Membrane Potential

Keith S Elmslie, Tulane University School of Medicine, New Orleans, Louisiana, USA
A thin lipid bilayer membrane with embedded proteins surrounds all cells. The potential difference across this membrane depends on the ionic concentrations on either side of this membrane and the permeability of the membrane to those ions.

Introductory article
Article Contents
. Introduction . Resting Membrane Potential: A Characteristic of All Living Cells . Action Potentials: A Characteristic of Excitable Cells . Electrical Signals Produced by Ionic Movement Across the Plasma Membrane: The Roles of Channels and Pumps . Single-ion Electrochemical Equilibrium: The Nernst Equation . Multi-ion Electrochemical Equilibrium: The Goldman Equation . High Resting Permeability to Potassium and the Membrane Potential . Summary

Introduction
If you were to place a sensitive electrical measuring device in the extracellular solution (surrounding a cell) you would nd no change in voltage as you moved the device (an electrode) through this solution. If you made small injections of current through the electrode you would nd that there was very little resistance to the electrical current in this solution. This means that the ions in the solution (sodium (Na 1 ), potassium (K 1 ), calcium (Ca2 1 ) and chloride (Cl 2 )) are free to move throughout the solution (no impediments). When, on the other hand, this electrode is placed into a cell, you measure a decrease in voltage of $ 60 mV. Thus, the inside of a cell is 2 60 mV compared to the outside of the cell. If you now made small current injections, you would nd a high resistance. The cells membrane resists the movement of ions, which is one factor resulting in the potential dierence across the cell membrane. However, the membrane is not completely impermeable to ions. (If that were the case, the potential dierence across the membrane would be zero.) A class of proteins called ion channels form passages through the membrane. A small number of ions diuse across the membrane generating the membrane potential that can be measured by the electrode. Ion channels can be selective for particular ions and they can be regulated. Thus, the cell can control the passage of ions across its membrane by controlling the activity of ion channels. The two forces that control the movement of ions through the open channels are concentration and electrical forces. The concentration force is generated by a class of proteins called ion pumps that use cellular energy (adenosine triphosphate, ATP) to establish dierential ion concentrations across the membrane. The electrical force is established by the ion selectivity of the membrane, allowing positively charged ions to leave the cell but trapping negatively charged ions inside the cell. Together these forces drive ions through the open channels, creating the membrane potential. (see Cell membranes: intracellular pH and electrochemical potential.) (see Ion channel biochemistry.)

Resting Membrane Potential: A Characteristic of All Living Cells

The net movement of molecules in a solution depends on the concentration gradient. Molecules move from areas of high concentration to areas of low concentration by the process of diusion (Figure 1a). If a pathway is provided across the cell membrane, the net direction of the movement of a molecule can be predicted by the dierence in the concentration. For example, urea is a compound that can move through the membrane (it is membrane permeant). If we place a cell that contains no urea into a solution containing 1 mmol L 2 1 urea, urea will diuse into the cell (down its concentration gradient) until the cellular concentration of urea equals 1 mmol L 2 1. (For simplicity we assume the volume of the cell is small relative to that of the bath, so the concentration of urea in the bath does not change.) At equilibrium (when the concentration is equalized) urea still crosses the membrane, but the movement into the cell equals the movement out of the cell; that is, the net movement of urea is zero at equilibrium. Thus, concentration gradients form a chemical force directing the net movement of molecules. All living cells maintain dierential ion concentrations across the cell membrane so that the concentration of each ion is larger on one side of the membrane than the other. Table 1 lists the main physiological ions for a typical mammalian neuron, together with their intracellular and extracellular concentrations. While these values are for a neuron, similar ion concentrations are found for other cells. Note that the concentration dierence is not the same for each ion; for example, the potassium (K 1 ) concentration is higher on the inside of the cell, while the sodium (Na 1 ) concentration is higher outside the cell. Since membrane is permeable to K 1 and Na 1 , the chemical force will drive these ions to
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Membrane Potential

Time = zero

Time = infinity (equilibrium) 1mmol L1 urea Chemical force 1mmol L1 urea Chemical force = zero

Zero mmol L1 urea (a) Time = zero Em = 0mV 100mmol L1 K+ 100mmol L1 Cl (b)

1mmol L1 urea

Time = infinity (equilibrium) Chemical force 10mmol L1 K+ Electrical force = zero 10mmol L1 Cl Em = 58mV 100 mmol L1 K+ 100 mmol L1 Cl Chemical force 10 mmol L1 K+ Electrical force 10 mmol L1 Cl

Figure 1 The forces that control the movement of molecules across the cell membrane. (a) Chemical forces control the movement of nonionic molecules across the membrane. At time zero a cell is placed into a bath containing 1 mmol L 2 1 urea. The concentration gradient across the membrane is initially large, which creates a large chemical force to move urea into the cell. At equilibrium, the concentration of urea is equal across the membrane and the chemical force has dropped to zero. The two headed arrow indicates that the urea still crosses the membrane, but at equilibrium efflux equals influx. (b) In this example, the cell membrane is permeable to K 1 , but not Cl 2 . At time zero, the cell containing 100 mmol L 2 1 KCl is placed into a bath containing 10 mmol L 2 1 KCl. Initially, the concentration gradient generates a concentration force that drives K 1 out of the cell. With time (a few milliseconds), a negative potential is created inside the cell by the Cl 2 left behind by K 1 efflux. This build-up of negative charge creates an electrical force that pulls K 1 back into the cell. At equilibrium the negative membrane potential generates an electrical force that exactly balances the chemical force. Thus, the net K 1 flux (summation of inward and outward flux) equals zero. Note that, unlike urea, the concentration of K 1 is virtually unchanged between the initial conditions and equilibrium. This is because only a small number of K 1 ions need to cross the membrane to generate a voltage large enough to balance the chemical force.

diuse down their concentration gradients. In order to maintain the gradients, the cell must expend energy in the form of ATP to pump the ions against their concentration gradient. (see ATPases: ion-motive.)

The movement of urea and other uncharged molecules is controlled by the concentration gradient; however, electrical forces together with chemical forces control the movement of ions. To illustrate the electrical force, let us assume a cell containing 100 mmol L 2 1 KCl is placed into a solution of 10 mmol L 2 1 KCl, but the membrane is only permeant to K 1 (Figure 1b). As K 1 begins to diuse from the cell down its concentration gradient, Cl 2 is left behind, as it cannot diuse across the membrane. Thus, as K 1 leaves the cell a negative potential is established across the membrane (because of the build-up of negative Cl 2 ions inside the cell). Opposite electrical charges attract, so the negative potential is a force that pulls the K 1 back into the cell. Note that in the case of K 1 the electrical and chemical forces oppose each other in a resting cell (membrane potential (Em) 5 2 60 mV). The chemical force drives K 1 out of the cell, while the electrical forces drive K 1 into the cell. K 1 will leave the cell (making the membrane more negative) until the electrical force becomes large enough to balance the chemical force. The potential at which this balance is achieved is called the equilibrium potential. The electrical and chemical forces together are termed the electrochemical force or gradient. Dierential ion concentration is one of the factors needed to generate the resting membrane potential (typically between 2 60 and 2 100 mV); however, no potential can develop if the membrane is equally permeable to all ions. The other factor in generating a membrane potential is the selective permeability of the membrane. At rest, the membrane is selectively permeable to K 1 . Thus, the resting membrane potential of all cells is sensitive to the K 1 gradient. If the extracellular K 1 concentration is raised without altering the intracellular K 1 concentration, the membrane potential is brought closer to zero (depolarized). Scientists studying the eect of membrane potential on cellular physiology and/or biochemistry often manipulate the extracellular K 1 concentration to alter the membrane potential. Equations presented below allow calculation of the membrane potential based on the ion concentration when only a single ion is permeant. When

Table 1 Concentrations of some ions outside and inside a mammalian neuron Ion K Na 1 Cl 2 Ca2 1 A2
1

[Outside] (mmol L 2 1) 5 150 125 2

[Inside] (mmol L 2 1) 150 15 9 0.0001 108

Ex (mV) 2 86 +58 2 66 $ +250 N/A

Values obtained from Hille (1992), Ganong (1997) and Matthews (1991). The equilibrium potentials (Ex) are calculated for room temperature of 208C. These Ex values would increase by a factor of 1.06 for body temperature (378C). A 2 represents membrane impermeant organic anions (primarily proteins, amino acids and phosphate ions). Because these anions do not cross the membrane, they do not have an equilibrium potential. N/A, not applicable.

Membrane Potential

the membrane is permeable to multiple ions, a second equation will be presented that considers both the ion concentrations and the relative membrane permeability in the calculation of membrane potential. Cells use dierential ion concentrations (and the resulting membrane potential) for many important functions. As we will see below, excitable cells (nerve and muscle cells) use the membrane potential for electrical signalling. However, nonexcitable cells (the majority of cells in the body) use the force generated by the electrochemical gradient to aid in the transport of essential substances across the cell membrane. In each case, the energy of the ion gradient of one ion (typically Na 1 ) is used to move a second molecule. For example, amino acids are transported into the cell via the Na 1 amino acid cotransporter protein. The concentration of amino acids is higher inside the cell and so energy must be used to move them against their concentration gradient. The cotransporter binds the amino acid and Na 1 simultaneously and uses the energy of the Na 1 electrochemical gradient to power the movement into the cell. Another example of this type of transport is called the Na 1 /Ca2 1 exchanger, because Na 1 and Ca2 1 are moved in opposite directions. The intracellular concentration of calcium (Ca2 1 ) is maintained at a very low level ( $ 100 nmol L 2 1) by the cells. This is compared to an extracellular concentration of $ 2 mmol L 2 1. As with Na 1 , both the electrical and chemical forces favour the movement of Ca2 1 into the cell. However, Ca2 1 is an important cellular messenger and increases in the intracellular concentration of Ca2 1 are therefore used to signal events. For this reason, random increases in intracellular Ca2 1 must be opposed, and signalling-induced increases must be rectied. One of the mechanisms the cell uses to maintain low intracellular Ca2 1 concentration is the Na 1 /Ca2 1 exchanger. This protein uses the electrochemical Na 1 gradient to transport Ca2 1 out of the cell. Thus, the electrochemical forces created by the ion gradient and selective membrane permeability play very important roles in cell physiology. (see Transport of small molecules.) (see Ion transport across nonexcitable membranes.) (see Calcium signalling and regulation of cell function.)

membrane. Passive propagation means that these potentials decay exponentially with distance from their starting point. Action potentials, on the other hand, are actively propagated along the membrane. This is accomplished by action potentials being sequentially induced in each small patch of membrane as they move along. The ionic mechanisms involved in the generation and propagation of the action potential is described elsewhere. Briey, the action potential involves a transient inux of Na 1 that depolarizes the membrane to nearly 1 40 mV. This is followed by a K 1 eux that rapidly returns the membrane to its resting level. The propagation occurs because the Na 1 inux at one membrane patch leads to the depolarization and the subsequent Na 1 inux in the next patch. (see Action potential: generation and propagation.) The action potential is the mechanism by which information is transmitted within most neurons in the nervous system (some neurons in the retina and ear use only receptor potentials). The important property of the action potential is that it can be transmitted long distances without alteration. This is extremely important because the axon extending from a single neuron can be over 1 metre long (e.g. sensory neurons that have axons extending from the tip of the toes to the base of the brain). The information carried by action potentials is accurately transmitted over these vast distances. (see Action potential: ionic mechanisms.)

Electrical Signals Produced by Ionic Movement Across the Plasma Membrane: The Roles of Channels and Pumps
Under physiological conditions, the membrane bilayer is impermeant to ions. The lipids that comprise the membrane are hydrophobic (dislike water), while ions are hydrophilic (like water). Thus, the ions will remain in the water and avoid the hydrophobic membrane. The ions cross the membrane via a class of transmembrane proteins called ion channels (Figure 2). These proteins form waterlled pores through the membrane that provide the pathway for ions to move in response to the electrochemical forces. One class of ion channels passes cations (positively charged ions) and the other class passes anions (namely Cl 2 ). Within the cation class there exist ion channels that are nonspecic, in that they pass cations without strongly selecting between them. More commonly, ion channels are selective in that they will primarily pass a single ion, such as Na 1 , K 1 or Ca2 1 . These ion channels are named according to their primary permeant ion (i.e. Na 1 channels, K 1 channels and Ca2 1 channels). (see Lipid bilayers.) (see Ion channels.) (see Sodium, calcium and potassium channels.)
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Action Potentials: A Characteristic of Excitable Cells

All cells have a resting membrane potential, but only excitable cells use the membrane potential to generate signals. The two types of electrical signals are receptor potentials and action potentials. Receptor potentials are generated in sensory nerve terminals in response to sensory stimulation and in postsynaptic cells in response to activation of receptor/ion channels by neurotransmitters. These potentials travel (or propagate) passively along the

Membrane Potential

Extracellular solution Plasma membrane

Cytoplasm (a)

required because the ions are transported across the membrane against their concentration gradients. The most important of these pumps is the Na 1 /K 1 ATPase (also called the Na 1 /K 1 pump). This protein simultaneously transports (or pumps) Na 1 out of the cell and K 1 into the cell. The Na 1 /K 1 ATPase is the reason for the dierential concentrations of Na 1 and K 1 across the cell membrane (Table 1). Thus, the leak channels establish the resting membrane potential by allowing Na 1 and K 1 to cross the membrane, while the Na 1 /K 1 ATPase maintains the dierential ion concentrations. (see Potassium channel diversity: functional consequences.) (see Adenosine triphosphate.)

Single-ion Electrochemical Equilibrium: The Nernst Equation

As stated above, the resting membrane potential is primarily controlled by the K 1 concentration across the cell membrane. Thus, as a rst approximation, we can model the membrane of a resting cell as being exclusively permeable to K 1 . This simplication will allow us to explore the relationship between the chemical and electrical forces discussed above. Specically, for a given concentration gradient across the membrane, we can calculate the membrane potential at which the electrical and chemical forces are balanced. This potential is called the equilibrium potential. To illustrate this, consider the example in Figure 1b where a cell containing 100 mmol L 2 1 KCl is placed into a solution of 10 mmol L 2 1 KCl, and the membrane is selectively permeable only to K 1 . At the equlibrium potential the K 1 inux driven by electrical force is equal to K 1 eux driven by the chemical force. The equilibrium potential can be calculated from the ion concentrations across the membrane using the Nernst equation: (see Nernst, Walther Hermann.)
Ex RT Xo ln zF Xi 1

ADP + Pi ATP (b)

Figure 2 Ion channels and pumps move ions across the plasma membrane. (a) Ion channels form water-filled pores that permit the hydrophilic ions to pass through the hydrophobic lipid bilayer membrane. The direction of ion flux through the open channel is governed by electrochemical forces. (b) Ion pumps move ions by using energy from ATP hydrolysis. In this cartoon the pump will simultaneously transport two different ions in opposite directions (analogous to the Na 1 /K 1 ATPase). The pumps move the ions against their concentration gradients. In other words, the ions are moved from an area of low concentration to an area of high concentration. From left to right: ions bind to sites in the pump (left). This binding triggers the hydrolysis of ATP (middle), which alters the conformation of the pump to release the ions on the opposite side of the membrane (right). Once the ions are released the pump returns to its resting position, ready to bind and transport more ions.

The role of the ion channels is to set the permeability of the membrane. The majority of those that are involved in setting the resting membrane potential are permeable to K 1 . A smaller number are permeable to Na 1 . These ion channels are often called leak channels because they are always slowly leaking K 1 and Na 1 ions to maintain a stable resting membrane potential. However, the activity of these channels would result in the loss of the ionic gradients across the cell membrane if it were not for the ion pumps, a class of proteins that use energy to move ions across the membrane. One type of pump described above was the Na 1 /Ca2 1 pump, which used the energy of the Na 1 gradient to move Ca2 1 out of the cell. Unlike the Na 1 /Ca2 1 pump, the ion pump that maintains the Na 1 and K 1 gradients utilizes the energy derived from ATP hydrolysis to power the movement of ions. This energy is

where X is the ion in question (K 1 in this example), R is the gas constant (8.315 J K 2 1 mol 2 1), T is the temperature in degrees Kelvin, z is the valence of ion X (z 5 1 1 for K 1 ) and F is Faradays constant (9.648 104 C mol 2 1). Below is an example calculation using the K 1 concentrations from Figure 1 and a room temperature of 208C,
Ex 8:315 J K1 mol1 293 K 10 mmol L1 o ln 1 100 mmol L1 i 1 9:648 104 C mol

which reduces to EK 5 2 0.0583 J C 2 1. Since 1 J (joule) 5 1 V C (volt coulomb), EK 5 2 58.3 mV. In biology we generally work with a simplied form of the Nernst equation where room temperature is 208C and the natural log (ln) has been transformed into log10. This

Membrane Potential

form of the equation is:

Xo 58 mV log z Xi

(E 5 IR) can be used to relate current with driving force and conductance:
2

Ex

Ix 5 Gx (Em 2 Ex)

[3]

It may be surprising that we are using initial conditions to calculate an equilibrium voltage. Indeed, it is clear that ions must cross the membrane to create a voltage. If ions are crossing the membrane, how can we use initial concentrations in this calculation? To answer this question, we need to know how many ions need to cross the membrane to achieve the equilibrium potential. Based on the electrical properties of the cell membrane, it can be calculated that only approximately one billionth of the total number of K 1 ions need to cross the membrane in order to achieve the equilibrium potential. Since the net movement of only a small number of ions is required to counter a large concentration force, it is valid to use the initial concentrations to calculate the equilibrium potential. The K 1 concentrations illustrated in Figure 1 were used to simplify the calculation of the equilibrium potential. As can be seen in Table 1, the K 1 concentration inside the cell is higher than in our example, and the concentration outside is lower. This results in the K 1 equilibrium potential of a real neuron being hyperpolarized to that we calculated in our example ( 2 86 mV versus 2 58 mV). In addition to K 1 , an equilibrium potential can be calculated for each permeant ion (Table 1). Note that Na 1 ions are more concentrated in the extracellular solution compared to the cytoplasm, which results in a positive equilibrium potential. Thus, unlike K 1 , at resting membrane potential both the chemical force and the electrical force are directed inward for Na 1 . Because the equilibrium potential is the voltage at which ion inux and eux are balanced, when the membrane potential deviates from the equilibrium potential those ions move in a direction that will return the membrane potential to the equilibrium potential. For example, if the membrane potential is set to 2 40 mV, K 1 will ow out of the cell in order to hyperpolarize the membrane to EK ( 2 58 mV in the example of Figure 1). On the other hand, if the membrane potential is 2 80 mV, K 1 will ow into the cell to depolarize the membrane to EK. Thus, with a constant concentration gradient the ion ux is directly proportional to the dierence between the membrane potential (Em) and the equilibrium potential for that ion (Ex). This dierence is called driving force and is formally written Em 2 Ex. Driving force dictates the direction of ion ux, while the magnitude of ion ux is determined by the driving force and the membrane permeability to that ion. One way to describe membrane permeability is as the conductance of the membrane to an ion (Gx), which is the ease with which an ion will cross the membrane. Ion ux can be measured as ionic current (I, in coulombs per second, C s 2 1). Ohms law

where Gx 5 1/Rx (resistance) and E 5 driving force (Em 2 Ex).

Multi-ion Electrochemical Equilibrium: The Goldman Equation

The single ion example nicely illustrates the forces on ion movement, but real cells have multiple permeant ions. Using the Nernst equation, we can calculate the equilibrium potential for each ion, but with multiple permeant ions the membrane potential is no longer equal to the equilibrium potential of a single ion. In order to calculate the membrane potential, we need to know the relative membrane permeability of each ion. This can be illustrated using Figure 3a, which shows the ion gradients for Na 1 and K 1 for a typical mammalian cell. The equilibrium potentials under these conditions are 2 86 mV and 1 58 mV for K 1 and Na 1 , respectively. Thus, in the extreme situation, if the membrane were exclusively permeant to K 1 the membrane potential would be 2 86 mV. Alternatively, if the membrane were exclusively permeant to Na 1 , the membrane potential would be 1 58 mV. Of course, this never happens. In reality the cell membrane is simultaneously permeant to several ions. Thus, the membrane potential is related to the relative permeability of the membrane to the permeant ions. For example, if the membrane were equally permeable to Na 1 and K 1 the membrane potential would be the average of ENa and EK, which is 2 14 mV. In a multi-ion system, we need to know the equilibrium potential for each permeant ion and the membrane permeability for each ion before we can calculate the membrane potential (Em). This relationship can be quantied using the Goldman equation, which is also called the constant eld equation:
RT pK K o pNa Na o pCl Cl i ln 4 F pK K i pNa Na i pCl Cl o where pX is the permeability of ion X and R, T and F have the same meaning as in the Nernst equation. Note that the intracellular and extracellular Cl 2 concentrations are reversed from those of Na 1 and K 1 . This is done to keep the sign positive, since ln (A/B) 5 2 ln (B/A). In the Goldman equation, each concentration term is scaled by its permeability. This demonstrates that an ion cannot contribute to the membrane potential if its membrane permeability is zero. It is much easier to experimentally measure relative permeability than actual permeability. In such a case, permeability is usually expressed in reference to the Em 5

Membrane Potential

Em = EK = 86 mV

Em = ENa = +58 mV

150 mmol L1 K+ 15 mmol L1 Na+ 9 mmol L1 Cl (a)

5 mmol L1 K+ 150 mmol L1 Na+ 125 mmol L1 Cl Em = ? mV

150 mmol L1 K+ 15 mmol L1 Na+ 9 mmol L1 Cl

5 mmol L1 K+ 150 mmol L1 Na+ 125 mmol L1 Cl

Na+K+ pump 150 mmol L1 K+ 15 mmol L1 Na+ 9 mmol L1 Cl 108 mmol L1 A K+ 5 mmol L1 Na+ 150 mmol L1 Cl 125 mmol L1

(b)
Figure 3 Relative permeability of ions determines the membrane potential for a given set of ion concentrations. (a) Two examples where either K 1 (left) or Na 1 (right) is the only permeant ion. In each case, the membrane potential equals the equilibrium potential for the permeant ion. (b) In a real cell the membrane is permeable to K 1 , Na 1 and Cl 2 . The Goldman equation is required to determine the membrane potential, as it considers both the ion concentrations across the membrane and the permeability of each ion.

potassium permeability. Therefore, the Goldman equation typically takes the form of:
K bNa o cCl i RT ln o F K i bNa i cCl o

High Resting Permeability to Potassium and the Membrane Potential

The simplied form of the Goldman equation allows us to explore the relative permeabilities of Na 1 and K 1 in relationship to the membrane potential. Using the ion concentrations of Table 1, we can calculate a Em of 2 62 mV if the membrane were 20 times more permeable to K 1 than Na 1 (b 5 0.05). This value is close to that for a neuron at rest. Therefore, we conclude that a neuron at rest is $ 20 times more permeable to K 1 than to Na 1 . On the other hand, if the membrane were 20 times more permeable to Na 1 than K 1 (b 5 20), Em would equal 1 48 mV, which is close to the peak of the action potential. From this we can conclude that at the peak of the action potential the Na 1 conductance is $ 20 times larger than that of K 1 . This change in the relative permeability of the membrane to Na 1 occurs as a result of the activation of voltage dependent Na 1 channels. The activation of these channels is transient, but the resulting depolarization activates voltage-dependent K 1 channels, which help return (repolarize) the membrane to the resting potential. (see Sodium channels.) (see Voltage-gated potassium channels.) In the example in Figure 1, Cl 2 was membrane impermeant. Recall that this was the source of the negative charge remaining in the cell which resulted in the electrical force that pulled K 1 back into the cell. However, the Goldman equation has a Cl 2 permeability term. In

Em

where b 5 pNa/pK and c 5 pCl/pK. The equation can be further simplied by removing Cl 2 . This simplication is valid in neurons because the Cl 2 conductance is small relative to that of potassium and contributes little to resting membrane potential. However, such simplication is not appropriate for other cells, like skeletal muscle cells, where resting Cl 2 conductance is high. This simplied form of the Goldman equation is:
K bNa o RT ln o F K i bNa i

Em

where b has the same meaning as in eqn [5]. Note that the equation can be further simplied by converting the natural log (ln) into the log10 and using room temperature to convert RT/F to 58 mV. If one is to use this form of the Goldman equation (eqn [6]) in research, it is up to the investigator to verify that pCl/pK ratio is negligible and that Cl 2 contributes little to membrane potential.
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Membrane Potential

addition, it was stated above that Cl 2 permeability is quite high in some cells (e.g. skeletal muscle cells). Yet these cells maintain an electrochemical force as strong as the cells with little Cl 2 permeability. How can the negative internal potential develop if the membrane is permeable to Cl 2 ? In real cells, a diverse group of organic molecules that cannot readily cross the membrane function as impermeant anions (Table 1, Figure 3). This group of anions, referred to as A 2 in Table 1, includes proteins, charged amino acids (glutamate and aspartate) and phosphate ions. In a cell with multiple permeant ions the membrane potential does not equal the equilibrium potential for any ion. Therefore, ions will move across the membrane in an eort to drive the membrane potential to their respective equilibrium potentials. Without intervention the ionic gradients would decline with time, resulting in a loss of membrane potential. As discussed above, ion pumps prevent the loss of the ionic gradient. The Na 1 /K 1 ATPase maintains the Na 1 and K 1 gradient, but it also contributes to the membrane potential. This contribution comes from this protein moving 3 Na 1 out of the cell for every 2 K 1 it transports into the cell. This 3 : 2 ratio means that the pump generates a negative current as it works and this current has been shown to hyperpolarize the cell membrane. In one study, the Na 1 /K 1 pump was shown to contribute $ 10 mV to the resting membrane potential. In the absence of the pump (blocked using a drug called oubain), the resting membrane potential averaged $ 2 65 mV. However, the resting potential was 2 75 mV with the pump working.

Summary
The regulation of selective ion channels allows the cell to set the permeability of its membrane to inorganic ions. The permeability of the membrane is one factor involved in setting the membrane potential. A second factor is the gradient of ion concentrations across the membrane. This gradient is established by ion pumps that use the energy of ATP hydrolysis to move ions from areas of low concentration to areas of high concentration. For each permeant ion we can calculate the membrane potential at which the chemical and electrical forces are balanced so that the net ux of that ion is zero. Intracellular impermeant anions, together with the concentration gradient and relatively high K 1 permeability, establish a resting membrane potential where the inside of the cell is $ 60 mV negative to the outside. Excitable cells (e.g. neurons) have voltagedependent ion channels that are selective for Na 1 and K 1 . Activation of the Na 1 channels depolarizes the membrane towards the Na 1 equilibrium potential. Subsequent activation of voltage-dependent K 1 channels returns the membrane to its resting potential.

Further Reading
Ganong WF (1997) Review of Medical Physiology, 18th edn. Stamford, CN: Appleton and Lange. Hille B (1992) Ionic Channels of Excitable Membranes, 2nd edn. Sunderland, MA: Sinauer. Levitan IB and Kaczmarek LK (1997) The Neuron: Cell and Molecular Biology, 2nd edn. New York: Oxford University Press. Matthews GG (1991) Cellular Physiology of Nerve and Muscle, 2nd edn. Boston, MA: Blackwell Scientic.