The Resting Membrane Potential Is Mainly Determined By

The resting membrane potential, a fundamental concept in neurobiology and cell physiology, is primarily determined by the distribution of ions across the cell membrane and the membrane's selective permeability to these ions. This electrical potential difference between the inside and outside of a cell, typically around -70 mV in neurons, is crucial for cellular communication, nerve impulse transmission, and muscle contraction. Understanding the factors that govern the resting membrane potential provides insight into how cells function and respond to stimuli.

Introduction to Resting Membrane Potential

The resting membrane potential (RMP) is the voltage difference across the cell membrane when the cell is not stimulated. This potential arises from the unequal distribution of ions, such as sodium (Na+), potassium (K+), chloride (Cl-), and calcium (Ca2+), between the intracellular and extracellular fluids. While all these ions contribute to the overall electrical properties of the cell, the RMP is predominantly determined by potassium ions and, to a lesser extent, sodium and chloride ions.

Key Factors Influencing Resting Membrane Potential

1. Ion Concentration Gradients: The differing concentrations of ions inside and outside the cell create a chemical driving force.
2. Membrane Permeability: The cell membrane's selective permeability to different ions allows some ions to cross more easily than others.
3. Ion Channels: These transmembrane proteins facilitate the movement of ions across the membrane.
4. Sodium-Potassium Pump (Na+/K+ ATPase): This active transport mechanism maintains the ion gradients.

The Role of Ion Concentration Gradients

Ion concentration gradients are fundamental to establishing the resting membrane potential. These gradients represent a form of potential energy that can be harnessed when ions move across the cell membrane.

Potassium (K+)

• Intracellular Dominance: Potassium ions are much more concentrated inside the cell than outside. In neurons, the intracellular concentration of K+ is typically around 150 mM, while the extracellular concentration is around 5 mM.
• Outward Diffusion: This concentration gradient drives K+ ions to diffuse out of the cell, following their concentration gradient. As positively charged K+ ions leave, they create an excess of negative charge inside the cell, contributing to the negative resting membrane potential.

Sodium (Na+)

• Extracellular Dominance: Sodium ions are more concentrated outside the cell than inside. The extracellular concentration of Na+ is around 150 mM, while the intracellular concentration is around 15 mM.
• Inward Diffusion: This gradient drives Na+ ions to diffuse into the cell. However, at rest, the membrane is much less permeable to Na+ than to K+, so the contribution of Na+ to the RMP is smaller.

Chloride (Cl-)

• Extracellular Dominance: Chloride ions are also more concentrated outside the cell.
• Equilibrium: In many cells, Cl- ions are passively distributed according to the membrane potential, meaning they are at equilibrium and do not significantly contribute to the RMP. However, in some neurons, particularly those with active chloride transporters, Cl- can play a more significant role.

Calcium (Ca2+)

• Low Intracellular Concentration: Calcium ions are kept at very low concentrations inside the cell, typically around 0.0001 mM, compared to an extracellular concentration of around 2 mM.
• Minimal Direct Contribution: Although Ca2+ plays critical roles in cell signaling, its direct contribution to the resting membrane potential is relatively small due to its low permeability at rest.

Membrane Permeability and Ion Channels

The cell membrane is a lipid bilayer that is impermeable to ions. Ion channels are transmembrane proteins that create pathways for ions to move across the membrane, allowing for selective permeability to different ions.

Potassium Channels

• Dominant Role: At rest, the cell membrane is much more permeable to potassium ions than to other ions. This is due to the presence of leak channels or resting potassium channels, which are open even when the cell is not stimulated.
• Selective Permeability: These channels allow K+ ions to flow down their concentration gradient, from inside to outside the cell.
• Impact on RMP: The high permeability to K+ and the large concentration gradient make K+ the primary determinant of the resting membrane potential. As K+ exits the cell, it carries positive charge, leaving behind a negative charge and creating the negative membrane potential.

Sodium Channels

• Limited Permeability at Rest: While there are sodium channels in the cell membrane, they are mostly closed at rest. This limits the permeability of the membrane to Na+ ions.
• Influx during Stimulation: When the cell is stimulated, voltage-gated sodium channels open, allowing Na+ to rush into the cell, which leads to depolarization and the generation of an action potential.

Chloride Channels

• Variable Role: The role of chloride channels in establishing the resting membrane potential varies depending on the cell type. In some neurons, chloride channels help to stabilize the RMP by allowing Cl- ions to move in or out of the cell, depending on the electrochemical gradient.

The Nernst Equation

The Nernst equation is used to calculate the equilibrium potential for a single ion. This is the membrane potential at which the electrical driving force is equal and opposite to the chemical driving force, resulting in no net movement of the ion across the membrane.

Formula

The Nernst equation is given by:

Eion = (RT / zF) * ln([ion]out / [ion]in)

Where:

• Eion = Equilibrium potential for the ion
• R = Ideal gas constant (8.314 J/(mol·K))
• T = Absolute temperature (in Kelvin)
• z = Valence of the ion
• F = Faraday's constant (96,485 C/mol)
• [ion]out = Extracellular concentration of the ion
• [ion]in = Intracellular concentration of the ion

Application to Potassium

Using typical intracellular and extracellular concentrations of K+ for a neuron (150 mM inside, 5 mM outside), and assuming a temperature of 37°C (310 K), the Nernst equation yields an equilibrium potential for potassium (EK) of approximately -90 mV. This indicates that if the membrane were permeable only to potassium, the membrane potential would be -90 mV.

Application to Sodium

Similarly, using typical concentrations of Na+ (15 mM inside, 150 mM outside), the Nernst equation yields an equilibrium potential for sodium (ENa) of approximately +60 mV. This suggests that if the membrane were permeable only to sodium, the membrane potential would be +60 mV.

The Goldman-Hodgkin-Katz (GHK) Equation

The Goldman-Hodgkin-Katz (GHK) equation, also known as the Goldman equation, is used to calculate the resting membrane potential when the membrane is permeable to multiple ions. It takes into account both the concentration gradients and the relative permeabilities of the ions.

Formula

The GHK equation is given by:

Vm = (RT / F) * ln((PK[K+]out + PNa[Na+]out + PCl[Cl-]in) / (PK[K+]in + PNa[Na+]in + PCl[Cl-]out))

Where:

• Vm = Membrane potential
• R = Ideal gas constant
• T = Absolute temperature
• F = Faraday's constant
• P = Permeability coefficient for the ion
• [ion]out = Extracellular concentration of the ion
• [ion]in = Intracellular concentration of the ion

Incorporating Permeability

The GHK equation highlights the importance of permeability in determining the membrane potential. The ion with the highest permeability will have the greatest influence on the membrane potential. In most neurons, the permeability to potassium is much greater than the permeability to sodium or chloride (e.g., PK : PNa : PCl = 1 : 0.04 : 0.45).

Realistic Calculation

Using the GHK equation with typical ion concentrations and permeabilities for a neuron, the calculated resting membrane potential is close to -70 mV. This value reflects the combined influence of potassium, sodium, and chloride ions, with potassium having the predominant effect due to its high permeability.

The Sodium-Potassium Pump (Na+/K+ ATPase)

The sodium-potassium pump is an active transport protein located in the cell membrane that maintains the ion concentration gradients by pumping sodium ions out of the cell and potassium ions into the cell.

Mechanism

• Active Transport: The Na+/K+ pump uses energy in the form of ATP to transport ions against their concentration gradients.
• 3 Na+ Out, 2 K+ In: For each molecule of ATP hydrolyzed, the pump transports three sodium ions out of the cell and two potassium ions into the cell.
• Electrogenic: This unequal exchange of ions creates a net outward movement of positive charge, contributing directly to the negative resting membrane potential, although its contribution is relatively small (estimated at around -5 to -10 mV).

Importance

• Maintaining Gradients: The primary role of the Na+/K+ pump is to maintain the concentration gradients of sodium and potassium, which are essential for establishing and maintaining the resting membrane potential.
• Cellular Function: By maintaining these gradients, the pump ensures that the cell is ready to respond to stimuli and generate action potentials.

Role of Other Ions

While potassium, sodium, and chloride ions are the primary determinants of the resting membrane potential, other ions, such as calcium, also play a role, albeit a smaller one.

Calcium (Ca2+)

• Low Permeability at Rest: The cell membrane has low permeability to calcium ions at rest.
• Signaling Role: Calcium ions play a critical role in cell signaling, and changes in intracellular calcium concentration can affect the membrane potential indirectly by modulating the activity of ion channels.

Other Ions

• Negligible Direct Impact: Other ions, such as magnesium (Mg2+), have a relatively small direct impact on the resting membrane potential due to their low concentrations and permeabilities.

Factors That Can Affect Resting Membrane Potential

Several factors can influence the resting membrane potential, including changes in ion concentrations, alterations in membrane permeability, and the action of various drugs and toxins.

Changes in Ion Concentrations

• Hyperkalemia: An increase in extracellular potassium concentration (hyperkalemia) reduces the potassium concentration gradient, leading to a less negative (depolarized) resting membrane potential.
• Hypokalemia: A decrease in extracellular potassium concentration (hypokalemia) increases the potassium concentration gradient, leading to a more negative (hyperpolarized) resting membrane potential.
• Sodium Imbalance: Changes in extracellular sodium concentration can also affect the resting membrane potential, although to a lesser extent due to the lower permeability of the membrane to sodium at rest.

Alterations in Membrane Permeability

• Channelopathies: Genetic mutations that affect the function of ion channels can alter membrane permeability and disrupt the resting membrane potential.
• Pharmacological Agents: Certain drugs can block or activate ion channels, changing membrane permeability and affecting the resting membrane potential.

Drugs and Toxins

• Local Anesthetics: Drugs like lidocaine block voltage-gated sodium channels, preventing the generation of action potentials and affecting the excitability of neurons.
• Tetrodotoxin (TTX): A potent neurotoxin found in pufferfish, TTX specifically blocks voltage-gated sodium channels, leading to paralysis.
• Ouabain: A cardiac glycoside that inhibits the Na+/K+ pump, leading to disruption of ion gradients and affecting the resting membrane potential.

Clinical Significance

Understanding the resting membrane potential is crucial for understanding many physiological processes and disease states.

Neurological Disorders

• Epilepsy: Abnormalities in ion channel function can lead to hyperexcitability of neurons and contribute to seizures.
• Multiple Sclerosis: Demyelination in multiple sclerosis can alter the electrical properties of neurons and affect their ability to generate action potentials.

Cardiac Arrhythmias

• Potassium Imbalance: Changes in extracellular potassium concentration can affect the resting membrane potential of cardiac cells and lead to arrhythmias.
• Antiarrhythmic Drugs: Many antiarrhythmic drugs work by blocking ion channels in cardiac cells, altering their electrical properties and preventing abnormal heart rhythms.

Muscle Disorders

• Myotonia: Genetic mutations that affect the function of chloride channels in muscle cells can lead to myotonia, a condition characterized by prolonged muscle contraction.
• Periodic Paralysis: Disorders that affect the function of sodium or calcium channels in muscle cells can lead to episodes of muscle weakness or paralysis.

Conclusion

The resting membrane potential is a critical property of cells that is primarily determined by the distribution of ions across the cell membrane and the membrane's selective permeability to these ions. Potassium ions play the most significant role due to their high intracellular concentration and the presence of leak channels that make the membrane highly permeable to potassium at rest. The Nernst equation and the GHK equation provide tools for calculating the equilibrium potential for individual ions and the overall resting membrane potential, respectively. The sodium-potassium pump actively maintains the ion concentration gradients, ensuring that cells are ready to respond to stimuli. Understanding the factors that influence the resting membrane potential is essential for understanding many physiological processes and disease states, making it a fundamental concept in biology and medicine.