Resting Membrane Potential: Why Cells Have an Electrical Difference

Every living cell separates positive and negative charges across its plasma membrane. When the cell is not actively firing an electrical signal, this separation is called the resting membrane potential (RMP). Understanding why this voltage exists is fundamental to neurobiology, muscle physiology, and cellular bioenergetics.

What is the resting membrane potential?

The RMP is defined as the electrical potential difference (in millivolts, mV) between the interior of the cell and the extracellular fluid, measured with the interior as the reference point. In most neurons the RMP is about –70 mV, meaning the inside is 70 mV more negative than the outside.¹

How is the RMP generated?

1. Ion concentration gradients

Across the membrane, major ions have very different concentrations. Typical values for a mammalian neuron are:

• Potassium (K⁺): high inside (~140 mM) and low outside (~5 mM)
• Sodium (Na⁺): low inside (~10 mM) and high outside (~145 mM)
• Chloride (Cl⁻): roughly equal, but slightly higher outside
• Negatively charged proteins and organic phosphates are essentially confined to the cytoplasm.

These gradients are established and maintained by active transporters, most importantly the Na⁺/K⁺‑ATPase, which pumps three Na⁺ out and two K⁺ in for each ATP hydrolyzed.¹

2. Selective membrane permeability

The lipid bilayer itself is largely impermeable to ions. Specific protein pathways—ion channels and transporters—provide the routes for ions to cross. At rest, the membrane is much more permeable to K⁺ than to Na⁺ because of abundant “leak” K⁺ channels. This selective permeability allows K⁺ to diffuse outward down its concentration gradient, leaving behind unpaired negative charges (mostly proteins) and creating a negative interior.

3. The Na⁺/K⁺‑ATPase (the “pump”)

While K⁺ leak tends to make the inside negative, the pump counteracts the loss of K⁺ and the accumulation of Na⁺ by continuously moving these ions against their gradients. The pump’s electrogenic nature (moving three positive charges out for every two moved in) contributes directly to the negative resting potential.⁴

4. The Donnan equilibrium

Because large anionic proteins cannot cross the membrane, the system reaches a balance (Donnan equilibrium) where the distribution of permeant ions (K⁺, Na⁺, Cl⁻) satisfies both electrical neutrality and the fixed negative charges inside. This equilibrium further stabilizes the RMP.³

Quantitative description: Nernst and Goldman equations

The Nernst equation predicts the equilibrium potential for a single ion based on its concentration ratio:

E_ion = (RT/zF) ln([ion]_out/[ion]_in)

For K⁺ in a typical neuron, E_K ≈ –90 mV; for Na⁺, E_Na ≈ +60 mV. The actual RMP is a weighted average of these individual potentials, given by the Goldman‑Hodgkin‑Katz (GHK) voltage equation, which incorporates the relative permeabilities (P) of each ion:

V_m = (RT/F) lnfrac{P_{K}[K^+]_{out}+P_{Na}[Na^+]_{out}+P_{Cl}[Cl^-]_{in}}{P_{K}[K^+]_{in}+P_{Na}[Na^+]_{in}+P_{Cl}[Cl^-]_{out}}

Because P_K ≫ P_Na at rest, the RMP lies close to E_K but is slightly less negative due to the small Na⁺ leak.²

Concrete example: a typical neuron

Using the typical ion concentrations listed above and assuming P_K ≈ 1, P_Na ≈ 0.04, and P_Cl ≈ 0.45, the GHK equation yields a membrane voltage of about –70 mV, matching experimental measurements in many neurons.² This value illustrates how the combination of concentration gradients, selective permeability, and pump activity produces a stable, negative interior.

Why does the electrical difference matter?

The RMP provides the “baseline” from which rapid changes (action potentials) can be generated. A small depolarizing stimulus that brings the membrane potential closer to the Na⁺ equilibrium can open voltage‑gated Na⁺ channels, leading to the all‑or‑none spike that propagates along axons. In muscle cells, the RMP is the starting point for excitation‑contraction coupling. Even non‑excitable cells use the RMP to drive secondary active transport (e.g., glucose uptake via Na⁺‑dependent cotransporters).

Limits of the simple model

While the classic description focuses on K⁺, Na⁺, and Cl⁻, real cells also involve Ca²⁺, Mg²⁺, and numerous other ions. Moreover, membrane permeability is not static; it can be modulated by hormones, neurotransmitters, and pathological conditions. Finally, the Nernst and GHK equations assume constant temperature and ignore electrogenic contributions from other transporters (e.g., H⁺ pumps).

Check your understanding

Question: If a drug blocks the Na⁺/K⁺‑ATPase, what immediate effect would you expect on the resting membrane potential of a neuron, and why?

Answer: The RMP would become less negative (depolarize) because the pump’s electrogenic contribution (export of three Na⁺ for two K⁺) would cease, and K⁺ would continue to leak out, reducing the intracellular positive charge while the accumulation of Na⁺ inside further diminishes the charge difference.

Next step

Having learned why cells maintain a resting voltage, the logical continuation is to explore how that voltage rapidly changes during an action potential and how the changes are propagated along an axon.