W10 RBC structure + function Flashcards
RBC Structure
lacks nucleus, mitochondria and ER.
It is essentially a “bag of haemoglobin
RBC link to membrane?
Structural properties are linked to membrane
RBC ability to move
Biconcave, 8 micron cells, but able to deform & pass through 3 micron capillaries or reticuloendothelial system without fragmentation
RBC membrane
Have flexible membrane with a high surface-to-volume ratio
RBC primary function
Transport of respiratory gases to and from the tissues
RBC structure-function
RBC should be capable of traversing the microvascular system without mechanical damage, and retain a shape.
The red cell membrane should be extremely tough yet highly flexible
Interactions between the membrane & cytoskeletal proteins determines strength and flexibility
RBC biconcave shape
Maximises the surface area to increase efficiency of oxygen absorption
Functions of the red cell membrane
RBC membrane function
A. Maintenance of cell volume
1. Na+ and K+content
2. Osmotic fragility
B. Ca+2 Homeostasis
C. Anion exchangeFactors affecting red cell deformability
Cytoplasmic viscosity
Intracellular rubbish
Membrane rigidity
Surface to volume ratio
What is red cell membrane structure?
A semi-permeable lipid bilayer; with proteins scattered throughout:
an outer hydrophilic portion composed of glycolipids, glycoproteins, and proteins
a central hydrophobic layer containing proteins, cholesterol, and phospholipids
an inner hydrophilic layer of mesh-like cytoskeletal proteins to support lipid bilayer
The red cell membrane consists of
Proteins~50%, Lipids~40%, Carbohydrates~10%
Lipds consist of 60% phospholipid, 30% natural lipids (mainly cholesterol) and 10% glycolipids
Cholestrol in RBC membrane
Cholesterol will not form a membrane by itself, but inserts into a bilayer of phospholipids with its polar hydroxyl group close to the phospholipid head
RBC elasticity
RBC is highly elastic (100-fold softer than a latex membrane of comparable thickness), rapidly responds to applied fluid stresses (time constants in the range of 100 milliseconds), and is stronger than steel in terms of structural resistance
RBC membrane lipids
Asymmetric phospholipid distribution.
Unesterified free cholesterol between.
Uncharged phospholipids of outer layer
Phosphatidyl choline and Sphingomyelin
Charged phospholipids of inner layer:
Phosphatidyl ethanolamine
Phosphatidyl serine
Glycolipids
Lipids with a carbohydrate attached by a glycosidic (covalent) bond
Glycolipids function
Tto maintain the stability of the cell membrane and to facilitate cellular recognition, which is crucial to the immune response and in the connections that allow cells to connect to one another to form tissues
Concentration of cholesterol in the membrane
Important determinant of membrane surface area and fluidity
Increase in membrane cholesterol leads to an increased surface area and decreased deformability
Membrane cholestrol in equilbrium with…
Membrane cholesterol exists in free equilibrium with plasma cholesterol:
an increase in free plasma cholesterol results in an accumulation of cholesterol in the RBC membrane
RBCs with increased cholesterol appear distorted resulting in acanthocytosis
an increase in cholesterol and phospholipid is a cause of target cells
Excess plasma CL w/in outer leaflet of RBC membranes
This makes the red blood cells less deformable and they are remodeled as they passage through the spleen, forming acanthocytes (spiked CM)
RBC membrane proteins
Integral membrane proteins: Extend from outer surface and traverse entire membrane to inner surface
2 major integral membrane proteins:
Glycophorins: types of glycophorins identified:A, B, and C
Band 3: anion transporter
Other integral proteins:-
Na+/K+ ATPase, Aquaporin 1, surface receptors, e.g. TfR
Glycophorins
are the major integral membrane proteins, accounting for location of RBC antigens. They impart –ve charge to cell, reducing interaction with other cells/endothelium.
They are all glycophorins are receptors or transport proteins 3 types: Glycophorins A, B, and C.
GlycophorinC/ Protein 4.1/ p55 complex, and
GlycophorinA, appear important for P falciparum invasion of and development in RBC
Band 3
(acts as anion transport channel). links lipid bilayer to underlying membrane cytoskeleton (ankyrin).
- Na+/K+ ATPase.
- glucose transport protein.
- surface receptors. (the most important is the transferrin receptors)
Peripheral proteins
Limited to cytoplasmic surface of membrane and forms the RBC cytoskeleton
Major peripheral proteins include:
Spectrin, Ankyrin, Protein 4.1 and Actin
RBC cytoskeleton
The Cytoskeleton provides rigid support and stability to lipid bilayer.
It is also responsible for deformability properties of the RBC membrane, leading to shape change
Strong cohesion between bilayer and membrane skeleton maintains surface area
Outer leaflet
leaflet consists predominantly of phosphatidylcholine, sphingomyelin, and glycolipids
Inner leaflet
inner leaflet contains phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol
Maintenance of asymmetric distribution of phospholipids
The maintenance of asymmetric distribution of phospholipids, in particular exclusive localization of PS and phosphoinositides to the inner monolayer, has several functional implications:
- macrophages recognize + phagocytose red cells that expose PS at their outer surface
- confinement of this lipid in the inner monolayer is essential if the cell is to survive its frequent encounter w/macrophages of the reticuloendothelial system, especially the spleen
Spectrin
The most abundant peripheral protein
composed of alpha & beta chains
very important in RBC membrane integrity;
binds with other peripheral proteins to form the cytoskeletal network of microfilaments.
controls biconcave shape and deformability of cell
Microfilaments
Microfilaments strengthen membrane, protecting cell from being broken
For spectrin to participate in interaction with other proteins, it must be phosphorylated by a protein kinase that requires ATP.
So decrease in ATP = decreased phosphorylation of spectrin
Unphosphorylated spectrin
Can no longer bind to actin to give the membrane its elastic properties, leading to loss in membrane deformability and decreased RBC survival time
Mutations in cytoskeletal proteins
(spectrin, protein 4.1) weaken the horizontal linkage, decrease the membrane mechanical stability and are responsible for hereditary
elliptocytosis (HE)
Ankyrin
Primarily anchors lipid bilayer to membrane skeleton
via interaction with spectrin and Band 3;
Protein 4.1
may link the cytoskeleton to the membrane by means of its associations with glycophorin;
stabilises interaction of spectrin with actin
Actin
responsible for contraction and relaxation of membrane
What does red cell membrane do?
Provides shape:
Provides the optimum surface area to volume ratio for respiratory exchange
Provides deformability, elasticity
allowing for passage through micro vessels (capillaries)
Regulates intracellular cation concentration
Defects of band 3, spectrin, ankyrin, or protein 4.2
Defects of band 3, spectrin, ankyrin, or protein 4.2 lead to destabilisation of the overlying lipid bilayer and release of lipid in microvesicles
What features allow RBC to withstand life without structural deterioration?
Geometry of cell; surface area to volume ratio.
facilitates deformation whilst maintaining constant surface area.
Membrane deformability
spectrin molecules undergo reversible change in conformation: some uncoiled and extended, others compressed and folded.
Cytoplasmic viscosity determined by MCHC
as MCHC rises, viscosity rises exponentially.
Haemoglobin structure
globular haemoprotein
group of specialized proteins that contain haem as a tightly bound prosthetic group
Haem is a complex of protoporphyrin IX and ferrous iron (Fe2+)
Iron held in the centre of haem molecule by bonds to the 4 nitrogen of a porphyrin ring
Prosthetic gp
The nonprotein component of a conjugated protein, as the heme group in haemoglobin
Metabolism provide energy required for
Maintenance of cation pumps
Maintenance of Hb in reduced state
Maintenance of reduced sulfhydryl groups in Hb and other proteins
Maintenance of RBC integrity and deformability
Key Metabolic Pathways for the RBC
Glycolytic or Embden-Meyerhof Pathway
Hexose Monophosphate Shunt
Methaemoglobin reductase Pathway
Luebering-Rapoport shunt
Glycolytic Pathway
Glucose is metabolized and generates two molecules of ATP (energy).
Generates 90- 95% of energy needed by RBCs
Functions in the maintenance of RBC shape, flexibility and the cation pumps
This pathway also produces NADPH needed by the enzyme methaemoglobin reductase
hexose monophosphate pathway
used for production of NADPH from NADP
ATP energy for…
ATP provides energy to maintain red cell volume, shape and flexibility
A membrane ATPase sodium pump
A membrane ATPase sodium pump requiring ATP is used to control movement of Na+ and K+; pumps 3 Na+ out and 2 K + into cells
Pentose Phosphate Pathway
Pentose Phosphate Pathway
The pentose phosphate shunt provides the reducing power, NADPH
NADPH maintains glutathione in the reduced form (GSH)
RBC uses GSH to protect it from oxidative damage
An alternative to glycolysis and generates NADPH (oxidative phase) and pentoses (5-carbon sugars, nonoxidative phase).
Methemoglobin Reductase pathway
Maintains iron in the ferrous (Fe++) state.
In the absence of this enzyme, methaemoglobin accumulates and it cannot carry oxygen
Luebering-Rapoport shunt
A biochemical pathway in mature erythrocytes involving the formation of 2,3-bisphosphoglycerate and which regulates oxygen release from haemoglobin and delivery to tissues.
Permits the accumulation of 2,3-DPG which is essential for maintaining normal oxygen tension, regulating haemoglobin affinity
