The Resting Membrane Potential

Many of the body’s solutes, including organic compounds such as pyruvate and lactate, are ions and, therefore, carry a net electrical charge. Potassium (K+) is the major cation within cells, and sodium (Na+) dominates the extracellular fluid (see Fig. 5.1). On the anion side, chloride ions (Cl) mostly remain with Na+ in the extracellular fluid. Phosphate ions and negatively charged proteins are the major anions of the intracellular fluid.

Resting Membrane Potential

Overall, the body is electrically neutral: for every cation, there is a matching anion. However, ions are not distributed evenly between the ECF and the ICF (FIG. 5.23a). The intracellular compartment contains some anions that do not have matching cations, giving the cells a net negative charge. At the same time, the extracellular compartment has the “missing” cations, giving the ECF a net positive charge. One consequence of this uneven distribution of ions is that the intracellular and extracellular compartments are not in electrical equilibrium. Instead, the two compartments exist in a state of electrical disequilibrium [here].

Membrane Potential

The concept of electrical disequilibrium traditionally is taught in chapters on nerve and muscle function because those tissues generate electrical signals known as action potentials. Yet one of the most exciting discoveries in physiology is the realization that other kinds of cells also use electrical signals for communication. In fact, all living organisms, including plants, use electrical signals! This section reviews the basic principles of electricity and discusses what creates electrical disequilibrium in the body. The chapter ends with a look at how the endocrine beta cells of the pancreas use electrical signaling to trigger insulin secretion.

Electricity Review

Atoms are electrically neutral [here]. They are composed of positively charged protons, negatively charged electrons, and uncharged neutrons, but in balanced proportions, so that an atom is neither positive nor negative. The removal or addition of electrons to an atom creates the charged particles we know as ions. We have discussed several ions that are important in the human body, such as Na+, K+, and H+. For each of these positive ions, somewhere in the body there is a matching electron, usually found as part of a negative ion. For example, when Na+ in the body enters in the form of NaCl, the “missing” electron from Na+ can be found on the Cl.

Remember the following important principles when you deal with electricity in physiological systems:

  1. The law of conservation of electrical charge states that the net amount of electrical charge produced in any process is zero. This means that for every positive charge on an ion, there is an electron on another ion. Overall, the human body is electrically neutral.

  2. Opposite charges (+ and −) are attracted to each other. The protons and electrons in an atom exhibit this attraction. Like charges (two charges of the same type, such as +/+, or −/−) repel each other.

  3. Separating positive charges from negative charges requires energy. For example, energy is required to separate the protons and electrons of an atom.

  4. When separated positive and negative charges can move freely toward each other, the material through which they move is called a conductor. Water is a good conductor of electrical charge. When separated charges cannot move through the material that separates them, the material is known as an insulator. The phospholipid bilayer of the cell membrane is a good insulator, as is the plastic coating on electrical wires.

The word electricity comes from the Greek word elektron, meaning “amber,” the fossilized resin of trees. The Greeks discovered that if they rubbed a rod of amber with cloth, the amber acquired the ability to attract hair and dust. This attraction (called static electricity) arises from the separation of electrical charge that occurs when electrons move from the amber atoms to the cloth. To separate these charged particles, energy (work) must be put into the system. In the case of the amber, work was done by rubbing the rod. In the case of biological systems, the work is usually done by energy stored in ATP and other chemical bonds.

The Cell Membrane Enables Separation of Electrical Charge in the Body

In the body, separation of electrical charge takes place across the cell membrane. This process is shown in Figure 5.23b. The diagram shows an artificial cell system. The cell is filled with positive K+ and large negative ions. The cell is placed in an aqueous solution of sodium chloride that has dissociated into Na+ and Cl. The phospholipid bilayer of the artificial cell, like the membrane of a real cell, is not permeable to ions, so it acts as an insulator and prevents the ions from moving. Water can freely cross this cell membrane, making the extracellular and intracellular osmotic concentrations equal.

In Figure 5.23b, both the cell and the solution are electrically neutral, and the system is in electrical equilibrium. However, it is not in chemical equilibrium. There are concentration gradients for all four types of ions in the system, and they would all diffuse down their respective concentration gradients if they could cross the cell membrane.

In Figure 5.23c, a leak channel for K+ is inserted into the membrane. Now the cell is permeable to K+, but only to K+. Because of the K+ concentration gradient, K+ moves out of the cell. The negative ions in the cell attempt to follow the K+ because of the attraction of positive and negative charges. But because the membrane is impermeable to negative ions, the anions remain trapped in the cell.

As soon as the first positive K+ leaves the cell, the electrical equilibrium between the extracellular fluid and intracellular fluid is disrupted: the cell’s interior has developed a net charge of −1 while the cell’s exterior has a net charge of +1. The movement of K+ out of the cell down its concentration gradient has created an electrical gradient—that is, a difference in the net charge between two regions. In this example, the inside of the cell has become negative relative to the outside.

If the only force acting on K+ were the concentration gradient, K+ would leak out of the cell until the K+ concentration inside the cell equaled the K+ concentration outside. The loss of positive ions from the cell creates an electrical gradient, however. The combination of electrical and concentration gradients is called an electrochemical gradient.

Because opposite charges attract each other, the negative proteins inside the cell try to pull K+ back into the cell (Fig.  5.23d). At some point in this process, the electrical force attracting K+ into the cell becomes equal in magnitude to the chemical concentration gradient driving K+ out of the cell. At that point, net movement of K+ across the membrane stops (Fig. 5.23e). The rate at which K+ ions move out of the cell down the concentration gradient is exactly equal to the rate at which K+ ions move into the cell down the electrical gradient. The system has reached electrochemical equilibrium.

For any given concentration gradient of a single ion, the membrane potential that exactly opposes the concentration gradient is known as the equilibrium potential, or Eion (where the subscript ion is replaced by the symbol for whichever ion we are looking at). For example, when the concentration gradient is 150 mM K+ inside and 5 mM K+ outside the cell, the equilibrium potential for potassium, or EK is −90 mV.

The equilibrium potential for any ion at 37 °C (human body temperature) can be calculated using the Nernst equation:

E ion = 61 Z log [ ion ] out [ ion ] in

where 61 is 2.303 RT/F at 37 °C*

The Nernst equation assumes that the cell in question is freely permeable to only the ion being studied. This is not the usual situation in living cells, however, as you will learn shortly.

All Living Cells Have a Membrane Potential

As the beginning of this chapter pointed out, all living cells are in chemical and electrical disequilibrium with their environment. This electrical disequilibrium, or electrical gradient between the extracellular fluid and the intracellular fluid, is called the resting membrane potential difference, or membrane potential for short. Although the name sounds intimidating, we can break it apart to see what it means.

  1. The resting part of the name comes from the fact that an electrical gradient is seen in all living cells, even those that appear to be without electrical activity. In these “resting” cells, the membrane potential has reached a steady state and is not changing.

  2. The potential part of the name comes from the fact that the electrical gradient created by active transport of ions across the cell membrane is a form of stored, or potential, energy, just as concentration gradients are a form of potential energy. When oppositely charged molecules come back together, they release energy that can be used to do work, in the same way that molecules moving down their concentration gradient can do work [see Appendix B]. The work done using electrical energy includes opening voltage-gated membrane channels and sending electrical signals.

  3. The difference part of the name is to remind you that the membrane potential represents a difference in the amount of electrical charge inside and outside the cell. The word difference is usually dropped from the name, as noted earlier, but it is important for remembering what a membrane potential means.

In living systems, we cannot measure absolute electrical charge, so we describe electrical gradients on a relative scale instead. Figure 5.23f compares the two scales. On an absolute scale, the extracellular fluid in our simple example has a net charge of +1 from the positive ion it gained, and the intracellular fluid has a net charge of −1 from the negative ion that was left behind. On the number line shown, this is a difference of two units.

In real life, because we cannot measure electrical charge as numbers of electrons gained or lost, we use a device that measures the difference in electrical charge between two points. This device artificially sets the net electrical charge of one side of the membrane to 0 and measures the net charge of the second side relative to the first. In our example, resetting the extracellular fluid net charge to 0 on the number line gives the intracellular fluid a net charge of −2. We call the ICF value the resting membrane potential (difference) of the cell.

The equipment for measuring a cell’s membrane potential is depicted in Figure 5.24. Electrodes are created from hollow glass tubes drawn to very fine points. These micropipettes are filled with a liquid that conducts electricity and then connected to a voltmeter, which measures the electrical difference between two points in units of either volts (V) or millivolts (mV). A recording electrode is inserted through the cell membrane into the cytoplasm of the cell. A reference electrode is placed in the external bath, which represents the extracellular fluid.

FIG. 5.24 Measuring membrane potential

In living systems, by convention, the extracellular fluid is designated as the ground and assigned a charge of 0 mV (Fig. 5.23f). When the recording electrode is placed inside a living cell, the voltmeter measures the membrane potential—in other words, the electrical difference between the intracellular fluid and the extracellular fluid. A recorder connected to the voltmeter can make a recording of the membrane potential versus time.

For resting nerve and muscle cells, the voltmeter usually records a membrane potential between −40 and −90 mV, indicating that the intracellular fluid is negative relative to the extracellular fluid (0 mV). (Throughout this discussion, remember that the extracellular fluid is not really neutral because it has excess positive charges that exactly balance the excess negative charges inside the cell, as shown in Fig. 5.23. The total body remains electrically neutral at all times.)

The Resting Membrane Potential Is Due Mostly to Potassium

Which ions create the resting membrane potential in animal cells? The artificial cell shown in Figure 5.23c used a potassium channel to allow K+ to leak across a membrane that was otherwise impermeable to ions. But what processes go on in living cells to create an electrical gradient?

In reality, living cells are not permeable to only one ion. They have open channels and protein transporters that allow ions to move between the cytoplasm and the extracellular fluid. Instead of the Nernst equation, we use a related equation called the Goldman equation that considers concentration gradients of the permeable ions and the relative permeability of the cell to each ion. [For more detail on the Goldman equation, see Chapter 8.]

The real cell illustrated in Figure 5.25 has a resting membrane potential of −70 mV. Most cells are about 40 times more permeable to K+ than to Na+. As a result, a cell’s resting membrane potential is closer to the EK of −90 mV than to the ENa of +60 mV. A small amount of Na+ leaks into the cell, making the inside of the cell less negative than it would be if Na+ were totally excluded. Additional Na+ that leaks in is promptly pumped out by the Na+-K+-ATPase. At the same time, K+ ions that leak out of the cell are pumped back in. The pump contributes to the membrane potential by pumping 3 Na+ out for every 2 K+ pumped in. Because the Na+-K+-ATPase helps maintain the electrical gradient, it is called an electrogenic pump.

FIG. 5.25 The resting membrane potential of cells

Figure Questions:

  1. What force(s) promote(s) Na+ leak into the cell?

  2. What force(s) promote(s) K+ leak out of the cell?

Not all ion transport creates an electrical gradient. Many transporters, like the Na+-K+−2 Cl (NKCC) symporter, are electrically neutral. Some make an even exchange: for each charge that enters the cell, the same charge leaves. An example is the HCO3 -Cl antiporter of red blood cells, which transports these ions in a one-for-one, electrically neutral exchange. Electrically neutral transporters have little effect on the resting membrane potential of the cell.

Concept Check

  1. What would happen to the resting membrane potential of a cell poisoned with ouabain (an inhibitor of the Na+-K+-ATPase)?

Changes in Ion Permeability Change the Membrane Potential

As you have just learned, two factors influence a cell’s membrane potential: (1) the concentration gradients of different ions across the membrane and (2) the permeability of the membrane to those ions. If the cell’s permeability to an ion changes, the cell’s membrane potential changes. We monitor changes in membrane potential using the same recording electrodes that we use to record resting membrane potential.

Figure 5.24 shows a recording of membrane potential plotted against time. The extracellular electrode is set at 0 mV, and the intracellular electrode records the membrane potential difference. The membrane potential (Vm) begins at a steady resting value of −70 mV. When the trace moves upward (becomes less negative), the potential difference between the inside of the cell and the outside (0 mV) is less, and the cell is said to have depolarized. A return to the resting membrane potential is termed repolarization. If the resting potential becomes more negative, we say the cell has hyperpolarized.

A major point of confusion when we talk about changes in membrane potential is the use of the phrases “the membrane potential decreased” or “the membrane potential increased.” Normally, we associate “increase” with becoming more positive and “decrease” with becoming more negative—the opposite of what is happening in our cell discussion. The best way to avoid trouble is to speak of the membrane potential becoming more or less negative or the cell depolarizing or hyperpolarizing. Another way to avoid confusion is to add the word difference after membrane potential. If the membrane potential difference is increasing, the value of Vm must be moving away from the ground value of 0 and becoming more negative. If the membrane potential difference is decreasing, the value of Vm is moving closer to the ground value of 0 mV and is becoming less negative.

What causes changes in membrane potential? In most cases, membrane potential changes in response to movement of one of four ions: Na+, Ca2+, Cl, and K+. The first three ions are more concentrated in the extracellular fluid than in the cytosol, and the resting cell is minimally permeable to them. If a cell suddenly becomes more permeable to any one of these ions, then those ions will move down their electrochemical gradient into the cell. Entry of Ca2+ or Na+ depolarizes the cell (makes the membrane potential more positive). Entry of Cl hyperpolarizes the cell (makes the membrane potential more negative).

Most resting cells are fairly permeable to K+ but making them more permeable allows even more K+ to leak out. The cell hyperpolarizes until it reaches the equilibrium potential for K+. Making the cell less permeable to K+ allows fewer K+ ions to leak out of the cell. When the cell retains K+, it becomes more positive and depolarizes. You will encounter instances of all these permeability changes as you study physiology.

It is important to learn that a significant change in membrane potential requires the movement of very few ions. The concentration gradient does not have to reverse to change the membrane potential. For example, to change the membrane potential by 100 mV (the size of a typical electrical signal passing down a neuron), only one of every 100,000 K+ must enter or leave the cell. This is such a tiny fraction of the total number of K+ ions in the cell that the concentration gradient for K+ remains essentially unchanged.