The resting membrane potential (RMP) is a fundamental electrical property of nerve cells, muscle cells, and other excitable tissues, representing the potential difference across the plasma membrane when the cell is in a stable, unstimulated state.

I. The Resting Membrane Potential

The membrane potential (Vm) is defined as the electrical potential inside the cell measured relative to the electrical potential outside.

• Polarity and Value: By convention, the RMP is expressed as the intracellular potential relative to the extracellular potential. In the resting state, the interior of the cell is negatively charged with respect to the exterior.

• Typical Range: In neurons, cardiac cells, and skeletal muscle cells, the RMP typically ranges from −60 mV to −90 mV. For mammalian neurons, the average RMP is often reported around −70 mV, while heart muscle cells may have an RMP of −85 mV.

II. Genesis and Basis of the Resting Membrane Potential

The RMP is a stable potential established by balancing multiple ionic fluxes.

A. Dependence on Ion Concentration Gradients

The immediate energy source underlying the RMP is the potential energy stored in the ion concentration gradients across the plasma membrane.

1. Asymmetrical Distribution: Biologically important ions, including Na+, K+, and Cl−, are distributed asymmetrically across the membrane, creating concentration gradients.

◦ K + concentration is much higher inside the cell (∼140 mM) than outside (∼5 mM).

◦ Na + concentration is much higher outside the cell (∼145 mM) than inside (∼14 mM).

      ◦ Cl- concentration is much higher outside the cell (∼100 mM) than inside (∼ 10 mM)

2. Selective Permeability: The plasma membrane is selectively permeable to ions due to the presence of ion channels. The RMP is determined by the relative permeabilities of the membrane to these various ions.

◦ The resting membrane is far more permeable to K+  than to Na+. In a resting neuron, the plasma membrane is about 20 times more permeable to K+ than to Na+.

◦ A second type of K+ channel, often called leakage channels, is not gated and is always open, contributing to the high basal permeability of K+.

3. K+  Diffusion Potential: Due to the steep concentration gradient and high permeability to K+, K+  ions tend to diffuse out of the cell.

◦ As positive K+  ions leave the cell, they introduce positive charges to the exterior while leaving behind fixed, negatively charged impermeant anions (such as proteins and organic phosphates/sulfates) on the inside.

◦ This net outward movement of positive charge rapidly generates an inside-negative electrical potential difference, known as the diffusion potential.

◦ Since K+  has the highest permeability, it contributes the most significantly to the RMP, driving the potential toward the K+  equilibrium potential (EK ). The calculation of electro chemical equivalance can determined by Nernst Equation. The calculated EK is highly negative, typically around −90 mV.

4. Na+  Leak and Deviation from EK : The actual RMP (e.g., −70 mV) is generally less negative than EK  (e.g., −90 mV) because the membrane is not completely impermeable to Na+.

◦ A small, steady leakage of Na+  into the cell occurs down its electrochemical gradient (both chemical and electrical forces favour Na+ entry).

◦ This slight inward Na+ movement counteracts the K+ efflux, making the RMP less negative than EK.

B. Quantitative Estimation - The RMP of a cell permeable to multiple monovalent ions (K+, Na+, Cl−) can be quantitatively estimated using the Goldman-Hodgkin-Katz (GHK) voltage equation. This equation incorporates the concentration gradients and the relative membrane permeabilities of these ions. The GHK equation yields the membrane potential at which the sum of all ionic currents across the membrane is zero (I total =0), defining the steady-state resting potential.

III. Role of the Na+/K+ Pump

The RMP is maintained through the action of the Na+ -K+ pump (Na+, K+  -ATPase), a primary active transport carrier found in all body cells.

• Maintenance of Gradients (Indirect Role): The pump expends energy (ATP) to counteract the small, steady leakage of Na+  inward and K+  outward. By doing so, the pump maintains the crucial Na+ and K+ concentration gradients that are necessary to generate the diffusion potentials that set the RMP.

• Electrogenic Contribution (Direct Role): The Na+ -K+ pump is electrogenic because it transports 3 Na+  ions out of the cell for every 2 K+ ions in. This net extrusion of one positive charge per cycle tends to generate an inside-negative Vm. This direct electrogenic effect adds approximately 3 mV to the membrane potential. However, this direct contribution is usually very small compared to the potential generated by the K+ concentration gradient and permeability.

IV. Factors Affecting Resting Membrane Potential

The RMP can be altered by external conditions that affect the factors governing the Nernst potentials and ion conductances (permeabilities).

1. Extracellular K+  Concentration ([K]o):

◦ A change in the concentration of any ion in the extracellular fluid will alter the RMP, but only to the extent that the membrane is permeable to that ion.

◦ Because the resting membrane is most permeable to K+, a change in the K+ concentration outside the cell has the greatest effect on the RMP.

◦ Hyperkalemia (increased [K]o) makes the membrane potential less negative (depolarization).

◦ Hypokalemia (decreased [K]o) makes the membrane potential more negative (hyperpolarization).

2. Membrane Permeability (Ion Channel Activity):

◦ A change in the membrane permeability to any given ion will change the membrane potential.

◦ If gated Na+ channels open, the membrane potential moves toward the Na+ equilibrium potential (ENa  ≈ +66 mV), becoming less negative (depolarizing).

◦ If gated K+ channels open, the membrane potential moves closer to the K+ equilibrium potential (EK ≈ −90 mV), becoming more negative (hyperpolarizing).

3. Na / K+ Pump Inhibition:

◦ If the Na+ -K+ pump is partially inhibited (e.g., by digitalis), the RMP becomes less negative than normal. Inhibition of the pump would ultimately lead to a decline in concentration gradients and the ability of the axon to produce action potentials, although the pump is not directly involved in the immediate action potential generation.