Biochemistry - The Chemical Reactions of Living Cells, Volume 1 - D. Metzler 1980

Membranes and Cell Walls
Metabolism and Membrane Functions
Nerve Impulse Conduction

The ability of membranes to maintain a concentration gradient of ions between the Cytoplasm and the extracellular environment underlies their excitability, which is of great practical importance. Charge Separation creates a kind of "battery" of readily available energy that can be used to conduct electrical signals across The Cell membrane. This signaling capacity of Cells is most pronounced in nerve fibers; however, it is not restricted to Nerve Cells and is found even in Protozoa, such as Paramecium [70, 70a], as well as likely in Bacteria.

At present, relatively little is known about the Chemical Nature of Nerve Impulse propagation, but the electrical characteristics of this process have been studied and described in detail. If a microelectrode is inserted into a cell through the membrane, the potential difference between the external medium and the cell interior can be measured. This potential difference, known as the Resting Potential, reaches 90 mV in nerve cells. Its origin is apparently due to differences in ion concentrations. Based on the value of ∆G for the dilution of an ion solution [equation (3-25)] and the relationship between ∆G and the electrode potential [equation (3-63)], the Nernst equation can be readily derived:

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According to this equation, which applies to a system containing only a single type of ion, a 10-fold difference in the concentration of a monovalent ion (n=1) across the membrane will generate a potential of 59 mV. Since membranes are relatively impermeable to sodium ions, it is generally accepted that the Membrane Potential is generated primarily by the concentration gradient of potassium ions. In addition to equation (5-2), a more comprehensive equation has been derived that takes into account both the concentrations of K⁺, Na⁺, and Cl^- ions and their membrane permeability [69, 71, 72].

If the permeability to sodium ions increases in any region of the membrane, these ions rush into the cell, neutralizing its negative charge. Consequently, the cell membrane depolarizes. During depolarization, a decremental electrical signal propagates along the membrane surface, much like current flowing through a coaxial cable. It is believed that the initiation of a nerve impulse is frequently associated with a local increase in membrane permeability to sodium ions. Other ions, particularly Ca²⁺, may also play a specific role in this process. However, the passive propagation of electrical signals driven by local membrane depolarization occurs only in very short nerve cells; signals cannot travel long distances by this mechanism. Most nerve cell axons utilize a more efficient method of impulse conduction based on the generation of an Action Potential. An action potential is an impulse that travels along the axon, specifically altering the membrane potential within a fraction of a millisecond (approximately 0.5 ms in mammalian nerves) (Fig. 5-6). The initial negative potential of ~50–70 mV rapidly drops to zero, then reaches a positive value of 40–50 mV, after which the resting potential is re-established. A striking feature of the action potential is that it propagates along axons at a velocity of 1–100 m/s without attenuation.

To study the chemical Nature of the action potential in the 1950s, A. Hodgkin and A. Huxley developed the voltage-clamp technique. Using this ingenious method, transmembrane current can be measured while maintaining the membrane potential at a desired level via a feedback control system [69, 71, 73]. The application of voltage clamping made it possible to measure the dependence of membrane conductance on both membrane potential and time. It turned out that immediately after the membrane potential is stepped down using the Voltage Clamp, the membrane permeability to sodium ions increases sharply. This increase in permeability automatically leads to depolarization of the adjacent membrane region and, consequently, to The formation of a self-propagating wave moving along the axon. The chemical nature of the processes altering membrane permeability remains unclear. Voltage-clamp experiments revealed that within fractions of a millisecond, membrane permeability to potassium ions also increases. Concurrently, sodium permeability decreases again, and after some time, the normal membrane potential is restored¹. The sequence of events in this process can be envisioned as follows: sodium "channels" open first (these are not identical to the Pores in the Na⁺ pump), followed by potassium channels, after which the channels close in the same sequence. The results of these studies enabled Hodgkin and Huxley to derive equations that allow the Quantitative evaluation of action potentials and the prediction of experimentally observed conduction velocities and various other characteristics of nerve impulses.

A distinctive feature of nerve fibers capable of very rapid impulse conduction is the presence of a myelin sheath. Myelin membranes reliably insulate the axon from the surrounding environment along its entire length, except at specialized regions known as the nodes of Ranvier, which are spaced 1–2 mm apart along the axon. This allows the nerve impulse to effectively "jump" from one node to the next. Such saltatory conduction occurs at a significantly higher velocity (up to 100 m/s) compared to conduction in unmyelinated axons.

What is known about the channels that conduct Na⁺ and K⁺ ions during nerve excitation? Using tetrodotoxin from pufferfishes (Fig. 16-7), it was conclusively demonstrated that separate channels exist for these two ions. This Conclusion was drawn because the Toxic Effect of tetrodotoxin was accompanied by the blockade of sodium channels, whereas K⁺ ion conduction remained unimpaired. At the same time, potassium channels were blocked using various quaternary ammonium salts. The high binding constant of tetrodotoxin (approximately 3·10⁸ M^-1) made it possible to determine the number of sodium channels by titration. Although data obtained by different authors varied, even the maximum values indicate a relatively small number of sodium channels—40–75 per 1 µm² of membrane surface [74] (for comparison, recall that the same membrane area contains 2·10⁶ phospholipid molecules). The number of sodium-conducting channels is apparently 10 times smaller than the number of "pump" channels, i.e., channels utilized by the (Na⁺ + K⁺)-dependent ATPase [75]. The number of potassium channels remains unknown.

FIG. 5-6. A. Action potential recorded with an electrode inserted into an axon previously freed of cytoplasm and then filled with a potassium sulfate solution (18°C). B. Action potential of an intact axon recorded with the same Amplification and time scale (18°C). The voltage scale indicates the potential difference between the internal electrode and an identical electrode immersed in the external solution (uncorrected for junction potential) (Hodgkin A., Conduction of Nervous Impulses, 1964; courtesy of Charles C. Thomas, Publisher, Springfield, Illinois).

¹ However, during the absolute refractory period (lasting approximately 0.5 ms), nerve impulse conduction is impossible.

Since the number of ion-conducting channels is small, The rate of sodium passage through open channels must be extremely high, estimated at ∼10⁸ ions per second. It follows that these channels cannot operate via ionophore carriers, but must instead represent simple "pores" that open and close in response to Changes in membrane potential. It has been suggested that before passing through the channels—which appear to be formed by protein molecules embedded in the membrane—potassium and sodium ions shed their Hydration shells.

How do the "gates" of Ion Channels open? The characteristic increase in conductance rate with changes in membrane potential clearly points to the cooperative nature of this process [74, 76]. Little can be added at present to what has already been stated in this section regarding nerve impulse conduction. Elucidating the chemical basis of ionic conductance in excitable membranes remains one of the most pressing challenges in biochemistry.