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^HIGUREHI^fe The diffusion of gases and lipid-soluble ^BtmmU^^^ molecules through the lipid bilayer. In this example, the diffusion of a solute across a plasma membrane is driven by the difference in concentration on the two sides of the membrane. The solute molecules move randomly by Brownian movement. Initially, random movement from left to right across the membrane is more frequent than movement in the opposite direction because there are more molecules on the left side. This results in a net movement of solute from left to right across the membrane until the concentration of solute is the same on both sides. At this point, equilibrium (no net movement) is reached because solute movement from left to right is balanced by equal movement from right to left.

Diffusion across a membrane has no preferential direction,- it can occur from the outside of the cell toward the inside or from the inside of the cell toward the outside. For any substance, it is possible to measure the permeability coefficient (P), which gives the speed of the diffusion across a unit area of plasma membrane for a defined driving force. Fick's law for the diffusion of an uncharged solute across a membrane can be written as:

which is similar to equation 1. P includes the membrane thickness, diffusion coefficient of the solute within the membrane, and solubility of the solute in the membrane. Dissolved gases, such as oxygen and carbon dioxide, have high permeability coefficients and diffuse across the cell membrane rapidly. Since diffusion across the plasma membrane usually implies that the diffusing solute enters the lipid bilayer to cross it, the solute's solubility in a lipid solvent (e.g., olive oil or chloroform) compared with its solubility in water is important in determining its permeability coefficient.

A substance's solubility in oil compared with its solubility in water is its partition coefficient. Lipophilic substances that mix well with the lipids in the plasma membrane have high partition coefficients and, as a result, high permeability coefficients,- they tend to cross the plasma membrane easily. Hydrophilic substances, such as ions and sugars, do not interact well with the lipid component of the membrane, have low partition coefficients and low permeability coefficients, and diffuse across the membrane more slowly.

For solutes that diffuse across the lipid part of the plasma membrane, the relationship between the rate of movement and the difference in concentration between the two sides of the membrane is linear (Fig. 2.4). The higher the difference in concentration (C — C2), the greater the amount of substance crossing the membrane per unit time.

Facilitated Diffusion via Carrier Proteins. For many solutes of physiological importance, such as sugars and amino acids, the relationship between transport rate and concentration difference follows a curve that reaches a plateau (Fig. 2.5). Furthermore, the rate of transport of these hydrophilic substances across the cell membrane is much faster than expected for simple diffusion through a lipid bilayer. Membrane transport with these characteristics is often called carrier-mediated transport because an integral membrane protein, the carrier, binds the transported solute on one side of the membrane and releases it at the other side. Although the details of this transport mechanism are unknown, it is hypothesized that the binding of the solute causes a conformational change in the carrier protein, which results in translocation of the solute (Fig. 2.6). Because there are limited numbers of these carriers in any cell membrane, increasing the concentration of the solute initially uses the existing "spare" carriers to transport the solute at a higher rate than by simple diffusion. As the concentration of the solute increases further and more solute molecules bind to carriers, the transport system eventually reaches saturation, when all the carriers are involved in translocating molecules of solute. At this point, additional increases in solute concentration do not increase the rate of solute transport (see Fig. 2.5).

The types of carrier-mediated transport mechanisms considered here can transport a solute along its concentration gradient only, as in simple diffusion. Net movement

Carrier Mediated Transport

Solute concentration (mmol/L) outside cell

Extracellular Solute Concentration

Solute concentration (mmol/L) outside cell

A graph of solute transport across a plasma membrane by simple diffusion. The rate of solute entry increases linearly with extracellular concentration of the solute. Assuming no change in intracellular concentration, increasing the extracellular concentration increases the gradient that drives solute entry.

A graph of solute transport across a plasma membrane by carrier-mediated transport.

The rate of transport is much faster than that of simple diffusion (see Fig. 2.4) and increases linearly as the extracellular solute concentration increases. The increase in transport is limited, however, by the availability of carriers. Once all are occupied by solute, further increases in extracellular concentration have no effect on the rate of transport. A maximum rate of transport (Vmax) is achieved that cannot be exceeded.

Muscle Membrane Proteins

^HIGUHEHII^^ The role of a carrier protein in facilitated ^BtmmU^^^ diffusion of solute molecules across a plasma membrane. In this example, solute transport into the cell is driven by the high solute concentration outside compared to inside. A, Binding of extracellular solute to the carrier, a membrane-spanning integral protein, may trigger a change in protein

^HIGUHEHII^^ The role of a carrier protein in facilitated ^BtmmU^^^ diffusion of solute molecules across a plasma membrane. In this example, solute transport into the cell is driven by the high solute concentration outside compared to inside. A, Binding of extracellular solute to the carrier, a membrane-spanning integral protein, may trigger a change in protein

Glut1 Mecanism
conformation that exposes the bound solute to the interior of the cell. B, Bound solute readily dissociates from the carrier because of the low intracellular concentration of solute. The release of solute may allow the carrier to revert to its original conformation (A) to begin the cycle again.

stops when the concentration of the solute has the same value on both sides of the membrane. At this point, with reference to equation 2, Ct = C2 and the value of J is 0. The transport systems function until the solute concentrations have equilibrated. However, equilibrium is attained much faster than with simple diffusion.

Equilibrating carrier-mediated transport systems have several characteristics:

• They allow the transport of polar (hydrophilic) molecules at rates much higher than expected from the partition coefficient of these molecules.

• They eventually reach saturation at high substrate concentration.

• They have structural specificity, meaning each carrier system recognizes and binds specific chemical structures (a carrier for d-glucose will not bind or transport l-glu-cose).

• They show competitive inhibition by molecules with similar chemical structure. For example, carrier-mediated transport of d-glucose occurs at a slower rate when molecules of d-galactose also are present. This is because galactose, structurally similar to glucose, competes with glucose for the available glucose carrier proteins. A specific example of this type of carrier-mediated transport is the movement of glucose from the blood to the interior of cells. Most mammalian cells use blood glucose as a major source of cellular energy, and glucose is transported into cells down its concentration gradient. The transport process in many cells, such as erythrocytes and the cells of fat, liver, and muscle tissues, involves a plasma membrane protein called GLUT 1 (glucose transporter 1). The erythrocyte GLUT 1 has an affinity for d-glucose that is about 2,000-fold greater than the affinity for l-glucose. It is an integral membrane protein that contains 12 membrane-spanning a-helical segments.

Equilibrating carrier-mediated transport, like simple diffusion, does not have directional preferences. It functions equally well in bringing its specific solutes into or out of the cell, depending on the concentration gradient. Net movement by equilibrating carrier-mediated transport ceases once the concentrations inside and outside the cell become equal.

The anion exchange protein (AEl), the predominant integral protein in the mammalian erythrocyte membrane, provides a good example of the reversibility of transporter action. AEl is folded into at least 12 transmembrane a-helices and normally permits the one-for-one exchange of Cl_ and HCO3~ ions across the plasma membrane. The direction of ion movement is dependent only on the concentration gradients of the transported ions. AE1 has an important role in transporting CO2 from the tissues to the lungs. The erythrocytes in systemic capillaries pick up CO2 from tissues and convert it to HCO3~, which exits the cells via AE1. When the erythrocytes enter pulmonary capillaries, the AE1 allows plasma HCO3~ to enter erythrocytes, where it is converted back to CO2 for expiration by the lungs (see Chapter 21).

Facilitated Diffusion Through Ion Channels. Small ions, such as Na+, K+, Cl", and Ca2+, also cross the plasma membrane faster than would be expected based on their partition coefficients in the lipid bilayer. An ion's electrical charge makes it difficult for the ion to move across the lipid bilayer. The rapid movement of ions across the membrane, however, is an aspect of many cell functions. The nerve action potential, the contraction of muscle, the pacemaker function of the heart, and many other physiological events are possible because of the ability of small ions to enter or leave the cell rapidly. This movement occurs through selective ion channels.

Ion channels are integral proteins spanning the width of the plasma membrane and are normally composed of several polypeptide subunits. Certain specific stimuli cause the protein subunits to open a gate, creating an aqueous channel through which the ions can move (Fig. 2.7). In this way, ions do not need to enter the lipid bilayer to cross the membrane; they are always in an aqueous medium. When the channels are open, the ions move rapidly from one side of the membrane to the other by facilitated diffusion. Specific interactions between the ions and the sides of the channel produce an extremely rapid rate of ion movement; in fact, ion channels permit a much faster rate of solute transport (about 108 ions/sec) than carrier-mediated systems.

Ion channels are often selective. For example, some channels are selective for Na+, for K+, for Ca2+, for Cl", and for other anions and cations. It is generally assumed that some kind of ionic selectivity filter must be built into the structure of the channel (see Fig. 2.7). No clear relation between the amino acid composition of the channel protein and ion selectivity of the channel has been established.

A great deal of information about the characteristic behavior of channels for different ions has been revealed by the patch clamp technique. The small electrical current caused by ion movement when a channel is open can be detected with this technique, which is so sensitive that the opening and closing of a single ion channel can be ob served (Fig. 2.8). In general, ion channels exist either fully open or completely closed, and they open and close very rapidly. The frequency with which a channel opens is variable, and the time the channel remains open (usually a few milliseconds) is also variable. The overall rate of ion transport across a membrane can be controlled by changing the frequency of a channel opening or by changing the time a channel remains open.

Most ion channels usually open in response to a specific stimulus. Ion channels can be classified according to their gating mechanisms, the signals that make them open or close. There are voltage-gated channels and ligand-gated channels. Some ion channels are always open and these are referred to as nongated channels (see Chapter 3).

Voltage-gated ion channels open when the membrane potential changes beyond a certain threshold value. Channels of this type are involved in the conduction of action potentials along nerve axons and they include sodium and potassium channels (see Chapter 3). Voltage-gated ion channels are found in many cell types. It is thought that some charged amino acids located in a membrane-spanning a-helical segment of the channel protein are sensitive to the transmembrane potential. Changes in the membrane potential cause these amino acids to move and induce a conformational change of the protein that opens the way for the ions.

Ligand-gated (or, chemically gated) ion channels cannot open unless they first bind to a specific agonist. The opening of the gate is produced by a conformational change in the protein induced by the ligand binding. The ligand can be a neurotransmitter arriving from the extracellular medium. It also can be an intracellular second messenger, produced in response to some cell activity or hormone action, that reaches the ion channel from the inside of the cell. The nicotinic acetylcholine receptor channel found in the postsynaptic neuromuscular junction (see Chapters 3 and 9) is a ligand-gated ion channel that is opened by an extracellular ligand (acetylcholine). Examples of ion channels gated by intracel-

Polypeptide Ion Channel

i An ion channel. Ion channels are formed be-^ammmmmm^ tween the polypeptide subunits of integral proteins that span the plasma membrane, providing an aqueous pore through which ions can cross the membrane. Different types of gating mechanisms are used to open and close channels. Ion channels are often selective for a specific ion.

i An ion channel. Ion channels are formed be-^ammmmmm^ tween the polypeptide subunits of integral proteins that span the plasma membrane, providing an aqueous pore through which ions can cross the membrane. Different types of gating mechanisms are used to open and close channels. Ion channels are often selective for a specific ion.

A patch clamp recording from a frog muscle fiber. Ions flow through the channel when it opens, generating a current. The current in this experiment is about 3 pA and is detected as a downward deflection in the recording. When more than one channel opens, the current and the downward deflection increase in direct proportion to the number of open channels. This record shows that up to three channels are open at any instant. (Modified from Kandel ER, Schwartz JH, Jessell TM. Principles of Neural Science. 3rd Ed. New York: Elsevier, 1991.)

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Responses

  • crispina greco
    How do lipophilic substances cross the cell membrane?
    8 years ago
  • danait adonay
    Why can charged ions move across plasma membrane faster a lipid bilayer?
    8 years ago

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