Microstructure




Nucleus

Red blood cells in mammals anucleate when mature, meaning that they lack a cell nucleus. In comparison, the red blood cells of other vertebrates have nuclei; the only known exceptions are salamanders of the genus Batrachoseps and fish of the genus Maurolicus.

The elimination of the nucleus in vertebrate red blood cells has been offered as an explanation for the subsequent accumulation of non-coding DNA in the genome. The argument runs as follows: Efficient gas transport requires red blood cells to pass through very narrow capillaries, and this constrains their size. In the absence of nuclear elimination, the accumulation of repeat sequences is constrained by the volume occupied by the nucleus, which increases with genome size.

Nucleated red blood cells in mammals consist of two forms: normoblasts, which are normal erythropoietic precursors to mature red blood cells, and megaloblasts, which are abnormally large precursors that occur in megaloblastic anemias.

Membrane composition

Red blood cells are deformable, flexible, are able to adhere to other cells, and are able to interface with immune cells. Their 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 proteins, 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 phospholipids and cholesterol.

Membrane lipids

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 phospholipids 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 “Flippases” move phospholipids from the outer to the inner monolayer, while others called “floppases” 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 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 protein 4.1R. Recent studies have shown that binding of spectrin to PS promotes membrane mechanical stability. PIP2 enhances the binding of protein band 4.1R to glycophorin C but decreases its interaction with 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 flotillins, stomatins (band 7), G-proteins, and β-adrenergic receptors. Lipid rafts that have been implicated in cell signaling events in nonerythroid cells have been shown in erythroid cells to mediate β2-adregenic receptor signaling and increase cAMP levels, and thus regulating entry of malarial parasites into normal red cells.

Membrane proteins

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 types of humans are due to variations in surface glycoproteins 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.

The red blood cell membrane proteins organized according to their function:

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 Blood Group;
  • Aquaporin 1 – water transporter, defines the Colton Blood Group;
  • Glut1 – glucose and L-dehydroascorbic acid transporter;
  • Kidd antigen protein – urea transporter;
  • RhAG – gas transporter, probably of carbon dioxide, defines Rh Blood Group and the associated unusual blood group phenotype Rhnull;
  • Na+/K+ – ATPase;
  • Ca2+ – ATPase;
  • Na+ K+ 2Cl− – cotransporter;
  • Na+-Cl− – cotransporter;
  • Na-H exchanger;
  • K-Cl – cotransporter;
  • Gardos Channel.

Cell adhesion

  • ICAM-4 – interacts with integrins;
  • BCAM – a glycoprotein that defines the Lutheran blood group and also known as 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 glycolytic enzymes, the presumptive CO2 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 function.
    • RhAG – also involved in transport, defines associated unusual blood group phenotype Rhmod.
  • Protein 4.1R-based macromolecular complex – proteins interacting with Protein 4.1R.
    • Protein 4.1R – weak expression of Gerbich antigens;
    • Glycophorin C and D – glycoprotein, defines Gerbich Blood Group;
    • XK – defines the Kell Blood Group and the Mcleod unusual phenotype (lack of Kx antigen and greatly reduced expression of Kell antigens);
    • RhD/RhCE – defines Rh Blood Group and the associated unusual blood group phenotype Rhnull;
    • Duffy protein – has been proposed to be associated with chemokine clearance;
    • Adducin – interaction with band 3;
    • Dematin- interaction with the Glut1 glucose transporter.

Surface electrostatic potential

The zeta potential is an electrochemical property of cell surfaces that is determined by the net electrical charge of molecules exposed at the surface of cell membranes of the cell. The normal zeta potential of the red blood cell is −15.7 millivolts (mV). Much of this potential appears to be contributed by the exposed sialic acid residues in the membrane: their removal results in zeta potential of −6.06 mV.

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