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You are watching: Why do nonpolar molecules diffuse more rapidly through membranes

Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002.

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We begin this section by describing the permeability properties of protein-free, synthetic lipid bilayers. We then introduce some of the terms used to describe the various forms of membrane transport and some strategies for characterizing the proteins and processes involved.

Protein-free Lipid Bilayers Are Highly Impermeable to Ions

Given enough time, virtually any molecule will diffuse across a protein-free lipid bilayer down its concentration gradient. The rate at which it does so, however, varies enormously, depending partly on the size of the molecule, but mostly on its relative solubility in oil. In general, the smaller the molecule and the more soluble it is in oil (the more hydrophobic, or nonpolar, it is), the more rapidly it will diffuse across a lipid bilayer. Small nonpolar molecules, such as O2 and CO2, readily dissolve in lipid bilayers and therefore diffuse rapidly across them. Small uncharged polar molecules, such as water or urea, also diffuse across a bilayer, albeit much more slowly (Figure 11-1). By contrast, lipid bilayers are highly impermeable to charged molecules (ions), no matter how small: the charge and high degree of hydration of such molecules prevents them from entering the hydrocarbon phase of the bilayer. Thus, synthetic bilayers are 109 times more permeable to water than to even such small ions as Na+ or K+ (Figure 11-2).


Figure 11-1

The relative permeability of a synthetic lipid bilayer to different classes of molecules. The smaller the molecule and, more importantly, the less strongly it associates with water, the more rapidly the molecule diffuses across the bilayer.


Figure 11-2

Permeability coefficients for the passage of various molecules through synthetic lipid bilayers. The rate of flow of a solute across the bilayer is directly proportional to the difference in its concentration on the two sides of the membrane. Multiplying (more...)

There Are Two Main Classes of Membrane Transport Proteins: Carriers and Channels

Like synthetic lipid bilayers, cell membranes allow water and nonpolar molecules to permeate by simple diffusion. Cell membranes, however, also have to allow the passage of various polar molecules, such as ions, sugars, amino acids, nucleotides, and many cell metabolites that cross synthetic lipid bilayers only very slowly. Special membrane transport proteins are responsible for transferring such solutes across cell membranes. These proteins occur in many forms and in all types of biological membranes. Each protein transports a particular class of molecule (such as ions, sugars, or amino acids) and often only certain molecular species of the class. The specificity of membrane transport proteins was first indicated in the mid-1950s by studies in which single gene mutations were found to abolish the ability of bacteria to transport specific sugars across their plasma membrane. Similar mutations have now been discovered in humans suffering from a variety of inherited diseases that affect the transport of a specific solute in the kidney, intestine, or many other cell types. Individuals with the inherited disease cystinuria, for example, are unable to transport certain amino acids (including cystine, the disulfide-linked dimer of cysteine) from either the urine or the intestine into the blood; the resulting accumulation of cystine in the urine leads to the formation of cystine stones in the kidneys.

All membrane transport proteins that have been studied in detail have been found to be multipass transmembrane proteins-that is, their polypeptide chains traverse the lipid bilayer multiple times. By forming a continuous protein pathway across the membrane, these proteins enable specific hydrophilic solutes to cross the membrane without coming into direct contact with the hydrophobic interior of the lipid bilayer.

Carrier proteins and channel proteins are the two major classes of membrane transport proteins. Carrier proteins (also called carriers, permeases, or transporters) bind the specific solute to be transported and undergo a series of conformational changes to transfer the bound solute across the membrane (Figure 11-3). Channel proteins, in contrast, interact with the solute to be transported much more weakly. They form aqueous pores that extend across the lipid bilayer; when these pores are open, they allow specific solutes (usually inorganic ions of appropriate size and charge) to pass through them and thereby cross the membrane (see Figure 11-3). Not surprisingly, transport through channel proteins occurs at a much faster rate than transport mediated by carrier proteins.


Figure 11-3

Carrier proteins and channel proteins. (A) A carrier protein alternates between two conformations, so that the solute-binding site is sequentially accessible on one side of the bilayer and then on the other. (B) In contrast, a channel protein forms a (more...)

Active Transport Is Mediated by Carrier Proteins Coupled to an Energy Source

All channel proteins and many carrier proteins allow solutes to cross the membrane only passively (“downhill”), a process called passive transport, or facilitated diffusion. In the case of transport of a single uncharged molecule, it is simply the difference in its concentration on the two sides of the membrane—its concentration gradient—that drives passive transport and determines its direction (Figure 11-4A).


Figure 11-4

Passive and active transport compared. (A) Passive transport down an electrochemical gradient occurs spontaneously, either by simple diffusion through the lipid bilayer or by facilitated diffusion through channels and passive carriers. By contrast, active (more...)

If the solute carries a net charge, however, both its concentration gradient and the electrical potential difference across the membrane, the membrane potential,influence its transport. The concentration gradient and the electrical gradient can be combined to calculate a net driving force, the electrochemical gradient, for each charged solute (Figure 11-4B). We discuss this in more detail in Chapter 14. In fact, almost all plasma membranes have an electrical potential difference (voltage gradient) across them, with the inside usually negative with respect to the outside. This potential difference favors the entry of positively charged ions into the cell but opposes the entry of negatively charged ions.

Cells also require transport proteins that will actively pump certain solutes across the membrane against their electrochemical gradient (“uphill”); this process, known as active transport, is mediated by carriers, which are also called pumps. In active transport, the pumping activity of the carrier protein is directional because it is tightly coupled to a source of metabolic energy, such as ATP hydrolysis or an ion gradient, as discussed later. Thus, transport by carriers can be either active or passive, whereas transport by channel proteins is always passive.

Ionophores Can Be Used as Tools to Increase the Permeability of Membranes to Specific Ions

Ionophores are small hydrophobic molecules that dissolve in lipid bilayers and increase their permeability to specific inorganic ions. Most are synthesized by microorganisms (presumably as biological weapons against competitors or prey). They are widely used by cell biologists as tools to increase the ion permeability of membranes in studies on synthetic bilayers, cells, or cell organelles. There are two classes of ionophores—mobile ion carriers and channel formers (Figure 11-5). Both types operate by shielding the charge of the transported ion so that it can penetrate the hydrophobic interior of the lipid bilayer. Since ionophores are not coupled to energy sources, they permit the net movement of ions only down their electrochemical gradients.

Figure 11-5

Ionophores: a channel-former and a mobile ion carrier. In both cases, net ion flow occurs only down an electrochemical gradient.

Valinomycin is an example of a mobile ion carrier. It is a ring-shaped polymer that transports K+ down its electrochemical gradient by picking up K+ on one side of the membrane, diffusing across the bilayer, and releasing K+ on the other side. Similarly, FCCP, a mobile ion carrier that makes membranes selectively leaky to H+, is often used to dissipate the H+ electrochemical gradient across the mitochondrial inner membrane, thereby blocking mitochondrial ATP production. A23187 is yet another example of a mobile ion carrier, only it transports divalent cations such as Ca2+ and Mg2+. When cells are exposed to A23187, Ca2+ enters the cytosol from the extracellular fluid down a steep electrochemical gradient. Accordingly, this ionophore is widely used to increase the concentration of free Ca2+ in the cytosol, thereby mimicking certain cell-signaling mechanisms (discussed in Chapter 15).

Gramicidin A is an example of a channel-forming ionophore. It is a dimeric compound of two linear peptides (of 15 hydrophobic amino acids each), which wind around each other to form a double helix. Two gramicidin dimers are thought to come together end to end across the lipid bilayer to form what is probably the simplest of all transmembrane channels, which selectively allows monovalent cations to flow down their electrochemical gradients. Gramicidin is made by certain bacteria, perhaps to kill other microorganisms by collapsing the H+, Na+, and K+ gradients that are essential for their survival, and it has been useful as an antibiotic.


Lipid bilayers are highly impermeable to most polar molecules. To transport small water-soluble molecules into or out of cells or intracellular membrane-enclosed compartments, cell membranes contain various membrane transport proteins, each of which is responsible for transferring a particular solute or class of solutes across the membrane. There are two classes of membrane transport proteins—carriers and channels. Both form continuous protein pathways across the lipid bilayer. Whereas transport by carriers can be either active or passive, solute flow through channel proteins is always passive. Ionophores, which are small hydrophobic molecules made by microorganisms, can be used as tools to increase the permeability of cell membranes to specific inorganic ions.

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