Membrane Potentials and Action Potentials
Electrical potentials exist across the membranes of virtually all cells in the body. Some cells, such as nerve and muscle cells, generate rapidly changing electrochemical impulses at their membranes to transmit signals. In other types of cells, like glandular cells, macrophages, and ciliated cells, local changes in membrane potentials activate many of the cell's functions.
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Basic Physics of Membrane Potentials
Membrane potentials are created by ion concentration differences across a selectively permeable membrane. When there's a concentration gradient of ions across a membrane that's permeable to those ions, diffusion occurs, creating an electrical potential difference.
Potassium Diffusion
When potassium concentration is higher inside a nerve fiber than outside, K+ ions diffuse outward, carrying positive charges. This creates positivity outside and negativity inside, generating a diffusion potential of about -94 millivolts in mammalian nerve fibers.
Sodium Diffusion
When sodium concentration is higher outside the membrane than inside, Na+ ions diffuse inward. This creates a membrane potential of opposite polarity, with negativity outside and positivity inside, about +61 millivolts in mammalian nerve fibers.
The Nernst Equation
The diffusion potential that exactly opposes the net diffusion of a particular ion through the membrane is called the Nernst potential for that ion. The magnitude of this potential is determined by the ratio of ion concentrations on the two sides of the membrane.
EMF (millivolts) = \pm \frac{61}{z} \times \log \frac{Concentration\ inside}{Concentration\ outside}
Where EMF is the electromotive force and z is the electrical charge of the ion (e.g., +1 for K+). When using this formula, it's usually assumed that the potential in the extracellular fluid outside the membrane remains at zero, and the Nernst potential is the potential inside the membrane.

The sign of the potential is positive (+) if the ion diffusing from inside to outside is a negative ion, and it is negative (-) if the ion is positive. For example, when the concentration of positive potassium ions inside is 10 times that outside, the Nernst potential calculates to be -61 millivolts inside the membrane.
The Goldman Equation
When a membrane is permeable to several different ions, the diffusion potential depends on three factors: (1) the polarity of the electrical charge of each ion, (2) the permeability of the membrane to each ion, and (3) the concentration of the respective ions inside and outside the membrane.
EMF (millivolts) = -61 \times \log \frac{C_{Na_i^+} P_{Na^+} + C_{K_i^+} P_{K^+} + C_{Cl_o^-} P_{Cl^-}}{C_{Na_o^+} P_{Na^+} + C_{K_o^+} P_{K^+} + C_{Cl_i^-} P_{Cl^-}}
Sodium, potassium, and chloride ions are the most important ions involved in the development of membrane potentials in nerve and muscle fibers.
The quantitative importance of each ion in determining the voltage is proportional to the membrane permeability for that particular ion.
A positive ion concentration gradient from inside to outside causes electronegativity inside the membrane.
During nerve impulse transmission, rapid changes in sodium and potassium permeability are primarily responsible for signal transmission in neurons.
Resting Membrane Potential in Different Cell Types
In some cells, such as cardiac pacemaker cells, the membrane potential is continuously changing. In many other cells, even excitable cells, there is a quiescent period in which a resting membrane potential can be measured.
The membrane potential is dynamic in excitable cells such as neurons. Even in nonexcitable cells, the membrane potential changes in response to various stimuli, which alter activities for ion transporters, ion channels, and membrane permeability for sodium, potassium, calcium, and chloride ions.
Electrochemical Driving Force
When multiple ions contribute to the membrane potential, the equilibrium potential for any contributing ion will differ from the membrane potential. This creates an electrochemical driving force (Vdf) for each ion that tends to cause net movement across the membrane.
V_{df} = V_m - V_{eq}
For Cations (Na+, K+)
  • Positive Vdf: Ion movement out of the cell
  • Negative Vdf: Ion movement into the cell
For Anions (Cl-)
  • Positive Vdf: Ion movement into the cell
  • Negative Vdf: Ion movement out of the cell
When Vm = Veq, there is no net movement of the ion into or out of the cell. The direction of ion flux through the membrane reverses as Vm becomes greater than or less than Veq; hence, the equilibrium potential (Veq) is also called the reversal potential.
Measuring the Membrane Potential
The method for measuring membrane potential involves using a small micropipette filled with an electrolyte solution. This micropipette is impaled through the cell membrane to the interior of the fiber. Another electrode, called the indifferent electrode, is placed in the extracellular fluid, and the potential difference is measured using a voltmeter.
This voltmeter is a highly sophisticated electronic apparatus capable of measuring small voltages despite extremely high resistance to electrical flow through the micropipette tip, which has a lumen diameter usually less than 1 micrometer and a resistance of more than 1 million ohms.
For recording rapid changes in the membrane potential during transmission of nerve impulses, the microelectrode is connected to an oscilloscope.
Distribution of Charges Across the Membrane
As a recording electrode passes through the voltage change area at the cell membrane (called the electrical dipole layer), the potential decreases abruptly to -70 millivolts. Moving across the center of the fiber, the potential remains at a steady -70-millivolt level but reverses back to zero the instant it passes through the membrane on the opposite side.
To create a negative potential inside the membrane, only enough positive ions to develop the electrical dipole layer at the membrane itself must be transported outward. The remaining ions inside the nerve fiber can be both positive and negative.

Transfer of an incredibly small number of ions through the membrane can establish the normal resting potential of -70 millivolts inside the nerve fiber—only about 1/3,000,000 to 1/100,000,000 of the total positive charges inside the fiber must be transferred.
Resting Membrane Potential of Neurons
The resting membrane potential of large nerve fibers when they are not transmitting nerve signals is about -70 millivolts. That is, the potential inside the fiber is 70 millivolts more negative than the potential in the extracellular fluid outside the fiber.
Na+-K+ Pump
All cell membranes have a powerful Na+-K+ pump that continually transports sodium ions to the outside of the cell and potassium ions to the inside. This is an electrogenic pump because three Na+ ions are pumped out for each two K+ ions pumped in, creating a net deficit of positive ions inside.
Ion Concentration Gradients
  • Na+ (outside): 142 mEq/L
  • Na+ (inside): 14 mEq/L
  • K+ (outside): 4 mEq/L
  • K+ (inside): 140 mEq/L
Origin of the Normal Resting Membrane Potential
Potassium Diffusion Potential
If potassium ions were the only factor causing the resting potential, it would be about -94 millivolts inside the fiber, based on the 35:1 ratio of potassium ions inside to outside.
Sodium Diffusion Contribution
The slight permeability of the membrane to sodium ions (through K+-Na+ leak channels) contributes to the membrane potential. The permeability to potassium is about 100 times greater than to sodium, resulting in a potential of about -86 millivolts.
Na+-K+ Pump Contribution
The continuous pumping of three sodium ions out for each two potassium ions pumped in creates an additional negativity (about -4 millivolts) inside the membrane, beyond that accounted for by diffusion alone.
The net membrane potential when all these factors operate simultaneously is about -90 millivolts, with additional contributions from other ions like chloride.
Neuron Action Potential
Nerve signals are transmitted by action potentials, which are rapid changes in the membrane potential that spread rapidly along the nerve fiber membrane. Each action potential begins with a sudden change from the normal resting negative membrane potential to a positive potential and ends with an almost equally rapid change back to the negative potential.
Resting Stage
The membrane is "polarized" with a -70 millivolts negative membrane potential.
Depolarization Stage
The membrane suddenly becomes permeable to sodium ions, allowing rapid diffusion of positively charged sodium ions to the interior, neutralizing the negative potential.
Repolarization Stage
Sodium channels begin to close, and potassium channels open more widely, allowing rapid diffusion of potassium ions to the exterior, reestablishing the negative resting potential.
Voltage-Gated Sodium and Potassium Channels
The key factors in causing both depolarization and repolarization of the nerve membrane during the action potential are the voltage-gated sodium and potassium channels. These are in addition to the Na+-K+ pump and the K+ leak channels.
Sodium Channel States
The voltage-gated sodium channel has two gates: an activation gate near the outside and an inactivation gate near the inside. In the resting state, the activation gate is closed. When the membrane potential becomes less negative (around -55 millivolts), the activation gate opens, allowing sodium ions to flow inward. Shortly after, the inactivation gate closes, stopping sodium flow.
Potassium Channel Activation
The voltage-gated potassium channel opens in response to membrane depolarization, but with a slight delay compared to sodium channels. This delayed opening coincides with sodium channel inactivation, speeding up repolarization by allowing increased potassium diffusion outward.
The Voltage Clamp Method
The voltage clamp method was pioneered by Hodgkin and Huxley, who received the Nobel Prize in 1963 for their work. This technique allows researchers to measure the flow of ions through different channels by controlling the membrane potential.
In this method, two electrodes are inserted into the nerve fiber: one to measure the membrane potential and another to conduct electrical current into or out of the fiber. The investigator sets a desired voltage, and the apparatus automatically injects positive or negative electricity to maintain that voltage.
When the membrane potential is suddenly increased from -70 millivolts to a positive value, voltage-gated channels open, and ions flow through the membrane. The current required to maintain the set voltage is measured, revealing the ion channel activity.
Summary of Events During the Action Potential
During the resting state, the conductance for potassium ions is 50 to 100 times greater than for sodium ions due to greater leakage of potassium through leak channels. At the onset of the action potential, sodium channels become activated, allowing up to a 5000-fold increase in sodium conductance.
1
Early Action Potential
The ratio of sodium to potassium conductance increases more than 1000-fold. More sodium ions flow inward than potassium ions outward, causing the membrane potential to become positive.
2
Inactivation Phase
Sodium channels begin to close through the inactivation process, while potassium channels continue opening.
3
Repolarization Phase
The ratio of conductance shifts in favor of high potassium conductance but low sodium conductance, allowing rapid loss of potassium ions to the exterior with virtually zero sodium inflow, quickly returning the action potential to baseline.
Roles of Other Ions During the Action Potential
Impermeant Negative Ions (Anions)
Inside the axon are many negatively charged ions that cannot pass through membrane channels, including protein anions and organic phosphate and sulfate compounds. These impermeant negative ions are responsible for the negative charge inside the fiber when there is a net deficit of positive ions.
Calcium Ions
Most cell membranes have a calcium pump similar to the sodium pump, creating a calcium ion gradient of about 10,000-fold (internal concentration ~10-7 molar vs. external ~10-3 molar).
Voltage-gated calcium channels contribute to the depolarizing phase of the action potential in some cells. These channels activate more slowly than sodium channels (10-20 times longer), providing a more sustained depolarization. They're particularly numerous in cardiac and smooth muscle cells.

When calcium ion concentration in the extracellular fluid falls, sodium channels become more easily activated, making nerve fibers highly excitable. A 50% drop in calcium can cause spontaneous discharge in peripheral nerves, sometimes leading to muscle tetany, which can be lethal if it affects respiratory muscles.
Initiation of the Action Potential
Under normal conditions, no action potential occurs in a nerve fiber unless it's stimulated. When the membrane potential rises sufficiently from -70 millivolts toward zero, voltage-gated sodium channels begin opening, allowing sodium ions to flow inward.
Initial Depolarization
A stimulus causes initial rise in membrane potential
Na+ Influx
Sodium ions flow inward through opened channels
Further Depolarization
Membrane potential rises further
More Channels Open
Additional voltage-gated sodium channels activate
This positive feedback cycle continues until all voltage-gated sodium channels are activated. An action potential will only occur when the initial rise in membrane potential is great enough to create this positive feedback—typically a sudden increase from -70 millivolts to about -55 millivolts, which is the threshold for stimulation.
Propagation of the Action Potential
An action potential elicited at any point on an excitable membrane usually excites adjacent portions of the membrane, resulting in propagation along the membrane.
When a nerve fiber is excited in its midportion, a local circuit of current flows from the depolarized areas to adjacent resting membrane areas. Positive charges carried by inward-diffusing sodium ions flow through the depolarized membrane and then for several millimeters in both directions along the axon core.
Direction of Propagation
An excitable membrane has no single direction of propagation. The action potential travels in all directions away from the stimulus—even along all branches of a nerve fiber—until the entire membrane has become depolarized.
All-or-Nothing Principle
Once an action potential has been elicited at any point on the membrane of a normal fiber, the depolarization process travels over the entire membrane if conditions are right, but it does not travel at all if conditions are not right.
For continued propagation to occur, the ratio of action potential to threshold for excitation must at all times be greater than 1. This "greater than 1" requirement is called the safety factor for propagation.
Re-establishing Ion Gradients After Action Potentials
Each action potential slightly reduces the concentration differences of sodium and potassium across the membrane. While a single action potential's effect is minute, over time (after 100,000 to 50 million impulses), the concentration differences may reach a point where action potential conduction ceases.
The Na+-K+ pump re-establishes these concentration differences by returning sodium ions that have diffused inward and potassium ions that have diffused outward to their original locations. This "recharging" process requires energy from the cell's ATP energy system, as shown by increased heat production during higher nerve impulse frequencies.

A special feature of the Na+-K+ ATP pump is that its activity is strongly stimulated when excess sodium ions accumulate inside the cell membrane. The pumping activity increases approximately in proportion to the third power of the intracellular sodium concentration. As internal sodium rises from 10 to 20 mEq/L, pump activity increases about eightfold.
Special Features of Action Potentials
Plateau Action Potentials
In some cases, like heart muscle fibers, the membrane doesn't repolarize immediately after depolarization. Instead, the potential remains on a plateau near the peak for many milliseconds, prolonging depolarization for 0.2-0.3 seconds in heart muscle.
This plateau results from voltage-activated calcium-sodium channels (L-type calcium channels) that open slowly and allow calcium ions to enter, plus delayed opening of potassium channels. The plateau ends when calcium-sodium channels close and potassium permeability increases.
Rhythmicity in Excitable Tissues
Repetitive self-induced discharges occur normally in the heart, most smooth muscle, and many central nervous system neurons, causing rhythmical beating of the heart, peristalsis of the intestines, and rhythmical control of breathing.
Myelinated and Unmyelinated Nerve Fibers
Nerve trunks contain both myelinated (large) and unmyelinated (small) fibers, with about twice as many unmyelinated fibers as myelinated ones. The myelin sheath is deposited around the axon by Schwann cells, which rotate around the axon laying down multiple layers of membrane containing sphingomyelin, an excellent electrical insulator.
At junctions between Schwann cells are nodes of Ranvier, small uninsulated areas where ions can flow through the axon membrane. In myelinated nerves, action potentials occur only at these nodes and are conducted from node to node by saltatory conduction.
Benefits of Saltatory Conduction
  • Increases velocity of nerve transmission 5-50 fold by causing the depolarization to jump long intervals
  • Conserves energy by depolarizing only at nodes, allowing perhaps 100 times less ion loss
Conduction Velocity
The velocity of action potential conduction varies from as little as 0.25 m/sec in small unmyelinated fibers to as much as 100 m/sec (the length of a football field in 1 second) in large myelinated fibers.