Physical base function biological membrance
All living cells and many of the tiny organelles internal to cells are bounded by thin membranes. These membranes are composed primarily of phospholipids and proteins and are typically described as phospholipid bi-layers.
In this sketch, the spheres represent the phosphate end, which is polar and water soluble (hydrophilic). The twin extensions represent the fatty acid components which are not water soluble (hydrophobic).
Cell membranes also contain cholesterol in the phospholipid bilayer. In some membranes there are only a few cholesterol molecules, but in others there are as many cholesterols as phospholipids according to Audesirk & Audesirk. Cholesterol makes the bilayer stronger, more flexible but less fluid, and less permeable to water-soluble substances such as ions and monosaccharides.
Transport may occur by diffusion and osmosis across the membrane. It can also occur when a vescicle attaches to the cell membrane from the inside and then opens to form a pocket, expelling its contents to the outside. This may be called exocytosis. The cell membrane may also envelope something on the outside and surround it, taking it into the cell. This may be called endocytosis or phagocytosis.
There are also examples where molecules move across a membrane from a region of low concentration to an region of high concentration, and this requires a source of energy to "pump" the molecules uphill in concentration. Such processes are called active transport.
Cell membranes in general, and membranes of nerve cells in particular, maintain a small voltage or "potential" across the membrane in its normal or resting state. In the rest state, the inside of the nerve cell membrane is negative with respect to the outside (typically about -70 millivolts). The voltage arises from differences in concentration of the electrolyte ions K+ and Na+.
If the cell membranes were simply permeable to these ions, they would approach an equilibrium with equal concentrations on each side of the membrane, and hence no voltage difference. This makes it clear that the processes which produce the membrane potential are not simply diffusion and osmosis.
In the selectively permeable cell membranes are ion channels which allow K+ ions to pass to the interior of the cell, but block Na+ ions. Negatively charged proteins on the interior of the cell are also denied passage across the membrane. In addition, there are active transport mechanisms at work. There is a process called the sodium-potassium pump which utilizes ATP to pump out three Na+ ions and pump in two K+ ions. The collective action of these mechanisms leaves the interior of the membrane about -70 mV with respect to the outside.
For the nerve cell, this equilibrium is disturbed by the arrival of a suitable stimulus. The dynamic changes in the membrane potential in response to the stimulus is called an action potential. After the action potential the mechanisms described above bring the cell membrane back to its resting state.
Many nerve cells are of the basic type illustrated above. Some kind of stimulus triggers an electric discharge of the cell which is analogous to the discharge of a capacitor. This produces an electrical pulse on the order of 50-70 millivolts called an action potential. The electrical impulse propagates down the fiber-like extension of the nerve cell (the axon). The speed of transmission depends upon the size of the fiber, but is on the order of tens of meters per second - not the speed of light transmission that occurs with electrical signals on wires. Once the signal reaches the axon terminal bundle, it may be transmitted to a neighboring nerve cell with the action of a chemical neurotransmitter.
The dendrites serve as the stimulus receptors for the neuron, but they respond to a number of different types of stimuli. The neurons in the optic nerve respond to electrical stimuli sent by the cells of the retina. Other types of receptors respond to chemical neurotransmitters.
The cell body contains the necessary structures for keeping the neuron functional. That includes the nucleus, mitochondria, and other organelles. Extending from the opposite side of the cell body is the long tubular extension called the axon. Surrounding the axon is the myelin sheath, which plays an important role in the rate of electrical transmission. At the terminal end of the axon is a branched structure with ends called synaptic knobs. From this structure chemical signals can be sent to neighboring neurons.
A nerve cell is like a receiver, transmitter and transmission line with the task of passing a signal along from its dendrites to the axon terminal bundle.
The stimulus triggers an action potential in the cell membrane of the nerve cell, and that action potential provides the stimulus for a neighboring segment of the cell membrane. When the propagating action potential reaches the axon, it proceeds down that "transmission line" by successive excitation of segments of the axon membrane.
Just the successive stimulation of action potentials would result in slow signal transmission down the axon. The propagation speed is considerably increased by the action of the myelin sheath.
The myelin sheath around the axon prevents the gates on that part of the axon from opening and exchanging their ions with the outside environment. There are gaps between the myelin sheath cells known as the Nodes of Ranvier. At those uncovered areas of the axon membrane, the ion exchange necessary for the production of an action potential can take place. The action potential at one node is sufficient to excite a response at the next node, so the nerve signal can propagate faster by these discrete jumps than by the continuous propagation of depolarization/repolarization along the membrane. This enhanced signal transmission is called saltatory conduction (from the Latin saltare, to jump or hop).
Tuzynski and Dixon offer some quantification of the sizes involved in these nerve cells. The axon is made up of connected segments of length about 2 mm and diameter typically 20 m. This diameter compares to about 100 m for the diameter of a human hair. Axon diameters may vary from 0.1 m to 20 m and may be up to a meter long. The much-studied squid has a giant axon of about a millimeter in diameter. The myelin sheaths are about 1mm in length. The action potential travels along the axon at speeds from 1 to 100 m/s.
There are numerous situations in living organisms when molecules move across cell membranes from an area of lower concentration toward an area of higher concentration. This is counter to what would be expected and is labeled "active transport".
There is a very strong tendency for molecules to move from higher concentration to low, just based on thermal energy. Molecules at normal temperatures have very high speeds and random motions. For example, water molecules at 20°C have an effective or rms speed of over 600 m/s or over 1400 miles/hr! This motion from areas of high concentration to low is called diffusion. There are times when membranes are impermeable to some molecules because of their size, polarity, etc. and only the smaller solvent molecules like water molecules will move across the membrane. This is called osmosis, and the tendency to transport the solvent molecules is quantified in terms of osmotic pressure.
If a molecule is to be transported from an area of low concentration to an area of high concentration, work must be done to overcome the influences of diffusion and osmosis. Since in the normal state of a cell, large concentration differences in K+, Na+ and Ca2+ are maintained, it is evident that active transport mechanisms are at work.
Many crucial processes in the life of cells depend upon active transport. Included in the illustration above is the sodium-potassium pump which is a vital cell process. Active transport mechanisms may draw their enegy from the hydrolysis of ATP, the absorbance of light, the transport of electrons, or coupling with other processes that are moving particles down their concentration gradients.
A vital active transport process that occurs in the electron transport process in the membranes of both mitochondria and chloroplasts is the transport of protons to produce a proton gradient. This proton gradient powers the phosphorylation of ATP associated with ATP synthase.
A vital active transport process that occurs in the electron transport process in the membranes of both mitochondria and chloroplasts is the transport of protons to produce a proton gradient. This proton gradient or proton potential powers the phosphorylation of ATP associated with ATP synthase.
The electron transport process in the thylakoid membranes of chloroplasts provides energetic electrons to the cytochrome complex which pumps protons across the membrane in the direction opposite the concentration gradient. The potential provided by this proton gradient then powers the conversion of ADP to ATP.
In the case of the mitochondrial membrane, the goal is to produce ATP as an energy currency for cell processes by oxidizing a food material (oxidative phosphorylation). The Complexes I, III and IV of the electron transport process pump protons against their concentration gradient . That proton potential provides the energy for ATP synthase to accomplish the ADP to ATP process of phosphorylation.
Diffusion refers to the process by which molecules intermingle as a result of their kinetic energy of random motion. Consider two containers of gas A and B separated by a partition. The molecules of both gases are in constant motion and make numerous collisions with the partition. If the partition is removed as in the lower illustration, the gases will mix because of the random velocities of their molecules. In time a uniform mixture of A and B molecules will be produced in the container.
The tendency toward diffusion is very strong even at room temperature because of the high molecular velocities associated with the thermal energy of the particles.
If two solutions of different concentration are separated by a semi-permeable membrane which is permeable to to the smaller solvent molecules but not to the larger solute molecules, then the solvent will tend to diffuse across the membrane from the less concentrated to the more concentrated solution. This process is called osmosis.
Osmosis is of great importance in biological processes where the solvent is water. The transport of water and other molecules across biological membranes is essential to many processes in living organisms. The energy which drives the process is usually discussed in terms of osmotic pressure.
The process of moving sodium and potassium ions across the cell membrance is an active transport process involving the hydrolysis of ATP to provide the necessary energy. It involves an enzyme referred to as Na+/K+-ATPase. This process is responsible for maintaining the large excessof Na+ outside the cell and the large excess of K+ ions on the inside. A cycle of the transport process is sketched below. It accomplishes the transport of three Na+ to the outside of the cell and the transport of two K+ ions to the inside. This unbalanced charge transfer contributes to the separation of charge across the membrane. The sodium-potassium pump is an important contributer to action potential produced by nerve cells. This pump is called a P-type ion pump because the ATP interactions phosphorylates the transport protein and causes a change in its conformation.
The sodium-potassium pump moves toward an equilibrium state with the relative concentrations of Na+ and K+ shown at left.
Mechanism of passive transport.
Full row of processes in the cell, for example excitation, synthesis of ATPh, keeping of ion composition and water content at constant rate, is connected with translation of the matter through the biological membrane. Changing of matter translation velocity can causes breakdown of bioenergetics processes, water-salt exchange, excitation ability and other phenomenon; the correction of these changing is a base of acting a great amount of medical drugs. They differ active and passive translation (transport) of no charged molecules and ions through the bio-membrane. The active transport occurs by means of spending chemical energy and of hydrolyzing ATPh or translation electron though breath chain of mitochondria. The passive transport is not connected with spending chemical energy; it occurs in the result of diffusion matters in direction of lesser diffusion electric chemical potential (in the case of thermal equilibrium). As an example of passive transport there can be the move of Na and K ions through the cytoplasm membrane of nervous filaments at spreading of acting potential. Nevertheless, and in the cell, which is in the state of rest, the ions penetrate through membranes because of its penetrability; at the pathology the penetrability grow in general. By cause of generation the passive transport of particles may be divided on three kind: 1) because only of particles concentration changing, 2) because of changing both the concentration and electric potential and 3) because of changing concentration, electric potential and the pressure in the system. Let us consider these three kinds of passive transport in detail.
The diffusion no charged particles at pressure constant.
The molecules in bodies (of solid, liquid, gaseous, liquid crystal forms) are in continuous move and that is why are moving from one position to another. In the result of this such moving of molecules causes the particles flux in certain direction. The phenomenon of particles moving from one position to another in the space is cold by the mechanism of particles translation, or transport. At the beginning let us consider the case of transport because of particles concentration changing in the space. We are interested in vital organisms; therefore let us consider the liquid and liquid crystal bodies. In such bodies the molecules are in certain concrete position during average time oscillating in it, and then jumping (immediately comparing with time of ; we assume so) in neighbor position. Let the average distance between molecules is , and all space, which correspond to molecular (ball), assume to be this molecular. Then, it is clear, that the diameter of the molecular is equal to the distance between molecules in such model. Let us find the flux of some particles (on the figure it is marked by gray color, and cold by kind of a) through the flat surface of area, which is crossing through the plane of molecules (see fig. 6).
Let from left side of plot there are molecules of a kind, then the concentration of these molecules in the coordinate of x is
where is the volume, which correspond to these molecules. Let from right side of plot there is molecules of a kind, then the concentration of these molecules in the coordinate of is the following
The molecules can jump up, down, left, right, to us and from us. So, there are six directions. That is why there is approximately one sixth of a kind particles part, which is from left to plot, will jumps in plot in time of . Therefore, we may say, that the projection of particles flux of a kind, which move from left to right through the plot, on axis of ÎÕ is the following
Let us remember, that the flux of particles is the vector physical value, which is numerically equal to number of particles, which comes perpendicular across the certain plot for time unit. Analogically to this the flux projection of particles, which move from the right side to the left, may be written down as follows
In this formula the sign of minus is right down because the flux projection is negative that is clear from the fact that the flux is opposite to the axis ÎÕ. Therefore the whole flux projection is as follows:
And for the projection of flux density (the flux through the area unit) we have:
Using expressions (1) and (2) we may express and by means of concentrations and . Then we shall have:
In order to the molecules concentration essentially changes in the region of much more area than the distance between the layers, we may assume, that in the region of one layer scope (the distance of value) the concentration changes linearly. Therefore the derivative of concentration along x coordinate can be written dawn as follows:
Extracting from hear the difference of concentrations and substituting it in expression (7) for the density flux projection we will have:
From another hand, as we knew from thermodynamics, the particles flux projection can be written down as follows:
where — the diffusion coefficient. Comparing the formulas (9) and (10) we may infer, that the diffusion coefficient can be written as follows:
If there are equal electric potentials on the surface of membrane and the pressure on both sides of the membrane are the same, then the formula (10) can be used in connection with the flux of certain kind particles through the membrane.
Let us find the particles flux through the membrane, expressing it by means of particles concentrations on both sides of the membrane (see fig. 7). Mainly, inside the membrane the solubility of the matters is lesser than outside, and that is why, if the membrane is symmetrical, and we consider so, then
where — somewhat proportional coefficient, which define in what times the concentration of particles inside of the membrane is greater than outside.
Moreover, inside of the membrane because of its small thickness the concentration of molecules is linearly changing. Therefore the derivation along of x can be written as following
where — thickness of the membrane. Substituting the derivation (14) in the equation (10) for the particles flux projection we will have such result:
where is cold by penetrating coefficient.
The equation (15) is cold by Fik law for passive transport of molecules through the membrane in case of its diffusion.
Translation charged particles at constant pressure.
The Fik equation describes translation of uncharged particles. Now let us consider the transport of charged particles at passive translation. As it is known from thermodynamics, if the system is at unchanging temperature by space (), then the projection of resultant force, which is acting on the particle, without the resistance force, which is acting from surrounding on the particle, can be written as follows:
, ( in the space), (16)
If particle mobility in curtain surrounding is , then its projection is as follows:
The projection of particles flux density on the axis ÎÕ is as follows:
As it is known from thermodynamics the diffusion electric potential have such form:
Let us consider the case, when both the temperature and the pressure are the same in every points of the system. Then, substituting the expression (19) in the expression (18), we will have:
If the notion of molar concentration is included, that is to say, it is the amount of molars per volume unit:
then the expression (20) can be written down as follows:
The ion charge can be written down as the product its charge, expressed in elementary charges z (the positron charge), and elementary charge e:
Using expression (23), the equation (22) can be rewritten as follows:
From school course of physics it is known, that is the Faraday, and is the gas constant. Using this, the equation (24) reduces to such of kind:
This equation describes electric diffusion processes, which take place with particles of somewhat kind, in the system with constant by time electrical potential and concentration certain particles, and also with constant by space temperature and pressure. The equation (25) is cold by the equation of Nernst-Plank.
Translation of particles in the systems with changing by space pressure.
We considered the cases, when the pressure in the system in every its point is the same. But there are many cases of translations, when pressure in various part of the system is of different value. This, for example, is in the case of translation of particles through the membrane. Inside of the membrane the pressure is larger than outside. Therefore, no the Fik equation no the Nernst-Plank equation describes such processes perfectly. It is need to gain a new equation. Thus, let us consider the case, when the pressure in various points of the system is of different value. In such case the chemical potential will be of different values in various points of the system too because of inconstancy of the pressure in the space. Substituting the expression (19) in expr. (18), instead of expression (20) we will gain of such form:
The equation (26) includes the possibility of pressure changing by space. Its no concretized recording has the form, which is expressed in the equation (18). Including the molar concentration correspondingly to the equation (21), the expression (18) can be rewritten as follows:
where is the molar diffusion electric chemical potential. Let us remember, that the equation (27) is correct only for the processes, which occur in the systems with constant temperature by space. The equation (27) has the name of the Theorell equation.
The examples of transports in living organisms.
The passive transport of the matters through the bio-membranes.
They differ some kinds of transports of matters through membranes
A. The simple diffusion.
B. The transport through the pores (channels).
C. Transport by means of carriers diffusing together with the matter in the membrane (the moveable carrier) or relay race transference of the matter from one molecular of the carrier to another one (the molecules of the carrier create temporary chain across the membrane).
At all variety of transport mechanisms it may be divided on two base groups:
The such, which is so that every molecular is translated separate from others and therefore there are absent the effects of density flux saturation (A and B);
The such, in which transport occurs after combining of translating molecular with carrier molecular; as the processes of free carrier molecules filling grow then it occurs the effect of saturation of translation velocity, that is to say, the flux density reaches its saturation (C).
The base equation for diffusion of particles through the membrane is the electric diffusion equation of Nernst-Plank (25). We neglect by small contribution of particles flux through the membrane by means of difference of pressure on both sides of the membrane. The partial case of this equation relates to diffusion of uncharged molecules through the membrane (see equation (15)). Let us remember, that the penetrating coefficient in equation (15) is proportional to the coefficient of the membrane matter diffusion , to the coefficient of the matter distribution in the system of membrane-water and inversely proportional to the thickness of the membrane.
For penetrating of the matter through the membrane, for example for diffusion oxygen into a cell, it is important not only diffusion through the hydrophobia layer of proteins, but and through the unmoving layers too (through the layers attached to the membrane). Let us consider this problem numerically (see. Fig. 8). Let the matter diffuse into a cell. The substance, which cross from one water solution (“outside”) with constant concentration into another, but the same in components view, from opposite side of the membrane (“inside”) with concentration , has to overcome three diffusive barriers: the first water layer, attached to the membrane, the membrane as oneself and the second water layer, attached to the membrane. The projections of the fluxes through these three layers are correspondingly to the Fik law equal to
where , , — the penetrating coefficients of the barriers correspondingly; ³ — the concentrations of the matter in the water phase on the boundary with the membrane (see fig. 8), which are connected by equations (12) and (13) with the matter concentrations in the membrane phase near the first and the second surfaces of the membrane. If the equations (28-30) are divided on correspondent penetrating coefficients and then it are summarized, so we have the following
In the stationary state all projections of the fluxes are the same: . From another side , where — the penetrating coefficient of the system as a whole. From this it is following that
Thus, the magnitude , inverse to the penetrating coefficient, is extremely reminding the magnitude of a circuit electric resistance, which is composed from consecutive conductors; the whole resistance is equal to the sum of its components. Let us call the magnitude by the flux resistance of the matter. It is vary important that this magnitude for the layers attached to the membrane is proportional to the thickness these layers ( ³ ). It is actually; from the definition of penetrating coefficient (see equation (15)) it is following that at for water layers we have
is the diffusion coefficient of the matter in the water phase.
These equations tell us, what value have the phenomenon of proto-plasma moving in between-membrane liquid for the diffusion processes: the retardation of this movement is equivalent to the growing of or , that is to say, to the lowering of . So, the deceleration of the living processes of the cell can brake the processes of passive transport of the matter through the membrane at the expense of lowering liquid mixing in the cell and out of the cell.
Electric diffusion of the ions.
In order to solve the differential equation of Nernct-Plank (25) , it is need to know the dependence between and or and in the cell.
Because the potential inside of the membrane is changing linearly along of coordinate x, that is to say, is of constant value, then instead of in the equation (25) it may be written down , where is the voltage between potentials on interior and exterior sides of the membrane. From here it follows that
It is frequently instead of one use the dimensionless voltage:
Using dependence between mobility of particle and the diffusion coefficient (see the lecture about thermodynamics):
the equation (34) may be rewritten as follows:
It is clear, that the concentration and the voltage depend only upon coordinate x, therefore separating variables and we have the following:
Integrating this expression along coordinate from 0 till l and along c from till ( is of constant value), we have:
Having expressed this equation in the form of exponential function, we have:
From here it is ease to find the expression for the flux :
Using the definition of the magnitude (see (12) and (13)), the concentrations of the matters in the membrane (near its boundaries with the water phase) and are clever to substitute by concentrations in the water surrounding n both sides of the membrane and . Finally, the magnitude may be substituted by the penetrating coefficient (see (15)) of the membrane for the ion. Then we shall have such expression for the flux of ions through the membrane:
This equation establishes the numerical connection between the molar concentrations of ions on both sides of the membrane and , the membrane voltage or , penetrating of the membrane for definite ion and projection of flux density .
If we neglect the water layers attached to the membrane, then the concentrations and may be correspondingly substituted by and . It can be done because the magnitude in the equation (32) is essentially less than and because of low solubility of inorganic ions in he membrane (<<1, see the equation (12) ³ (13)), and that is why the whole resistance of the membrane and water layers to the flux of ions is closed to the resistance of the membrane as itself . Thus, finally the projection of particles flux through the membrane may be written as follows:
Cell membranes. Transport of substances through plasmalema
1. Fluid-mosaic model of the plasma membrane.
1.1. Lipid component.
1.2. Protein component.
2. Function of plasmalemma.
3. Movement of molecules into and out of cells.
3.4. Transport by carriers.
3.5. Active transport. Structure and function of ATP.
3.6. Endocytosis and exocytosis.
4. Receptors of the cells.
5. Junctions between cells.
The plasma membrane is about 7.5 nanometers (nm) thick and consists of a lipid bilayer and associated proteins.The inner leaflet of the plasma membrane faces the cytoplasm and the outer leaflet faces the extracellular environment. The plasma membrane displays a trilaminar (unit membrane) structure when examined by transmission electron microscopy (ÒÅÌ).
1. The plasma membrane envelops the cell and maintains its structural and functional integrity.
2. It acts as a semipermeable membrane between the cytoplasm and the external environment.
3. It permits the cell to recognize (and be recognized by) other cells and macromolecules.
Fluid mosaic model of the plasma membrane.
The lipid bilayer is composed of phospholipids, glycolipids, and cholesterol. Phospholipids consist of one hydrophillic head and two hydrophobic fatty acyl tails. Glycolipids are restricted to the outer leaflet. Polar carbohydrate residues of glycolipids extend from the outer leaflet into the extracellular space and form part of the glycocalyx. Cholesterol constitutes 2% of plasmalemma lipids, is present in both leaflets, and helps to maintain the structural integrity of the membrane. Fluidity of the lipid bilayer is crucial to exocytosis, endocytosis, membrane trafficking, and membrane biogenesis.
Membrane proteins include integral proteins and peripheral proteins. Integral proteins are dissolved in the lipid bilayer. Transmembrane proteins span the entire plasma membrane and function as membrane receptors and transport proteins. Most transmembrane proteins are glycoproteins. Transmembrane proteins are amphipathic and contain hydrophilic and hydrophobic amino acids, some of them interact with the hydrocarbon tails of the membrane phospholipids.
Peripheral proteins do not extend into the lipid bilayer. These proteins are located on the cytoplasmic aspect of the inner leaflet. The outer leaflets of some cells possess covalently linked glycolipids to which peripheral proteins are anchored; thus these peripheral proteins project into the extracellular space. Peripheral proteins bond to the phospholipid polar groups or integral proteins of the membrane via noncovalent interactions. They usually function as a part of the cytoskeleton or as a part of an intracellular second messenger system.
The lipid-to-protein ratio in plasma membranes ranges from 1:1 (by weight) in most cells to 4:1 in myelin.
Glycocalyx (cell coat) is the sugar coat located on the outer surface of the outer leaflet of the plasmalemma. When it is examined by ÒÅÌ, it varies in appearance (fuzziness) and thickness (up to 50 nm).
Function. 1) The glycocalyx aids in attachment of cells (e.g., fibroblasts but not epithelial cells) to extracellular matrix components. 2) It binds antigens and enzymes to the cell surface. 3) It facilitates cell-cell recognition and interaction.
Plasma Membrane Transport Processes. These processes include transport of a single molecule (uniport) or cotransport of two different molecules in the same (symport) or opposite (antiport) direction.
Passive transport includes simple and facilitated diffusion.
Neither of these processes requires energy because molecules move across the plasma membrane down a concentration or electrochemical gradient.
1. Simple diffusion transports small nonpolar molecules (e.g., 02 and N2) and small, uncharged, polar molecules (e.g., H20, C02, and glycerol). It exhibits little specificity, and the diffusion rate is proportional to the concentration gradient of the diffusing molecule.
2. Facilitated diffusion occurs via ion channel and/or carrier proteins, structures that exhibit specificity for the transported molecules. It is faster than simple diffusion; ions and large polar molecules are thus capable of traversing membranes that would otherwise be impermeable to them.
a. Ion channel proteins are highly folded transmembrane proteins that form small aqueous pores across membranes through which specific small water-soluble molecules and ions pass down an electrochemical gradient.
b. Carrier proteins are highly folded transmembrane proteins that undergo reversible conformational change, thus transporting specific molecules across the membrane; these proteins function in both passive transport and active transport.
3. Osmosis is the diffusion of water across a selectively permeable membrane in response to its concentration gradient.
a. When solute concentrations are equal on both sides of a cell membrane, there is no net movement of water in either direction; the two fluids are said to be isotonic (“iso-“ means same).
b. When solute concentrations are not equal, one fluid is hypotonic (has fewer solutes) and the other is hypertonic (has more solutes). Because water moves down its concentration gradient, it tends to move from a hypotonic solution to a hypertonic one.
Active transport is an energy-requiring process which transports a molecule against an electrochemical gradient via carrier proteins.
Na+-K+ pump mechanism. The Na+-K+ pump involves the antiport transport of Na+ and K+ ions mediated by the carrier protein, Na+-K+ ATPase. Na+ ions are pumped out of the cell and two K+ ions are pumped into the cell. The hydrolysis of a single ATP molecule by the Na+-K+ ATPase is required to transport five ions.
ATP (adenosine triphosphate) – is the common energy currency of cells; when cells require energy, they “spend” ATP. ATP production occurs at the cristae of mitochondria. The average male needs to produce about 8 kJ of ATP an hour. ATP is a nucleotide composed of the base adenine and the sugar ribose (together they are called adenosine) and 3 phosphate groups. Function of ATP: 1) Chemical function. It supplies the energy needed to synthesize macromolecules that make up the cell. 2) Transport function. It supplies the energy needed to pump substances across the plasma membrane. 3) Mechanical function. It supplies the energy needed to cause muscles to contract, cilia and flagella to beat, chromosomes to move etc. All organisms use ATP. It illustrates the chemical unity of all living things.
Endocytosis and exocytosis are ways that substances can enter and exit cells. Part of the plasma membrane pinches off and forms small membrane-bound sacs, or vesicles, around some substance. Vesicles are formed even around tiny cells (such as a bacteria) and fluids. During exocytosis, vesicles are formed inside the cytoplasm and then move to the plasma membrane and are fused with it, so their content is transferred outside. During endocytosis, a patch of plasma membrane encloses material at the cell surface. Then it sinks in and pinches off, forming a vesicle that either transports the material into the cytoplasm or stores it there. Phagocytosis (cell eating) is transport process by which amoeboid-type cells engulf large material, forming an intracellular vacuole. When macromolecules are taken in by endocytosis, the process is called pinocytosis (cell drinking), and the result is formation of vesicle. Both phagocytic vacuoles and pinocytic vesicles can fuse with lysosomes, whose enzymes digest their contents.
Passage of Molecules into and out of Cells
Toward lesser concentration
Toward lesser concentration
Toward greater concentration
Carrier plus energy
Sugars and amino acids
Sugars, amino acids, and
Cells and subcellular material
Vesicle fuses with plasma membrane
Receptor-mediated endocytic cycle is a form of pinocytosis that is very specific because it involves the use of plasma membrane receptors. A macromolecule that binds to a receptor is called a ligand. The binding of ligands to specific receptor sites causes the receptors to gather at one location before endocytosis occurs. This location is called a coated pit because there is a layer of fibrous protein, called clathrin, on the cytoplasmic side. Clathrin is a protein designed to form lattices around membranous vesicles. When a vesicle forms, it also is coated, but soon it loses its coat. At this point the ligands can directly enter the cell or else end up in lysosomes, which digest them to smaller molecules, which enter the cell. In any case, the receptors return to the plasma membrane and exocytosis occurs. The importance of receptor-mediated endocytosis is exemplified by the occurrence of a genetic disease. Normally cells take up cholesterol, which is carried in the blood by a lipoprotein called low density lipoprotein (LDL). When cells need more cholesterol for membrane production they produce receptors for LDL. After LDL molecules bind to receptors, receptor-mediated endocytosis occurs. Later, the receptors are returned to the plasma membrane and lysosomes disengage cholesterol from LDL. This whole process goes awry in individuals who lack a gene or inherit a faulty gene for the LDL receptor. Because cholesterol is unable to enter their cells, it builds up and forms plaque on blood vessel walls leading to cardiovascular disease and heart attacks. Children with this genetic disorder have been known to have heart attacks even as early as 6 years old.
Introduction to hemodialysis
Hemodialysis is the most common method used to treat advanced and permanent kidney failure. Since the 1960s, when hemodialysis first became a practical treatment for kidney failure, we've learned much about how to make hemodialysis treatments more effective and minimize side effects. In recent years, more compact and simpler dialysis machines have made home dialysis increasingly attractive. But even with better procedures and equipment, hemodialysis is still a complicated and inconvenient therapy that requires a coordinated effort from your whole health care team, including your nephrologist, dialysis nurse, dialysis technician, dietitian, and social worker. The most important members of your health care team are you and your family. By learning about your treatment, you can work with your health care team to give yourself the best possible results, and you can lead a full, active life.
Healthy kidneys clean your blood by removing excess fluid, minerals, and wastes. They also make hormones that keep your bones strong and your blood healthy. When your kidneys fail, harmful wastes build up in your body, your blood pressure may rise, and your body may retain excess fluid and not make enough red blood cells. When this happens, you need treatment to replace the work of your failed kidneys.
In hemodialysis, your blood is allowed to flow, a few ounces at a time, through a special filter that removes wastes and extra fluids. The clean blood is then returned to your body. Removing the harmful wastes and extra salt and fluids helps control your blood pressure and keep the proper balance of chemicals like potassium and sodium in your body.
One of the biggest adjustments you must make when you start hemodialysis treatments is following a strict schedule. Most patients go to a clinic-a dialysis center-three times a week for 3 to 5 or more hours each visit. For example, you may be on a Monday-Wednesday-Friday schedule or a Tuesday-Thursday-Saturday schedule. You may be asked to choose a morning, afternoon, or evening shift, depending on availability and capacity at the dialysis unit. Your dialysis center will explain your options for scheduling regular treatments.
Researchers are exploring whether shorter daily sessions, or longer sessions performed overnight while the patient sleeps, are more effective in removing wastes. Newer dialysis machines make these alternatives more practical with home dialysis. But the Federal Government has not yet established a policy to pay for more than three hemodialysis sessions a week.
Picture of Hemodialysis
Several centers around the country teach people how to perform their own hemodialysis treatments at home. A family member or friend who will be your helper must also take the training, which usually takes at least 4 to 6 weeks. Home dialysis gives you more flexibility in your dialysis schedule. With home hemodialysis, the time for each session and the number of sessions per week may vary, but you must maintain a regular schedule by giving yourself dialysis treatments as often as you would receive them in a dialysis unit.
Adjusting to Changes
Even in the best situations, adjusting to the effects of kidney failure and the time you spend on dialysis can be difficult. Aside from the "lost time," you may have less energy. You may need to make changes in your work or home life, giving up some activities and responsibilities. Keeping the same schedule you kept when your kidneys were working can be very difficult now that your kidneys have failed. Accepting this new reality can be very hard on you and your family. A counselor or social worker can answer your questions and help you cope.
Many patients feel depressed when starting dialysis, or after several months of treatment. If you feel depressed, you should talk with your social worker, nurse, or doctor because this is a common problem that can often be treated effectively.
One important step before starting hemodialysis is preparing a vascular access, a site on your body from which your blood is removed and returned. A vascular access should be prepared weeks or months before you start dialysis. It will allow easier and more efficient removal and replacement of your blood with fewer complications. For more information about the different kinds of vascular accesses and how to care for them, see the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) fact sheet Vascular Access for Hemodialysis.
When you first visit a hemodialysis center, it may seem like a complicated mix of machines and people. But once you learn how the procedure works and become familiar with the equipment, you'll be more comfortable.
Picture of a Graft
The dialysis machine is about the size of a dishwasher. This machine has three main jobs:
pump blood and watch flow for safety
clean wastes from blood
watch your blood pressure and the rate of fluid removal from your body
The dialyzer is a large canister containing thousands of small fibers through which your blood is passed. Dialysis solution, the cleansing fluid, is pumped around these fibers. The fibers allow wastes and extra fluids to pass from your blood into the solution, which carries them away. The dialyzer is sometimes called an artificial kidney.
Reuse. Your dialysis center may use the same dialyzer more than once for your treatments. Reuse is considered safe as long as the dialyzer is cleaned before each use. The dialyzer is tested each time to make sure it's still working, and it should never be used for anyone but you. Before each session, you should be sure that the dialyzer is labeled with your name and check to see that it has been cleaned, disinfected, and tested.
Dialysis solution, also known as dialysate, is the fluid in the dialyzer that helps remove wastes and extra fluid from your blood. It contains chemicals that make it act like a sponge. Your doctor will give you a specific dialysis solution for your treatments. This formula can be adjusted based on how well you handle the treatments and on your blood tests.
Many people find the needle sticks to be one of the hardest parts of hemodialysis treatments. Most people, however, report getting used to them after a few sessions. If you find the needle insertion painful, an anesthetic cream or spray can be applied to the skin. The cream or spray will numb your skin briefly so you won't feel the needle.
Most dialysis centers use two needles-one to carry blood to the dialyzer and one to return the cleaned blood to your body. Some specialized needles are designed with two openings for two-way flow of blood, but these needles are less efficient and require longer sessions. Needles for high-flux or high-efficiency dialysis need to be a little larger than those used with regular dialyzers.
Picture of arterial and venous needles
Some people prefer to insert their own needles. You'll need training on inserting needles properly to prevent infection and protect your vascular access. You may also learn a "ladder" strategy for needle placement in which you "climb" up the entire length of the access session by session so that you don't weaken an area with a grouping of needle sticks. A different approach is the "buttonhole" strategy in which you use a limited number of sites but insert the needle back into the same hole made by the previous needle stick. Whether you insert your own needles or not, you should know these techniques to better care for your access.
Tests to See How Well Your Dialysis Is Working
About once a month, your dialysis care team will test your blood by using one of two formulas-URR or Kt/V-to see whether your treatments are removing enough wastes. Both tests look at one specific waste product, called blood urea nitrogen (BUN), as an indicator for the overall level of waste products in your system. For more information about these measurements, see the NIDDK fact sheet Hemodialysis Dose and Adequacy.
Your kidneys do much more than remove wastes and extra fluid. They also make hormones and balance chemicals in your system. When your kidneys stop working, you may have problems with anemia and conditions that affect your bones, nerves, and skin. Some of the more common conditions caused by kidney failure are extreme tiredness, bone problems, joint problems, itching, and "restless legs." Restless legs will keep you awake as you feel them twitching and jumping.
Anemia and Erythropoietin (EPO)
Anemia is a condition in which the volume of red blood cells is low. Red blood cells carry oxygen to cells throughout the body. Without oxygen, cells can't use the energy from food, so someone with anemia may tire easily and look pale. Anemia can also contribute to heart problems.
Anemia is common in people with kidney disease because the kidneys produce the hormone erythropoietin, or EPO, which stimulates the bone marrow to produce red blood cells. Diseased kidneys often don't make enough EPO, and so the bone marrow makes fewer red blood cells. EPO is available commercially and is commonly given to patients on dialysis.
For more information about the causes of and treatments for anemia in kidney failure, see the NIDDK fact sheet Anemia in Kidney Disease and Dialysis.
The term "renal" describes things related to the kidneys. Renal osteodystrophy, or bone disease of kidney failure, affects 90 percent of dialysis patients. It causes bones to become thin and weak or formed incorrectly and affects both children and adults. Symptoms can be seen in growing children with kidney disease even before they start dialysis. Older patients and women who have gone through menopause are at greater risk for this disease.
Many people treated with hemodialysis complain of itchy skin, which is often worse during or just after treatment. Itching is common even in people who don't have kidney disease; in kidney failure, however, itching can be made worse by wastes in the bloodstream that current dialyzer membranes can't remove from the blood.
The problem can also be related to high levels of parathyroid hormone (PTH). Some people have found dramatic relief after having their parathyroid glands removed. The four parathyroid glands sit on the outer surface of the thyroid gland, which is located on the windpipe in the base of your neck, just above the collarbone. The parathyroid glands help control the levels of calcium and phosphorus in the blood.
But a cure for itching that works for everyone has not been found. Phosphate binders seem to help some people; these medications act like sponges to soak up, or bind, phosphorus while it is in the stomach. Others find relief after exposure to ultraviolet light. Still others improve with EPO shots. A few antihistamines (Benadryl, Atarax, Vistaril) have been found to help; also, capsaicin cream applied to the skin may relieve itching by deadening nerve impulses. In any case, taking care of dry skin is important. Applying creams with lanolin or camphor may help.
Patients on dialysis often have insomnia, and some people have a specific problem called the sleep apnea syndrome, which is often signaled bysnoring and breaks in snoring. Episodes of apnea are actually breaks in breathing during sleep. Over time, these sleep disturbances can lead to "day-night reversal" (insomnia at night, sleepiness during the day),headache, depression, and decreased alertness. The apnea may be related to the effects of advanced kidney failure on the control of breathing. Treatments that work with people who have sleep apnea, whether they have kidney failure or not, include losing weight, changing sleeping position, and wearing a mask that gently pumps air continuously into the nose (nasal continuous positive airway pressure, or CPAP).
Many people on dialysis have trouble sleeping at night because of aching, uncomfortable, jittery, or "restless" legs. You may feel a strong impulse to kick or thrash your legs. Kicking may occur during sleep and disturb a bed partner throughout the night. The causes of restless legs may include nerve damage or chemical imbalances.
Moderate exercise during the day may help, but exercising a few hours before bedtime can make it worse. People with restless leg syndrome should reduce or avoid caffeine, alcohol, and tobacco; some people also find relief with massages or warm baths. A class of drugs called benzodiazepines, often used to treat insomnia or anxiety, may help as well. These prescription drugs include Klonopin, Librium, Valium, and Halcion. A newer and sometimes more effective therapy is levodopa (Sinemet), a drug used to treat Parkinson's disease.
Sleep disorders may seem unimportant, but they can impair your quality of life. Don't hesitate to raise these problems with your nurse, doctor, or social worker.
Dialysis-related amyloidosis (DRA) is common in people who have been on dialysis for more than 5 years. DRA develops when proteins in the blood deposit on joints and tendons, causing pain, stiffness, and fluid in the joints, as is the case with arthritis. Working kidneys filter out these proteins, but dialysis filters are not as effective.
How Diet Can Help
Eating the right foods can help improve your dialysis and your health. Your clinic has a dietitian to help you plan meals. Follow the dietitian's advice closely to get the most from your hemodialysis treatments. Here are a few general guidelines.
Fluids. Your dietitian will help you determine how much fluid to drink each day. Extra fluid can raise your blood pressure, make your heart work harder, and increase the stress of dialysis treatments. Remember that many foods-such as soup, ice cream, and fruits-contain plenty of water. Ask your dietitian for tips on controlling your thirst.
Potassium. The mineral potassium is found in many foods, especially fruits and vegetables. Potassium affects how steadily your heart beats, so eating foods with too much of it can be very dangerous to your heart. To control potassium levels in your blood, avoid foods like oranges, bananas, tomatoes, potatoes, and dried fruits. You can remove some of the potassium from potatoes and other vegetables by peeling and soaking them in a large container of water for several hours, then cooking them in fresh water.
Phosphorus. The mineral phosphorus can weaken your bones and make your skin itch if you consume too much. Control of phosphorus may be even more important than calcium itself in preventing bone disease and related complications. Foods like milk and cheese, dried beans, peas, colas, nuts, and peanut butter are high in phosphorus and should be avoided. You'll probably need to take a phosphate binder with your food to control the phosphorus in your blood between dialysis sessions.
Salt (sodium chloride). Most canned foods and frozen dinners contain high amounts of sodium. Too much of it makes you thirsty, and when you drink more fluid, your heart has to work harder to pump the fluid through your body. Over time, this can cause high blood pressureand congestive heart failure. Try to eat fresh foods that are naturally low in sodium, and look for products labeled "low sodium."
Protein. Before you were on dialysis, your doctor may have told you to follow a low-protein diet to preserve kidney function. But now you have different nutritional priorities. Most people on dialysis are encouraged to eat as much high-quality protein as they can. Protein helps you keep muscle and repair tissue, but protein breaks down into urea (blood urea nitrogen, or BUN) in your body. Some sources of protein, called high-quality proteins, produce less waste than others. High-quality proteins come from meat, fish, poultry, and eggs. Getting most of your protein from these sources can reduce the amount of urea in your blood.
Calories. Calories provide your body with energy. Some people on dialysis need to gain weight. You may need to find ways to add calories to your diet. Vegetable oils-like olive, canola, and safflower oils-are good sources of calories and do not contribute to problems controlling your cholesterol. Hard candy, sugar, honey, jam, and jelly also provide calories and energy. If you have diabetes, however, be very careful about eating sweets. A dietitian's guidance is especially important for people with diabetes.
Supplements. Vitamins and minerals may be missing from your diet because you have to avoid so many foods. Dialysis also removes some vitamins from your body. Your doctor may prescribe a vitamin and mineral supplement designed specifically for people with kidney failure. Take your prescribed supplement after treatment on the days you have hemodialysis. Never take vitamins that you can buy off the store shelf, since they may contain vitamins or minerals that are harmful to you.
You can also ask your dietitian for recipes and titles of cookbooks for patients with kidney disease. Following the restrictions of a diet for kidney disease might be hard at first, but with a little creativity, you can make tasty and satisfying meals. For more information, see the NIDDK booklet Eat Right to Feel Right on Hemodialysis.
Treatment for kidney failure is expensive, but Federal health insurance plans pay much of the cost, usually up to 80 percent. Often, private insurance or State programs pay the rest. Your social worker can help you locate resources for financial assistance. For more information, see the NIDDK fact sheet Financial Help for Treatment of Kidney Failure.
The NIDDK, through its Division of Kidney, Urologic, and Hematologic Diseases, supports several programs and studies devoted to improving treatment for patients with progressive kidney disease and permanent kidney failure, including patients on hemodialysis.
The End-Stage Renal Disease Program promotes research to reduce medical problems from bone, blood, nervous system, metabolic, gastrointestinal, cardiovascular, and endocrine abnormalities in kidney failure and to improve the effectiveness of dialysis and transplantation. The research focuses on evaluating different hemodialysis schedules and on finding the most useful information for measuring dialysis adequacy. The program also seeks to increase kidney graft and patient survival and to maximize quality of life.
The HEMO Study, completed in 2002, tested the theory that a higher dialysis dose and/or high-flux membranes would reduce patient mortality (death) and morbidity (medical problems). Doctors at 15 medical centers recruited more than 1,800 hemodialysis patients and randomly assigned them to high or standard dialysis doses and high- or low-flux filters. The study found no increase in the health or survival of patients who had a higher dialysis dose, who dialyzed with high-flux filters, or who did both.
The U.S. Renal Data System (USRDS) collects, analyzes, and distributes information about the use of dialysis and transplantation to treat kidney failure in the United States. The USRDS is funded directly by the NIDDK in conjunction with the Centers for Medicare & Medicaid Services. The USRDS publishes an Annual Data Report, which identifies the total population of people being treated for kidney failure; reports on incidence, prevalence, death rates, and trends over time; and develops data on the effects of various treatment approaches. The report also helps identify problems and opportunities for more focused special studies of renal research issues.
The Hemodialysis Vascular Access Clinical Trials Consortium is conducting a series of multicenter, clinical trials of drug therapies to reduce the failure and complication rate of arteriovenous (AV) grafts and fistulas in hemodialysis. These studies are randomized and placebo controlled, which means the studies meet the highest standard for scientific accuracy. AV grafts and fistulas prepare the arteries and veins for regular dialysis. See the NIDDK fact sheet Vascular Access for Hemodialysis for more information. Recently developed drugs to prevent blood clots may be evaluated in these large clinical trials.
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