Learning Objectives✓ Why are membranes impermeable to most substances?

✓ What is the driving force for membrane formation?

✓ How do proteins function to make membranes selectively permeable?

✓ What are the basic components of all signal-transduction pathways?

✓ How are the various types of membrane receptors differentiated?

The boundaries of cells are formed by biological membranes, the barriers thatdefine the inside and the outside of a cell. These barriers are intrinsically

impermeable, preventing molecules generated inside the cell from leaking outand unwanted molecules from diffusing in; yet they also contain transport sys-tems that allow the cell to take up specific molecules and remove unwantedones. Such transport systems confer on membranes the important property ofselective permeability.

SECTION

5Cell Membranes,Channels, Pumps, and Receptors

Selective permeability is conferred by two classes of membrane proteins,pumps and channels. Pumps use a source of free energy to drive the thermody-namically uphill transport of ions or molecules. Pump action is an example ofactive transport. Channels, in contrast, enable molecules, usually ions, to flowrapidly through membranes in a thermodynamically downhill direction. Channelaction illustrates passive transport, or facilitated diffusion.

The cell membrane is also impermeable to most information molecules, such ashormones, growth factors, and molecules in food or aromas that communicate tasteor smell. Again, proteins serve to allow information to enter the cell from the envi-ronment. Membrane proteins called receptors sense information in the environmentand transmit or transduce the information across the membrane to the cell interior.

We will first examine the basic structure of membranes and the proteinsthat are responsible for the property of selective permeability. Then, we willexamine a special circumstance of transport across membranes—how environ-mental information is conveyed across the membrane to alter the biochemicalworkings of the cell.

Chapter 11: Membrane Structureand Function

Chapter 12: Signal-TransductionPathways

156

CHAPTER

11 Membrane Structure and Function

11.1 Phospholipids and GlycolipidsForm Bimolecular Sheets

11.2 Proteins Carry Out MostMembrane Processes

11.3 Lipids and Many MembraneProteins Diffuse Laterally in theMembrane

11.4 Membrane Fluidity Is Controlledby Fatty Acid Composition andCholesterol Content

11.5 A Major Role of MembraneProteins Is to Function AsTransporters

Membranes of different cells and structures are as diverse in structure as theyare in function. However, they do have in common a number of important

attributes:

1. Membranes are sheetlike structures, only two molecules thick, that form closedboundaries between different compartments. The thickness of most mem-branes is between 60 Å (6 nm) and 100 Å (10 nm).

2. Membranes consist mainly of lipids and proteins. Membranes also containcarbohydrates that are linked to lipids and proteins (p. 133).

3. Membrane lipids are small molecules that have both hydrophilic and hydropho-bic moieties. These lipids spontaneously form closed bimolecular sheets in aque-ous media. These lipid bilayers are barriers to the flow of polar molecules.

4. Specific proteins mediate distinctive functions of membranes. Proteins serve aspumps, channels, receptors, energy transducers, and enzymes. Membrane pro-teins are embedded in lipid bilayers, which creates suitable environments fortheir action.

5. Membranes are noncovalent assemblies. The constituent protein and lipidmolecules are held together by many noncovalent interactions, which actcooperatively.

Cell membranes are not static structures. The membrane of this fibroblast cell (stained red)shows irregularities called ruffles. The ruffles are required for movement and phagocytosis.The green stain is a cytoskeleton protein attached to the membrane. [Catherine Nobes andAlan Hall/Wellcome Images.]

15711.1 Lipid Bilayers

6. Membranes are asymmetric. The two faces of biological membranes alwaysdiffer from each other.

7. Membranes are fluid structures. Lipid molecules diffuse rapidly in the planeof the membrane, as do proteins, unless they are anchored by specific inter-actions. In contrast, lipid molecules and proteins do not readily rotate acrossthe membrane.

8. Most cell membranes are electrically polarized, such that the inside is negative.Membrane potential plays a key role in transport, energy conversion, andexcitability.

11.1 Phospholipids and Glycolipids Form Bimolecular Sheets

Recall from our earlier examination of membrane lipids that, although the reper-toire of lipids is extensive, these lipids possess common structural elements: theyare amphipathic molecules with a hydrophilic (polar) head group and ahydrophobic hydrocarbon tail (p. 150). Membrane formation is a consequence ofthe amphipathic nature of the molecules. Their polar head groups favor contactwith water, whereas their hydrocarbon tails interact with one another in prefer-ence to water. How can molecules with these preferences arrange themselves inaqueous solutions?

The favored structure for most phospholipids andglycolipids in aqueous media is a lipid bilayer, composed oftwo lipid sheets. The hydrophobic tails of each individualsheet interact with one another, forming a hydrophobicinterior that acts as a permeability barrier. Thehydrophilic head groups interact with the aqueousmedium on each side of the bilayer. The two opposingsheets are called leaflets (Figure 11.1).

Lipid bilayers form spontaneously by a self-assemblyprocess. In other words, the structure of a bimolecularsheet is inherent in the structure of the constituent lipidmolecules. The growth of lipid bilayers from phospho-lipids is rapid and spontaneous in water. The hydrophobic effect is the major driving force for the formation of lipid bilayers. Recall that the hydrophobic effectalso plays a dominant role in the folding of proteins (p. 53). Water molecules arereleased from the hydrocarbon tails of membrane lipids as these tails becomesequestered in the nonpolar interior of the bilayer. Furthermore, van der Waalsattractive forces between the hydrocarbon tails favor close packing of the tails.Finally, there are electrostatic and hydrogen-bonding attractions between the polarhead groups and water molecules.

Clinical Insight

Lipid Vesicles Can Be Formed from PhospholipidsThe propensity of phospholipids to form membranes has been used to create animportant experimental and clinical tool. Lipid vesicles, or liposomes, are aqueouscompartments enclosed by a lipid bilayer (Figure 11.2). These structures can beused to study membrane permeability or to deliver chemicals to cells. Liposomesare formed by suspending a membrane lipid in an aqueous medium and then son-icating (i.e., agitating by high-frequency sound waves) to give a dispersion ofclosed vesicles that are quite uniform in size. Vesicles formed by this method arenearly spherical in shape and have a diameter of about 500 Å (50 nm). Ions or

Inner aqueouscompartment

Outer aqueouscompartment

Bilayer membrane

Figure 11.2 A liposome. A liposome, orlipid vesicle, is a small aqueouscompartment surrounded by a lipid bilayer.

Figure 11.1 A space-filling model of asection of phospholipid bilayer membrane.An idealized view showing regularstructures.

molecules can be trapped in the aqueous compartments of lipid vesicles if thevesicles are formed in the presence of these substances (Figure 11.3).

Experiments are underway to develop clinical uses for liposomes. For exam-ple, liposomes containing DNA for gene-therapy experiments or drugs can beinjected into patients. These liposomes fuse with the plasma membrane of manykinds of cells, introducing into the cells the molecules that they contain. Theadvantage of drug delivery by liposomes is that the drugs are more targeted thannormal systemic drugs, which means that less of the body is exposed to potentiallytoxic drugs. Liposomes are especially useful in targeting tumors and sites ofinflammation, which have a high density of blood vessels. Liposomes concentratein such areas of increased blood circulation, reducing the amount of drugsdelivered to normal tissue. Lipid vesicles that target particular kinds of cells canbe created by embedding proteins in the liposome that will recognize the targetcell. The selective fusion of these vesicles with the target cells is a promising meansof controlling the delivery of drugs to target cells. ■

Lipid Bilayers Are Highly Impermeable to Ions and Most Polar MoleculesThe results of permeability studies of lipid bilayers have shown that lipid bilayermembranes have a very low permeability for ions and most polar molecules. The abil-ity of molecules to move through a lipid environment, such as a membrane, isquite varied (Figure 11.4). For example, Na� and K� traverse these membranes109 times more slowly than H2O. Tryptophan, a zwitterion at pH 7, crosses themembrane 103 times more slowly than indole, a structurally related molecule thatlacks ionic groups. In fact, experiments show that the permeability of small mole-cules is correlated with their relative solubilities in water and nonpolar solvents. Thisrelation suggests that a small molecule might traverse a lipid bilayer membrane inthe following way: first, it sheds the water with which it is associated, called thesolvation shell; then, it dissolves in the hydrocarbon core of the membrane; and,finally, it diffuses through this core to the other side of the membrane, where it isresolvated by water. An ion such as Na� cannot cross the membrane, because thereplacement of its shell of polar water molecules by nonpolar interactions withthe membrane interior is highly unfavorable energetically.

Sonication

Filtration

Glycine in H2O

Phospholipid

Glycine trappedin lipid vesicle

Figure 11.3 The preparation of glycine-containing liposomes. Liposomescontaining glycine are formed by thesonication of phospholipids in thepresence of glycine. Free glycine isremoved by filtration.

K+

Cl− Glucose

Tryptophan

IndoleUrea

GlycerolNa+ H2O

Increasing permeability

Figure 11.4 Relative ability to cross a lipid bilayer. The ability of molecules to cross alipid bilayer spans a wide range.

Tryptophan

Indole

CH2

C

H

COO–+H3N

C

CC

HN

CH

NH

CH

CH

HC

HC

158

11.2 Proteins Carry Out Most Membrane ProcessesWe now turn to membrane proteins, which are responsible for most of thedynamic processes carried out by membranes. Membrane lipids form a perme-ability barrier and thereby establish compartments, whereas specific proteins medi-ate nearly all other membrane functions. In particular, proteins transport chemicalsand information across a membrane.

Membranes that differ in function differ in their protein content. Myelin, amembrane that serves as an electrical insulator around certain nerve fibers, has alow content of protein (18%). Membranes composed almost entirely of lipids aresuitable for insulation because the hydrophobic components do not conduct

currents well. In contrast, the plasma membranes, or exterior membranes, of mostother cells must conduct the traffic of molecules into and out of the cells and socontain many pumps, channels, receptors, and enzymes. The protein content ofthese plasma membranes is typically 50%. Energy-transduction membranes, suchas the internal membranes of mitochondria and chloroplasts, have the highestcontent of protein—typically, 75%. In general, membranes performing differentfunctions contain different kinds and amounts of proteins.

Proteins Associate with the Lipid Bilayer in a Variety of WaysMembrane proteins can be classified as being either peripheral or integral on thebasis of the ease with which they are removed from the membrane (Figure 11.5).Integral membrane proteins are embedded in the hydrocarbon chains of mem-brane lipids, and they can be released only when the membrane is physically dis-rupted. In fact, most integral membrane proteins span the lipid bilayer. Incontrast, peripheral membrane proteins are primarily bound to the head groups oflipids, by electrostatic and hydrogen-bond interactions. These polar interactionscan be disrupted by adding salts or by changing the pH of the membrane’senvironment. Many peripheral membrane proteins are bound to the surfaces ofintegral proteins, on either the cytoplasmic or the extracellular side of the mem-brane. Others are anchored to the lipid bilayer by a covalently attached hydropho-bic chain, such as a fatty acid (p. 143).

15911.2 Membrane Proteins

Cytoplasm

Figure 11.6 Structure ofbacteriorhodopsin. Notice that

bacteriorhodopsin consists largely ofmembrane-spanning � helices(represented by yellow cylinders). The viewis through the membrane bilayer. Theinterior of the membrane is green and thehead groups are red. [Drawn from1 BRX.pdb.]

Figure 11.5 Integral and peripheralmembrane proteins. Integral membraneproteins (a, b, and c) interact extensivelywith the hydrocarbon region of the bilayer.Most known integral membrane proteinstraverse the lipid bilayer. Other proteinsare tightly anchored to the membrane by acovalently attached lipid molecule (d).Peripheral membrane proteins (e and f )bind to the surfaces of integral proteins.Some peripheral membrane proteinsinteract with the polar head groups of thelipids (not shown).

f

a b

e

c

d

Proteins can span the membrane with � helices. For instance, consider bacte-riorhodopsin, which uses light energy to transport protons from inside the cell tooutside, generating a proton gradient used to form ATP (Figure 11.6). Bacteri-orhodopsin is built almost entirely of � helices; seven closely packed � helices,arranged almost perpendicularly to the plane of the cell membrane, span its width.

Examination of the primary structure of bacteriorhodopsin reveals that most ofthe amino acids in these membrane-spanning � helices are nonpolar and only avery few are charged (Figure 11.7). Just as the nonpolar hydrocarbon moieties ofphospholipids associate with one another, the nonpolar � helices of bacteri-orhodopsin associate with the hydrocarbon core of the lipid bilayer. Membrane-spanning a helices are the most common structural motif in membrane proteins.

A Q I T G R P E W I W L A L G T A L M G L G T L Y F L V K G M G V S D P D A K K F Y A I T T L V P AI A F T M Y L S M L L G Y G L T M V P F G G E Q N P I Y W A R Y A D W L F T T P L L L L D L A L L V

L F F G F T S K A E S M R P E V A S T F K V L R N V T V V L W S A Y V V V W L I G S E G A G I V P LN I E T L L F M V L D V S A K V G F G L I L L R S R A I F G E A E A P E P S A D G A A A T S

D A D Q G T I L A L V G A D G I M I G T G L V G A L T K V Y S Y R F V WW A I S T A A M L Y I L Y V

Figure 11.7 Amino acid sequence of bacteriorhodopsin. The seven helical regions arehighlighted in yellow and the charged residues in red.

(A) (B)

Periplasm

Figure 11.8 The structure ofbacterial porin (from

Rhodopseudomonas blastica). Notice thatthis membrane protein is built entirely of� strands. (A) Side view. (B) View from theperiplasmic space (region between thebacterium’s inner and outer membranes).Only one monomer of the trimeric proteinis shown. [Drawn from 1 PRN.pdb.]

EISLNGYGRFGLQYVE

N term

TTGVINIRLRSSIITD

TFGAKLRMQWDD

YSTWFQA

VTVSVGN

ISYTVAIGN

GVNLYLSYVD

NSWDAAIGFE

MISLAAAYTT

KYAAGVFAI

AGTVGLNWYD

FAYNGYLTVQD

ATTVRAYVSDID

FQYDAGIGYA

GVKVSGSVQSG

FDFRVGVDAVTE

C term

Figure 11.9 The amino acid sequence of aporin. Some membrane proteins such asporins are built from � strands that tendto have hydrophobic and hydrophilicamino acids in adjacent positions. Thesecondary structure of porin fromRhodopseudomonas blastica is shown,with the diagonal lines indicating thedirection of hydrogen bonding along the �sheet. Hydrophobic residues (F, I, L, M, V,W, and Y) are shown in yellow. Theseresidues tend to lie on the outside of thestructure, in contact with the hydrophobiccore of the membrane.

160

The membrane-spanning parts of proteins can also be formed from �strands. Porin, a protein from the outer membranes of bacteria such as E. coli,represents a class of membrane proteins that are built from � strands andcontain essentially no � helices (Figure 11.8). The arrangement of � strandsis quite simple: each strand is hydrogen bonded to its neighbor in an antipar-allel arrangement, forming a single � sheet. The � sheet curls up to form ahollow cylinder that, as the protein’s name suggests, forms a pore, or chan-nel, in the membrane. The outside surface of porin is appropriately nonpo-lar, given that it interacts with the hydrocarbon core of the membrane. Incontrast, the inside of the channel is quite hydrophilic and is filled withwater. This arrangement of nonpolar and polar surfaces is accomplished bythe alternation of hydrophobic and hydrophilic amino acids along each �strand (Figure 11.9).

Another means of associating a protein with a membrane is to embedjust part of the protein into the membrane. The structure of the endoplasmicreticulum membrane-bound enzyme prostaglandin H2 synthase-1 exempli-fies this type of association. Prostaglandin H2 synthase-1 lies along the outersurface of the membrane but is firmly bound by a set of � helices withhydrophobic surfaces that extend from the bottom of the protein into themembrane (Figure 11.10).

Clinical Insight

The Association of Prostaglandin H2 Synthase-l with the Membrane Accounts for the Action of AspirinThe localization of prostaglandin H2 synthase-l in the mem-brane is crucial to its function. Prostaglandin H2 synthase-1catalyzes the conversion of arachidonic acid into prostaglandinH2, which promotes inflammation and modulates gastric acidsecretion. Arachidonic acid is a fatty acid generated by thehydrolysis of membrane lipids. Arachidonic acid moves fromthe nonpolar core of the lipid bilayer, where it is generated, tothe active site of the enzyme without entering an aqueous envi-ronment by traveling through a hydrophobic channel in theprotein (Figure 11.11). Indeed, nearly all of us have experi-enced the importance of this channel: drugs such as aspirinand ibuprofen block the channel and prevent prostaglandinsynthesis, thereby reducing the inflammatory response.Aspirin donates an acetyl group to a serine residue (Ser 530)that lies along the path to the active site, thereby blocking thechannel (Figure 11.12). ■

16111.2 Membrane Proteins

Hydrophobic amino acidside chains

Figure 11.10 The attachment ofprostaglandin H2 synthase-1 to the

membrane. Notice that prostaglandin H2synthase-1 is held in the membrane by aset of � helices (orange) coated withhydrophobic side chains. One monomer ofthe dimeric enzyme is shown. [Drawn from 1 PTH.pdb.]

Ser 530

Hydrophobicchannel

Figure 11.11 The hydrophobic channel of prostaglandin H2synthase-1. A view of prostaglandin H2 synthase-1 from the

membrane reveals the hydrophobic channel that leads to the activesite. The membrane-anchoring helices are shown in orange. [Drawnfrom 1PTH.pdb.]

O OH

O CH3

O

O CH3

O

Ser530

Aspirin(Acetylsalicyclic acid)

Figure 11.12 Aspirin’s effects on prostaglandin H2 synthase-1.Aspirin acts by transferring an acetyl group to a serine residue inprostaglandin H2 synthase-1.

First, a cell-surface component, such as a protein or the head group of a phos-pholipid, is fluorescently labeled. A small region of the cell surface (�3 �m2) isviewed through a fluorescence microscope. The fluorescent molecules in thisregion are then destroyed (bleached) by an intense pulse of light from a laser.The fluorescence of this region is subsequently monitored as a function of time.If the labeled component is mobile, bleached molecules leave and unbleachedmolecules enter the affected region, which results in an increase in the fluores-cence intensity. The rate of recovery of fluorescence depends on the lateralmobility of the fluorescence-labeled component. Such experiments show that aphospholipid molecule moves an average distance of 2 �m in 1 s. This ratemeans that a lipid molecule can travel from one end of a bacterium to the other ina second. In contrast, proteins vary markedly in their lateral mobility. Some proteinsare nearly as mobile as lipids, whereas others are virtually immobile. Proteins areimmobilized by attachment to the cytoskeleton or structural components out-side the cell, called the extracellular matrix.

Although the lateral diffusion of membrane components can be rapid, thespontaneous rotation of lipids from one face of a membrane to the other is a veryslow process. The transition of a molecule from one membrane surface to theother is called transverse diffusion or flip-flopping. The results of experiments showthat a phospholipid molecule flip-flops once in several hours. Thus, a phospholipidmolecule takes about 109 times as long to flip-flop across a membrane as it takesto diffuse a distance of 50 Å in the lateral direction (Figure 11.14). The free-energybarriers to flip-flopping are even larger for protein molecules than for lipidsbecause proteins have more-extensive polar regions. In fact, the flip-flopping of aprotein molecule has not been observed. Hence, membrane asymmetry can be pre-served for long periods.

Bleach Recovery

(A) (B) (C) (D)

Fluo

resc

ence

inte

nsity

Time

Bleach

Recovery

Nucleus

Figure 11.13 The technique of fluorescence recovery after photobleaching (FRAP). (A) Thecell surface fluoresces because of a labeled surface component. (B) The fluorescent moleculesof a small part of the surface are bleached by an intense light pulse. (C) The fluorescenceintensity recovers as bleached molecules diffuse out of the region and unbleached moleculesdiffuse into it. (D) The rate of recovery depends on the diffusion coefficient.

Rapid

Lateral diffusion

Very slow

Tranverse diffusion(flip-flopping)

Figure 11.14 Lipid movement inmembranes. Lateral diffusion of lipids ismuch more rapid than transverse diffusion(flip-flopping).

16211 Membrane Structure and Function

11.3 Lipids and Many Membrane Proteins Diffuse Laterally in the Membrane

Biological membranes are not rigid, static structures. On the contrary, lipids and manymembrane proteins are constantly in motion, a process called lateral diffusion. The rapidlateral movement of membrane proteins has been visualized with the use of fluores-cence microscopy and the technique of fluorescence recovery after photobleaching (FRAP;Figure 11.13).

11.4 Membrane Fluidity Is Controlled by Fatty AcidComposition and Cholesterol Content

Many membrane processes, such as transport or signal transduction, depend onthe fluidity of the membrane lipids, which in turn depends on the properties offatty acid chains. The fatty acid chains in membrane bilayers may be arranged inan ordered, rigid state or in a relatively disordered, fluid state. The transition fromthe rigid to the fluid state takes place rather abruptly as the temperature is raisedabove Tm, the melting temperature (Figure 11.15). This transition temperaturedepends on the length of the fatty acid chains and on their degree of unsaturation.Long fatty acids interact more strongly because of the increased number of vander Waals interactions than do short ones and thus favor the rigid state. The presenceof saturated fatty acid residues further favors the rigid state because their straighthydrocarbon chains interact very favorably with one another (Figure 11.16). Onthe other hand, a cis double bond produces a bend in the hydrocarbon chain. Thisbend interferes with a highly ordered packing of fatty acid chains, and so Tmis lowered.

163

Solid

like

Flui

dlik

e

Tm

Temperature

Figure 11.15 The phase-transition, ormelting, temperature (Tm) for aphospholipid membrane. As thetemperature is raised, the phospholipidmembrane changes from a packed,ordered state to a more random one.

(B)(A)

Figure 11.16 The packing of fatty acid chains in a membrane. The highly ordered packing offatty acid chains is disrupted by the presence of cis double bonds. The space-filling modelsshow the packing of (A) three molecules of stearate (C18, saturated) and (B) a molecule ofoleate (C18, unsaturated) between two molecules of stearate.

Cholesterol

Figure 11.17 Cholesterol disrupts the tightpacking of the fatty acid chains. [After S. L.Wolfe, Molecular and Cellular Biology(Wadsworth, 1993).]

QUICK QUIZ 1 Predict the effecton membrane-lipid composition if the

temperature of a bacterial culture is raisedfrom 37°C to 42°C.

Bacteria regulate the fluidity of their membranes by varying the number ofdouble bonds and the length of their fatty acid chains. In animals, cholesterol isthe key modulator of membrane fluidity. Cholesterol contains a bulky steroidnucleus with a hydroxyl group at one end and a flexible hydrocarbon tail at theother end. The molecule inserts into bilayers with its long axis perpendicular tothe plane of the membrane. Cholesterol’s hydroxyl group forms a hydrogen bondwith a carbonyl oxygen atom of a phospholipid head group, whereas its hydrocar-bon tail is located in the nonpolar core of the bilayer. The different shape of cho-lesterol compared with that of phospholipids disrupts the regular interactionsbetween fatty acid chains (Figure 11.17).

Cholesterol appears to form specific complexes with some phospholipids,notably sphingolipids. Such complexes may concentrate in specific regionswithin membranes. The resulting structures are thicker, more stable, and lessfluid than the rest of the membrane and are often referred to as lipid rafts ormembrane rafts. Lipid rafts may also play a role in concentrating proteins thatparticipate in signal-transduction pathways.

11.5 A Major Role of Membrane Proteins Is to Function As Transporters

Transporter proteins are a specific class of pump or channel that facilitates the move-ment of molecules across a membrane. Each cell type expresses a specific set of trans-porters in its plasma membrane. The set of transporters expressed is crucial becausethese transporters largely determine the ionic composition inside a cell and the com-pounds that can be taken up from the cell’s environment. In some senses, the arrayof transporters expressed by a cell determines the cell’s characteristics because a cellcan execute only those biochemical reactions for which it has taken up the substrates.

Two factors determine whether a small molecule will cross a membrane: (1) theconcentration gradient of the molecule across the membrane and (2) the molecule’ssolubility in the hydrophobic environment of the membrane. In accord with theSecond Law of Thermodynamics, molecules spontaneously move from a region ofhigher concentration to one of lower concentration. For many molecules, thecell membrane is an obstacle to this movement, but, as discussed earlier (p. 158),some molecules can pass through the membrane because they dissolve in the lipidbilayer. Such molecules are called lipophilic molecules. The steroid hormones pro-vide a physiological example. These cholesterol relatives can pass through a mem-brane in their path of movement in a process called simple diffusion.

Matters become more complicated when the molecule is highly polar. Forexample, sodium ions are present at 143 mM outside a typical cell and at 14 mMinside the cell, yet sodium does not freely enter the cell, because the charged ioncannot pass through the hydrophobic membrane interior. In some circumstances,such as in a nerve impulse, sodium ions must enter the cell. How are these ionsable to cross the hydrophobic membrane interior? Sodium ions pass through spe-cific channels in the hydrophobic barrier—channels that are formed by mem-brane proteins. This means of crossing the membrane is called facilitated diffusionbecause the diffusion across the membrane is facilitated by the channel. It is alsocalled passive transport because the energy driving the ion movement originatesin the ion gradient itself, without any contribution by the transport system. Chan-nels, like enzymes, display substrate specificity in that they facilitate the transportof some ions but not other ions, not even those that are closely related.

How is the sodium gradient established in the first place? In this case, sodiummust move, or be pumped, against a concentration gradient. Because moving theion from a low concentration to a higher concentration results in a decrease inentropy, it requires an input of free energy. Protein pumps embedded in the mem-

brane are capable of using an energy source to move the molecule up aconcentration gradient in a process called active transport.

The Na�–K� ATPase Is an Important Pump in Many CellsThe extracellular fluid of animal cells has a salt concentration similar to thatof seawater. However, cells must control their intracellular salt concentrationsto prevent unfavorable interactions with high concentrations of ions and tofacilitate specific processes such as a nerve impulse. In particular, most ani-mal cells contain a high concentration of K� and a low concentration of Na�

relative to the extracellular fluid. These ionic gradients are generated by a spe-cific transport system, an enzyme called the Na�–K� pump or the Na�–K�

ATPase. The hydrolysis of ATP by the pump provides the energy needed forthe active transport of three Na� ions out of the cell and two K� ions intothe cell, generating the gradients (Figure 11.18). In other words, the Na�–K�

ATPase is an ATP-driven pump.The active transport of Na� and K� is of great physiological signifi-

cance. Indeed, more than a third of the ATP consumed by a resting ani-mal is used to pump these ions. The Na�–K� gradient in animal cells

16411 Membrane Structure and Function

ATP + H2O ADP + Pi

Na+–K+ ATPase

Na+Na+

Na+Na+

Na+

Na+

2 K+

3 Na+

Na+

K+

K+ K+

K+ K+

K+

Figure 11.18 Energy transduction by membraneproteins. The Na�–K� ATPase converts the freeenergy of phosphoryl transfer into the free energy ofa Na� ion gradient.

controls cell volume, renders neurons and muscle cells electrically excitable, anddrives the active transport of sugars and amino acids. This third phenomenon iscalled secondary active transport (p. 166) because the sodium gradient generatedby the Na�–K� ATPase (the primary instance of active transport) can be used topower active transport of other molecules (the secondary instance of active trans-port) when the sodium flows down its gradient.

The pump is called the Na�–K� ATPase because the hydrolysis of ATP takesplace only when Na� and K� are present. The Na�–K� ATPase is referred to as aP-type ATPase because it forms a key phosphorylated intermediate. In the forma-tion of this intermediate, a phosphoryl group obtained from ATP is linked to theside chain of a specific conserved aspartate residue in the pump to form phospho-rylaspartate. Other examples of P-type ATPases include the Ca2� ATPase, whichtransports calcium ions out of the cytoplasm and into the extracellular fluid,mitochondria, and sarcoplasmic reticulum of muscle cells, a key process in mus-cle contraction; and the gastric H�–K� ATPase, which is responsible for pumpingprotons into the stomach to lower the pH below 1.0.

Clinical Insight

Digitalis Inhibits the Na�–K� Pump by Blocking Its DephosphorylationHeart failure can result if the muscles in the heart are not able to contract withsufficient strength to effectively pump blood. Certain steroids derived from plants,such as digitalis and ouabain, are known as cardiotonic steroids because of theirability to strengthen heart contractions. Interestingly, cardiotonic steroids exerttheir effect by inhibiting the Na�–K� pump. This inhibition has the effect ofincreasing the calcium ion concentration in the heart. An increase in Ca2� con-centration causes muscle contraction, or the heartbeat. Calcium ions are pumpedout of the muscle by a sodium–calcium exchanger. When Na� flows into muscle,Ca2� flows out, terminating the contraction.

Digitalis is a mixture of cardiotonic steroids derived from the dried leaf of thefoxglove plant Digitalis purpurea (Figure 11.19). The compound increases theforce of contraction of heart muscle and is consequently a choice drug in the treat-ment of congestive heart failure. Inhibition of the Na�–K� pump by digitalismeans that Na� is not pumped out of the cell, which leads to a higher level of Na�

inside the cell. The increased concentration of Na� in turn affects the sodium–calcium exchanger. This exchanger, an example of secondary active transport,relies on a low Na� concentration to pull Na� into the cell, simultaneously pow-ering the expulsion of Ca� from the cell. The diminished Na� gradient results inslower extrusion of Ca2� by the sodium–calcium exchanger. The subsequentincrease in the intracellular level of Ca2� enhances the ability of cardiac muscleto contract. Interestingly, digitalis was used effectively long before the discoveryof the Na�–K� ATPase. In 1785, William Withering, a British physician, heardtales of an elderly woman, known as “the old woman of Shropshire,” who curedpeople of “dropsy” (which today would be recognized as congestive heart failure)with an extract of foxglove. Withering conducted the first scientific study of theeffects of foxglove on congestive heart failure and documented its effectiveness. ■

Multidrug Resistance Highlights a Family of Membrane Pumps with ATP-Binding DomainsStudies of human disease revealed another large and important family of active-transport proteins, with structures and mechanisms quite different from those ofthe P-type ATPase family. Tumor cells in culture often become resistant to drugs thatwere initially quite toxic to the cells. Remarkably, the development of resistance toone drug also makes the cells less sensitive to a range of other compounds. This phe-nomenon is known as multidrug resistance. In a significant discovery, the onset of

16511.5 Transporters

NH

C

O

H

CO

P

O

OO

O 2–

Phosphorylaspartate

Figure 11.19 Foxglove. Digitalis, one ofthe most widely used drugs, is obtainedfrom foxglove (Digitalis purpurea).[Inga Spence/Visuals Unlimited.]

165

multidrug resistance was found to correlate with the expression of a protein that actsas an ATP-dependent pump that extrudes a wide range of small molecules from cellsthat express it. The protein is called the multidrug-resistance (MDR) protein orP-glycoprotein (“glyco” because it includes a carbohydrate moiety). When cells areexposed to a drug, the MDR pumps the drug out of the cell before the drug canexert its effects. The MDR comprises four domains: two membrane-spanningdomains and two ATP-binding domains (Figure 11.20A). The ATP-bindingdomains of these proteins are called ATP-binding cassettes (ABCs). Transportersthat include these domains are called ABC transporters.

Another example of an ABC transporter is the cystic fibrosis transmembraneconductance regulator (CFTR; Figure 11.20B). CFTR acts as an ATP-regulatedchloride channel in the plasma membranes of epithelial cells. Mutations in thegene for CFTR cause a decrease in fluid and salt secretion by CFTR and result incystic fibrosis. As a consequence of the malfunctioning CFTR, secretion from thepancreas is blocked and heavy, dehydrated mucus accumulates in the lungs, lead-ing to chronic lung infections.

Clinical Insight

Harlequin Ichthyosis Is a Dramatic Result of a Mutation in an ABCTransporter ProteinA number of human diseases in addition to cystic fibrosis result from defects inABC transporter proteins. One especially startling disorder is harlequinichthyosis, which results from a defective ABC transporter for lipids in ker-atinocytes, a common type of skin cell. Babies suffering from this very rare disor-der are born encased in thick skin, which restricts their movement. As the skindries out, hard diamond shaped plaques form, severely distorting facial features.The newborns usually die within a few days because of feeding difficulties, respi-ratory distress, or infections that are likely due to cracks in the skin. ■

Secondary Transporters Use One Concentration Gradient to Power the Formation of AnotherMany active-transport processes are not directly driven by the hydrolysis of ATP.Instead, the thermodynamically uphill flow of one species of ion or molecule iscoupled to the downhill flow of a different species. Membrane proteins that pumpions or molecules uphill by this means are termed secondary transporters orcotransporters. These proteins can be classified as either antiporters or symporters.Antiporters couple the downhill flow of one species to the uphill flow of anotherin the opposite direction across the membrane; symporters use the flow of onespecies to drive the flow of a different species in the same direction across themembrane (Figure 11.21).

166

Antiporter

A

B

Symporter

A B

Figure 11.21 Antiporters and symporters.Secondary transporters can transport twosubstrates in opposite directions(antiporters) or two substrates in the samedirection (symporters).

N

C

N

C

Membrane-spanningdomain

ATP-bindingcassette

N

(B)

(A)

C

N C

Multidrug resistance protein (MDR)

Cystic fibrosis transmembrane regulator (CFTR)

Figure 11.20 ABC transporters. The multidrugresistance protein (MDR) and the cysticfibrosis transmembrane regulator (CFTR) arehomologous proteins composed of twotransmembrane domains and two ATP-bindingdomains, called ATP-binding cassettes (ABCs).

Glucose is pumped into some animal cells by a symporter powered by thesimultaneous entry of Na�. This free-energy input of Na� flowing down its con-centration gradient is sufficient to generate a 66-fold concentration gradient of anuncharged molecule such as glucose (Figure 11.22). Recall that the sodium ion gra-dient was initially generated by the Na�–K� ATPase, demonstrating that the actionof the secondary active transporter depends on the primary active transporter.

Specific Channels Can Rapidly Transport Ions Across MembranesPumps can transport ions at rates approaching several thousand ions per second.Other membrane proteins, the passive-transport systems called ion channels, arecapable of ion-transport rates that are more than 1000 times as fast. These rates oftransport through ion channels are close to rates expected for ions diffusing freelythrough aqueous solution. Yet, ion channels are not simply tubes that span mem-branes through which ions can rapidly flow. Instead, they are highly sophisticatedmolecular machines that respond to chemical and physical changes in their environ-ments and undergo precisely timed conformational changes to regulate when ionscan flow into and out of the cell. Channels can be classified on the basis of theenvironmental signals that activate them. Voltage-gated channels are opened inresponse to changes in membrane potential,whereas ligand-gated channels are openedin response to the binding of small molecules (ligands), such as neurotransmitters.

Among the most important manifestations of ion-channel action is the nerveimpulse, which is the fundamental means of communication in the nervous system.A nerve impulse or action potential is an electrical signal produced by the flow of ionsacross the plasma membrane of a neuron. In particular, Na� transiently flows intothe cell and K� flows out. This ion traffic is through protein channels that are bothspecific and rapid. The importance of ion channels is illustrated by the effect oftetrodotoxin, which is produced by the pufferfish (Figure 11.23). Tetrodotoxininhibits the Na� channel, and the lethal dose for human beings is 10 ng.

16711.5 Transporters

ATP + H2O ADP + Pi

Na+–K+ ATPase

Na+Na+

Na+Na+

Na+Na+ Na+

Na+ Na+ Na+

K+K+

K+

K+

K+K+

K+

K+

K+

K+

K+K+

Na+ Na+

Na+Na+

Na+

Na+

Na+

Na+

2 K+

3 Na+

Na+

Na+

Na+Glucose Na+

Glucose

GlucoseGlucose

Na+–glucosesymporter

Figure 11.22 Secondary transport. The iongradient set up by the Na�–K� ATPasecan be used to pump materials into thecell, through the action of a secondarytransporter such as the Na�–glucosesymporter.

Figure 11.23 Pufferfish. The pufferfish isregarded as a culinary delicacy in Japan.Tetrodotoxin is produced by the pufferfish.Several people die every year in Japanfrom eating poorly prepared pufferfish.[Digital Vision/Alamy.]

OO

O–

OH

OH

HO

HO

H

HNNHHO

NH2

+

Tetrodotoxin

The Structure of the Potassium Ion Channel Reveals the Basis of Ion SpecificityThe K� channel provides us with a clear example of how a channel function canbe both specific and rapid. Beginning from the inside of the cell, the pore startswith a diameter of approximately 10 Å and then constricts to a smaller cavity witha diameter of 8 Å (Figure 11.24). Both the opening to the outside and the centralcavity of the pore are filled with water, and a K� ion can fit in the pore withoutlosing its shell of bound water molecules. Approximately two-thirds of the waythrough the membrane, the pore becomes more constricted (3-Å diameter). Atthat point, any K� ions must give up their water molecules and interact directlywith groups from the protein. The channel structure effectively reduces thethickness of the membrane from 34 Å to 12 Å by allowing the solvated ions topenetrate into the membrane before the ions must directly interact with the channel.

The restricted part of the pore is built from residues contributed by the twotransmembrane � helices. In particular, a stretch of five amino acids within thisregion functions as the selectivity filter that determines the preference for K� overother ions (Figure 11.25). This region of the strand lies in an extended conforma-tion and is oriented such that the peptide carbonyl groups are directed into thechannel, in a good position to interact with the potassium ions. The potassiumion relinquishes its associated water molecules because it can bind with the oxy-gen atoms of the carbonyl groups of the selectivity filter.

16811 Membrane Structure and Function

12 Å

34 Å

10 Å

3 Å

Figure 11.24 A path through a channel. A potassium ion entering the K� channel can passa distance of 22 Å into the membrane while remaining solvated with water (blue). At thispoint, the pore diameter narrows to 3 Å (yellow), and potassium ions must shed their waterand interact with carbonyl groups (red) of the pore amino acids.

K+

K+

Thr

Val

Gly

Gly

Tyr

Figure 11.25 The selectivity filter of thepotassium ion channel. Potassium ionsinteract with the carbonyl groups of theselectivity filter, located at the 3-Å-diameter pore of the K� channel. Only twoof the four channel subunits are shown.

Potassium ion channels are 100-fold more permeable to K� than to Na�.How is this high degree of selectivity achieved? Ions having a radius larger than1.5 Å cannot pass into the narrow diameter (3 Å) of the selectivity filter of the K�

channel. However, a bare Na� is small enough to pass through the pore. Indeed,the ionic radius of Na� (0.95 Å) is substantially smaller than that of K� (1.33 Å).How, then, is Na� rejected?

Sodium ions are too small to react with the selectivity filter. For ions to relin-quish their water molecules, other polar interactions—such as those that takeplace between the K� ion and the selectivity filter’s carbonyl groups—mustreplace the interactions with water. The key point is that the free-energy costs ofdehydrating these ions are considerable. The channel pays the cost of dehydratingpotassium ions by providing compensating interactions with the carbonyl oxygenatoms lining the selectivity filter (Figure 11.26). Sodium ions are rejected becausethe higher cost of dehydrating them would not be recovered. The K� channel doesnot closely interact with sodium ions, which must stay hydrated and, hence,cannot pass through the channel.

The Structure of the Potassium Ion Channel Explains Its Rapid Rate of TransportThe tight binding sites required for ion selectivity should slow the progress of ionsthrough a channel, yet ion channels achieve rapid rates of ion transport. How isthis apparent paradox resolved? A structural analysis of the K� channel at highresolution provides an appealing explanation. Four K�-binding sites crucial forrapid ion flow are present in the constricted region of the K� channel. Considerthe process of ion conductance starting from inside the cell (Figure 11.27). Ahydrated potassium ion proceeds into the channel and through the relativelyunrestricted part of the channel. The ion then gives up its coordinated watermolecules and binds to a site within the selectivity-filter region. The ion can movebetween the four sites within the selectivity filter because they have similar ionaffinities. As each subsequent potassium ion moves into the selectivity filter, itspositive charge will repel the potassium ion at the nearest site, causing it to shiftto a site farther up the channel and in turn push upward any potassium ionalready bound to a site farther up. Thus, each ion that binds anew favors therelease of an ion from the other side of the channel. This multiple-binding-sitemechanism solves the apparent paradox of high ion selectivity and rapid flow.

Na+ in K+-channel site

K+ in K+-channel site

Desolvationenergy

Resolvation withinK+-channel site

Desolvationenergy

Resolvation withinK+-channel site

K(OH2)8+

Na(OH2)6+

Potassium Sodium

Figure 11.26 The energetic basis of ion selectivity. The energy cost of dehydrating apotassium ion is compensated by favorable interactions with the selectivity filter. Because asodium ion is too small to interact favorably with the selectivity filter, the free energy ofdesolvation cannot be compensated, and the sodium ion does not pass through the channel.

169

QUICK QUIZ 2 What determinesthe direction of flow through an ion

channel?

SUMMARY

11.1 Phospholipids and Glycolipids Form Bimolecular SheetsMembrane lipids spontaneously form extensive bimolecular sheets inaqueous solutions. The driving force for membrane formation is thehydrophobic effect. The hydrophobic tails then interact with one anotherby van der Waals interactions. The hydrophilic head groups interact withthe aqueous medium. Lipid bilayers are cooperative structures, heldtogether by many weak bonds. These lipid bilayers are highly impermeableto ions and most polar molecules, yet they are quite fluid, which enablesthem to act as a solvent for membrane proteins.

11.2 Proteins Carry Out Most Membrane ProcessesSpecific proteins mediate distinctive membrane functions such as trans-port, communication, and energy transduction. Many integral membraneproteins span the lipid bilayer, whereas others are only partly embeddedin the membrane. Peripheral membrane proteins are bound to membranesurfaces by electrostatic and hydrogen-bond interactions. Membrane-spanning proteins have regular structures, including � strands, althoughthe � helix is the most common membrane-spanning structure.

11.3 Lipids and Many Membrane Proteins Diffuse Laterally in the MembraneMembranes are dynamic structures in which proteins and lipids diffuse rapidlyin the plane of the membrane (lateral diffusion), unless restricted by specialinteractions. In contrast, the rotation of lipids from one face of a membrane tothe other (transverse diffusion, or flip-flopping) is usually very slow. Proteinsdo not rotate across bilayers; hence, membrane asymmetry can be preserved.

11.4 Membrane Fluidity Is Controlled by Fatty Acid Composition and Cholesterol ContentThe degree of fluidity of a membrane partly depends on the chain length ofits lipids and the extent to which their constituent fatty acids are unsatu-rated. In animals, cholesterol content also regulates membrane fluidity.

170

Figure 11.27 A model for K�-channeltransport. The selectivity filter has fourbinding sites (white circles). Hydratedpotassium ions can enter these sites, oneat a time, losing their hydration shells (red lines). When two ions occupy adjacentsites, electrostatic repulsion forces themapart. Thus, as ions enter the channel fromone side, other ions are pushed out theother side.

Cellexterior

Cellinterior

Repulsion

Repulsion

K+

K+

K+

K+

K+

K+

K+

K+

K+

K+

K+

K+

K+

K+

K+

K+

K+

K+

K+

K+

K+

K+

K+

K+

K+

K+

K+

K+K+K+

K+

K+

171Answers to Quick Quizzes

11.5 A Major Role of Membrane Proteins Is to Function As TransportersFor a net movement of molecules across a membrane, two features are required:(1) the molecule must be able to cross a hydrophobic barrier and (2) an energysource must power the movement. Lipophilic molecules can pass through amembrane’s hydrophobic interior by simple diffusion. These molecules willmove down their concentration gradients. Polar or charged molecules requireproteins to form passages through the hydrophobic barrier. Passive transportor facilitated diffusion takes place when an ion or polar molecule moves downits concentration gradient. If a molecule moves against a concentration gradi-ent, an external energy source is required; this movement is referred to as activetransport and results in the generation of concentration gradients.

Active transport is often carried out at the expense of ATP hydrolysis.P-type ATPases pump ions against a concentration gradient and becometransiently phosphorylated in the process of transport. P-type ATPases,such as the Na�–K� ATPase, are integral membrane proteins.

Membrane proteins containing ATP-binding cassette domains areanother family of ATP-dependent pumps. The multidrug-resistance pro-teins confer resistance on cancer cells by pumping chemotherapeutic drugsout of a cancer cell before the drugs can exert their effects.

Many active-transport systems couple the uphill flow of one ion ormolecule to the downhill flow of another. These membrane proteins,called secondary transporters or cotransporters, can be classified asantiporters or symporters. Antiporters couple the downhill flow of onetype of ion in one direction to the uphill flow of another in the oppositedirection. Symporters move both ions in the same direction.

Ion channels allow the rapid movement of ions across the hydrophobicbarrier of the membrane. In regard to K� channels, hydrated potassiumions must transiently lose their coordinated water molecules as they moveto the narrowest part of the channel, termed the selectivity filter. Rapid ionflow through the selectivity filter is facilitated by ion–ion repulsion, withone ion pushing the next ion through the channel.

Key Terms

lipid bilayer (p. 157)liposome (p. 157)integral membrane protein (p. 159)peripheral membrane protein (p. 159)channel (p. 160)lateral diffusion (p. 162)lipid raft (p. 163)simple diffusion (p. 164)facilitated diffusion (passive

transport) (p. 164)pump (p. 164)

active transport (p. 164)Na�–K� pump

(Na�–K�ATPase) (p. 164)ATP-driven pump (p. 164)P-type ATPase (p. 165)multidrug resistance (p. 165)multidrug-resistance (MDR) protein

(P-glycoprotein) (p. 166)ATP-binding cassette (ABC) domain

(p. 166)

secondary transporter(cotransporter) (p. 166)

antiporter (p. 166)symporter (p. 166)ion channel (p. 167)selectivity filter (p. 168)

Answers to QUICK QUIZZES

1. The increase in temperature will increase the fluidity ofthe membrane. To prevent the membrane from becomingtoo fluid, the bacteria will incorporate longer-chain fattyacids into the membrane phospholipids. This alteration willincrease van der Waals interactions among the chains anddecrease fluidity.

2. Ion channels allow ion flow in either direction. Inaccordance with the Second Law of Thermodynamics, ionswill flow down their concentration gradient.

0.4

�A

100 s

1�

A

100 s

0.6

�A

100 s

2�

A

100 s

pH 6(A) ASIC1a

pH 6ASIC1b

pH 5ASIC2a

pH 4 ASIC3

100

0

20

40

60

80

[PcTX1], nM1010.10.01AS

IC1a

pea

k cu

rren

t(%

)

(B)

(A) Electrophysiological recordings of cells exposed to tarantulatoxin. (B) Plot of peak current of a cell containing the ASIC1aprotein versus the toxin concentration. [From P. Escoubas et al., J. Biol.Chem. 275:25116–25121, 2000.]

(a) Which of the ASIC family members—ASIC1a, ASIC1b,ASIC2a, or ASIC3—is most sensitive to the toxin?(b) Is the effect of the toxin reversible? Explain.(c) What concentration of PcTX1 yields 50% inhibition ofthe sensitive channel?

172 11 Membrane Structure and Function

1. Solubility matters. Arrange the following substances inorder of increasing permeability through a lipid bilayer:(a) glucose; (b) glycerol; (c) Cl�; (d) indole; (e) tryptophan.2. Energy considerations. Explain why an � helix is espe-cially suitable for a transmembrane protein segment.3. A helping hand. Differentiate between simple diffusionand facilitated diffusion.4. Gradients. Differentiate between passive transport andactive transport.5. Desert fish. Certain fish living in desert streams altertheir membrane-lipid composition in the transition fromthe heat of the day to the cool of the night. Predict thenature of the changes.6. Commonalities. What are two fundamental propertiesof all ion channels?7. Opening channels. Differentiate between ligand-gatedand voltage-gated channels.8. Behind the scenes. Is the following statement true orfalse? Explain.The sodium–glucose cotransporter does not depend on thehydrolysis of ATP.9. Powering movement. List two forms of energy that canpower active transport.10. Looking-glass structures. Phospholipids form lipid bilay-ers in water. What structure might form if phospholipidswere placed in an organic solvent?11. Greasy patch. A stretch of 20 amino acids is sufficient toform an � helix long enough to span the lipid bilayer of amembrane. How could this piece of information be used tosearch for membrane proteins in a data bank of primarysequences of proteins?12. Water-fearing. Lipid bilayers are self-sealing. If a hole isintroduced, the hole is filled in immediately. What is theenergetic basis of this self-sealing?13. Like pulling teeth. Differentiate between peripheral pro-teins and integral proteins in regard to their ease of removalfrom the membrane.14. Water-loving. All biological membranes are asymmet-ric. What is the energetic basis of this asymmetry?15. Pumping sodium. Design an experiment to show thatthe action of the Na�–glucose cotransporter can be reversedin vitro to sodium ions.16. Different directions. The K� channel and the Na� chan-nel have similar structures and are arranged in the same ori-entation in the cell membrane. Yet, the Na� channel allowssodium ions to flow into the cell and the K� channel allowspotassium ions to flow out of the cell. Explain.17. A dangerous snail. Cone snails are carnivores that injecta powerful set of toxins into their prey, leading to rapid

paralysis. Many of these toxins are found to bind to specificion-channel proteins. Why are such molecules so toxic?How might such toxins be useful for biochemical studies?

Chapter Integration Problem

18. Speed and efficiency matter. The neurotransmitteracetylcholine is rapidly destroyed by the enzyme acetyl-cholinesterase. This enzyme, which has a turnover numberof 25,000 per second, has attained catalytic perfection witha kcat/KM of 2 � 108 M�1 s�1. Why is the efficiency of thisenzyme physiologically crucial?

Data Interpretation Problem

19. Tarantula toxin. Acid sensing is associated with pain, tast-ing, and other biological activities. Acid sensing is carried outby a ligand-gated channel that permits Na� influx in responseto H�. This family of acid-sensitive ion channels (ASICs)comprises a number of members. Psalmotoxin 1 (PcTX1), avenom from the tarantula, inhibits some members of thisfamily. The following electrophysiological recordings of cellscontaining several members of the ASIC family were made inthe presence of the toxin at a concentration of 10 nM. Thechannels were opened by changing the pH from 7.4 to theindicated values. PcTX1 was present for a short time (indi-cated by the black bar above the recordings), after which timeit was rapidly washed from the system.

Problems

Selected readings for this chapter can be found online at www.whfreeman.com/Tymoczko