Editing Red blood cell (section)

===Membrane composition===
Red blood cells are deformable, flexible, are able to adhere to other cells, and are able to interface with immune cells. Their [[cell membrane|membrane]] plays many roles in this. These functions are highly dependent on the membrane composition. The red blood cell membrane is composed of 3 layers: the [[glycocalyx]] on the exterior, which is rich in [[carbohydrates]]; the [[lipid bilayer]] which contains many [[transmembrane protein]]s, besides its lipidic main constituents; and the membrane skeleton, a structural network of proteins located on the inner surface of the lipid bilayer. Half of the membrane mass in human and most mammalian red blood cells are proteins.  The other half are lipids, namely [[phospholipid]]s and [[cholesterol]].<ref name="Yazdanbakhsh2000">{{cite journal | vauthors = Yazdanbakhsh K, Lomas-Francis C, Reid ME | title = Blood groups and diseases associated with inherited abnormalities of the red blood cell membrane | journal = Transfusion Medicine Reviews | volume = 14 | issue = 4 | pages = 364–374 | date = October 2000 | pmid = 11055079 | doi = 10.1053/tmrv.2000.16232 }}</ref>

====Membrane lipids====
[[Image:Erythrocyte Membrane lipids.jpg|thumb|250px|The most common red blood cell membrane lipids, schematically disposed as they are distributed on the bilayer. Relative abundances are not at scale.]]
The red blood cell membrane comprises a typical [[lipid bilayer]], similar to what can be found in virtually all human cells. Simply put, this lipid bilayer is composed of [[cholesterol]] and [[phospholipid]]s in equal proportions by weight. The lipid composition is important as it defines many physical properties such as membrane permeability and fluidity. Additionally, the activity of many membrane proteins is regulated by interactions with lipids in the bilayer.

Unlike cholesterol, which is evenly distributed between the inner and outer leaflets, the 5 major phospholipids are asymmetrically disposed, as shown below:

'''Outer monolayer'''
* [[Phosphatidylcholine]] (PC);
* [[Sphingomyelin]] (SM).

'''Inner monolayer'''
* [[Phosphatidylethanolamine]] (PE);
* [[Phosphoinositol]] (PI) (small amounts).
* [[Phosphatidylserine]] (PS);

This asymmetric phospholipid distribution among the bilayer is the result of the function of several energy-dependent and energy-independent [[phospholipid]] transport proteins. Proteins called "[[Flippase]]s" move phospholipids from the outer to the inner monolayer, while others called "[[floppase]]s" do the opposite operation, against a concentration gradient in an energy-dependent manner. Additionally, there are also "[[scramblase]]" proteins that move phospholipids in both directions at the same time, down their concentration gradients in an energy-independent manner. There is still considerable debate ongoing regarding the identity of these membrane maintenance proteins in the red cell membrane.

The maintenance of an asymmetric phospholipid distribution in the bilayer (such as an exclusive localization of PS and PIs in the inner monolayer) is critical for the cell integrity and function due to several reasons:
* [[Macrophages]] recognize and [[phagocytose]] red cells that expose PS at their outer surface. Thus the confinement of PS in the inner monolayer is essential if the cell is to survive its frequent encounters with macrophages of the [[reticuloendothelial system]], especially in the [[spleen]].
* Premature destruction of [[Thalassemia|thallassemic]] and sickle red cells has been linked to disruptions of lipid asymmetry leading to exposure of PS on the outer monolayer.
* An exposure of PS can potentiate adhesion of red cells to vascular endothelial cells, effectively preventing normal transit through the microvasculature. Thus it is important that PS is maintained only in the inner leaflet of the bilayer to ensure normal blood flow in microcirculation.
* Both PS and [[phosphatidylinositol 4,5-bisphosphate]] (PIP2) can regulate membrane mechanical function, due to their interactions with skeletal proteins such as [[spectrin]] and [[Band 4.1|protein 4.1R]]. Recent studies have shown that binding of spectrin to PS promotes membrane mechanical stability. PIP2 enhances the binding of [[Band 4.1|protein band 4.1R]] to [[glycophorin C]] but decreases its interaction with [[Band 3|protein band 3]], and thereby may modulate the linkage of the bilayer to the membrane skeleton.

The presence of specialized structures named "[[lipid rafts]]" in the red blood cell membrane have been described by recent studies. These are structures enriched in [[cholesterol]] and [[sphingolipids]] associated with specific membrane proteins, namely [[FLOT1|flotillin]]s, [[STOM]]atins (band 7), [[G-proteins]], and [[Beta-adrenergic receptor|β-adrenergic receptor]]s. [[Lipid rafts]] that have been implicated in cell signaling events in nonerythroid cells have been shown in erythroid cells to mediate [[Beta-adrenergic receptor|β2-adregenic receptor]] signaling and increase [[Cyclic adenosine monophosphate|cAMP]] levels, and thus regulating entry of [[malaria]]l parasites into normal red cells.<ref name="Mohandas2008">{{cite journal | vauthors = Mohandas N, Gallagher PG | title = Red cell membrane: past, present, and future | journal = Blood | volume = 112 | issue = 10 | pages = 3939–3948 | date = November 2008 | pmid = 18988878 | pmc = 2582001 | doi = 10.1182/blood-2008-07-161166 }}</ref><ref>{{cite journal | vauthors = Rodi PM, Trucco VM, Gennaro AM | title = Factors determining detergent resistance of erythrocyte membranes | journal = Biophysical Chemistry | volume = 135 | issue = 1–3 | pages = 14–18 | date = June 2008 | pmid = 18394774 | doi = 10.1016/j.bpc.2008.02.015 | hdl-access = free | hdl = 11336/24825 }}</ref>

====Membrane proteins====
[[File:RBC Membrane Proteins SDS-PAGE gel.jpg|thumb|Red blood cell membrane proteins separated by [[Polyacrylamide gel electrophoresis|SDS-PAGE]] and [[Silver staining|silverstained]]<ref>{{cite journal |vauthors=Hempelmann E, Götze O | title =Characterization of membrane proteins by polychromatic silver staining| journal = Hoppe-Seyler's Z Physiol Chem| volume = 365| pages = 241–42| year = 1984 }}</ref>]]
The proteins of the membrane skeleton are responsible for the deformability, flexibility and durability of the red blood cell, enabling it to squeeze through capillaries less than half the diameter of the red blood cell (7–8 μm) and recovering the discoid shape as soon as these cells stop receiving compressive forces, in a similar fashion to an object made of rubber.

There are currently more than 50 known membrane proteins, which can exist in a few hundred up to a million copies per red blood cell. Approximately 25 of these membrane proteins carry the various blood group antigens, such as the A, B and Rh antigens, among many others. These membrane proteins can perform a wide diversity of functions, such as transporting ions and molecules across the red cell membrane, adhesion and interaction with other cells such as endothelial cells, as signaling receptors, as well as other currently unknown functions. The [[blood type]]s of humans are due to variations in surface [[glycoprotein]]s of red blood cells. Disorders of the proteins in these membranes are associated with many disorders, such as [[hereditary spherocytosis]], [[hereditary elliptocytosis]], [[hereditary stomatocytosis]], and [[paroxysmal nocturnal hemoglobinuria]].<ref name="Yazdanbakhsh2000"/><ref name="Mohandas2008"/>

The red blood cell membrane proteins organized according to their function:
[[File:RBC membrane major proteins.png|thumb|Red blood cell membrane major proteins]]
'''Transport'''
* [[Band 3]] – Anion transporter, also an important structural component of the red blood cell membrane, makes up to 25% of the cell membrane surface, each red cell contains approximately one million copies. Defines the [[Diego antigen system|Diego Blood Group]];<ref>{{cite journal | vauthors = Iolascon A, Perrotta S, Stewart GW | title = Red blood cell membrane defects | journal = Reviews in Clinical and Experimental Hematology | volume = 7 | issue = 1 | pages = 22–56 | date = March 2003 | pmid = 14692233 }}</ref>
* [[Aquaporin 1]] – water transporter, defines the [[Colton antigen system|Colton Blood Group]];
* [[Glut1]] – glucose and [[Dehydroascorbic acid|L-dehydroascorbic acid]] transporter;
* [[MCT1]] – [[Monocarboxylate transporter]] for exporting [[Lactic acid]] to the liver. See [[Cori cycle]].;<ref name="pmid29660777">{{cite journal | vauthors = Fisel P, Schaeffeler E, Schwab M | title = Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy | journal = Clinical and Translational Science | volume = 11 | issue = 4 | pages = 352–364 | date = July 2018 | pmid = 29660777 | pmc = 6039204 | doi = 10.1111/cts.12551 }}</ref>
* [[Kidd antigen system|Kidd antigen protein]] – urea transporter;
* [[RHAG]] – gas transporter, probably of carbon dioxide, defines Rh Blood Group and the associated unusual blood group phenotype Rh<sub>null</sub>;
* [[Na+/K+-ATPase|Na<sup>+</sup>/K<sup>+</sup> – ATPase]];
* [[Calcium ATPase|Ca<sup>2+</sup> – ATPase]];
* [[Na-K-2Cl cotransporter|Na<sup>+</sup> K<sup>+</sup> 2Cl<sup>−</sup> – cotransporter]];
* [[Sodium-chloride symporter|Na<sup>+</sup>-Cl<sup>−</sup> – cotransporter]];
* [[Na-H exchanger]];
* [[K-Cl cotransporter|K-Cl – cotransporter]];
* [[KCNN4|Gardos Channel]].

'''Cell adhesion'''
* [[ICAM4|ICAM-4]] – interacts with [[integrins]];
* [[Basal cell adhesion molecule|BCAM]]  – a glycoprotein that defines the [[lutheran antigen system|Lutheran blood group]] and also known as [[Lutheran antigen system|Lu]] or [[laminin]]-binding protein.

'''Structural role''' – The following membrane proteins establish linkages with skeletal proteins and may play an important role in regulating cohesion between the lipid bilayer and membrane skeleton, likely enabling the red cell to maintain its favorable membrane surface area by preventing the membrane from collapsing (vesiculating).
* [[Ankyrin]]-based macromolecular complex – proteins linking the bilayer to the membrane skeleton through the interaction of their cytoplasmic domains with [[Ankyrin]].
** [[Band 3]] – also assembles various [[Glycolysis|glycolytic]] enzymes, the presumptive CO<sub>2</sub> transporter, and [[carbonic anhydrase]] into a macromolecular complex termed a "[[metabolon]]," which may play a key role in regulating red cell metabolism and ion and gas transport [[#Role in CO2 transport|function]].
** [[RHAG]] – also involved in transport, defines associated unusual blood group phenotype Rh<sub>mod</sub>.
* [[Band 4.1|Protein 4.1R]]-based macromolecular complex – proteins interacting with [[Band 4.1|Protein 4.1R]].
** [[Band 4.1|Protein 4.1R]] – weak expression of [[Gerbich antigen system|Gerbich]] antigens;
** [[Glycophorin C]] and D – glycoprotein, defines [[Gerbich antigen system|Gerbich Blood Group]];
** [[XK protein|XK]] – defines the Kell Blood Group and the Mcleod unusual phenotype (lack of Kx antigen and greatly reduced expression of Kell antigens);
** [[Rh factor|RhD/RhCE]] – defines Rh Blood Group and the associated unusual blood group phenotype Rh<sub>null</sub>;
** [[Duffy antigen system|Duffy protein]] – has been proposed to be associated with [[chemokine]] clearance;<ref>{{cite journal | vauthors = Denomme GA | title = The structure and function of the molecules that carry human red blood cell and platelet antigens | journal = Transfusion Medicine Reviews | volume = 18 | issue = 3 | pages = 203–231 | date = July 2004 | pmid = 15248170 | doi = 10.1016/j.tmrv.2004.03.006 }}</ref>
** [[ADD1|Adducin]] – interaction with band 3;
** [[EPB49|Dematin]]- interaction with the Glut1 glucose transporter.
<ref name="Yazdanbakhsh2000"/><ref name="Mohandas2008"/>