy
*Alzheimer's disease

AGE receptors

Besides RAGE there are other receptors which are believed to bind advanced glycation endproducts. However, these receptors could play a role in removal of AGE rather than in signal transduction as it is the case for RAGE. Other AGE receptors are:

*SR-A (Macrophage scavenger receptor Type I and II)
*OST-48 (Oligosaccharyl transferase-4) (AGE-R1)
*80 K-H phosphoprotein (Proteinkinase C substrate) (AGE-R2)
*Galectin-3 (AGE-R3)
*LOX-1 (Lectin-like oxidized low density lipoprotein receptor-1)
*CD-36

References

Further reading

PBB_Further_reading
citations =
*cite journal | author=Naka Y, Bucciarelli LG, Wendt T, "et al." |title=RAGE axis: Animal models and novel insights into the vascular complications of diabetes. |journal=Arterioscler. Thromb. Vasc. Biol. |volume=24 |issue= 8 |pages= 1342–9 |year= 2005 |pmid= 15155381 |doi= 10.1161/01.ATV.0000133191.71196.90
*cite journal | author=Simm A, Bartling B, Silber RE |title=RAGE: a new pleiotropic antagonistic gene? |journal=Ann. N. Y. Acad. Sci. |volume=1019 |issue= |pages= 228–31 |year= 2004 |pmid= 15247020 |doi= 10.1196/annals.1297.038
*cite journal | author=Nawroth P, Bierhaus A, Marrero M, "et al." |title=Atherosclerosis and restenosis: is there a role for RAGE? |journal=Curr. Diab. Rep. |volume=5 |issue= 1 |pages= 11–6 |year= 2005 |pmid= 15663911 |doi=

External links

*

PBB_Controls
update_page = yes
require_manual_inspection = no
update_protein_box = yes
update_summary = no
update_citations = yes