The Resting Membrane Potential

Every living cell maintains a voltage difference across its plasma membrane, called the membrane potential (Vₘ), defined as the electrical potential inside the cell minus the potential outside. In a "resting" neuron — one not currently firing an action potential or receiving strong synaptic input — this voltage settles at a stable value called the resting membrane potential, typically −60 to −70 mV in mammalian central neurons (often cited as −65 mV as a representative value; the classic squid giant axon rests near −60 mV). The negative sign means the cell interior is electrically negative relative to the extracellular fluid. This voltage is not caused by an overall charge imbalance in the bulk solutions — both intracellular and extracellular fluids are electrically neutral overall — but by a microscopically thin layer of excess negative charge lining the inner face of the membrane and excess positive charge lining the outer face, held apart by the lipid bilayer's insulating properties. The membrane behaves like a charged capacitor with ion channels acting as selective, leaky resistors in parallel. The resting potential arises from two facts working together. First, ion concentration gradients exist across the membrane: potassium (K⁺) is concentrated inside the cell, sodium (Na⁺) and calcium (Ca²⁺) are concentrated outside, and chloride (Cl⁻) is typically more concentrated outside. Second, the resting membrane is selectively permeable, meaning ions cross it at different rates depending on how many channels are open for each species. At rest, far more K⁺-selective "leak" channels are open than Na⁺ channels, so the membrane behaves electrically as though it were almost — but not quite — a pure potassium electrode. This concept connects directly to Ion Channels and Selective Permeability, which governs which ions can move at any moment, and to The Nernst Equation and Equilibrium Potentials, which quantifies the voltage a single ion gradient alone would produce.

Step 1 — The gradients are set up and maintained by active transport. The Na⁺/K⁺-ATPase (sodium-potassium pump), embedded in the plasma membrane, uses the energy of one ATP hydrolysis to export 3 Na⁺ ions and import 2 K⁺ ions per cycle, both against their concentration gradients. This pump runs continuously and is responsible for establishing the concentration gradients in the first place; without it, ions would eventually equilibrate and all electrical excitability would vanish. Because it moves 3 positive charges out for every 2 in, the pump is electrogenic, contributing a small direct hyperpolarizing current (typically only a few mV of the total resting potential), but its major contribution is indirect: maintaining the concentration gradients that drive diffusion potentials. Typical mammalian neuron concentrations (approximate, in mM):

Step 2 — At rest, K⁺ leak channels dominate membrane permeability. The resting membrane contains many open two-pore-domain K⁺ channels (K2P family) and other K⁺ leak channels, but relatively few open voltage-gated Na⁺ channels (most are closed at resting voltage). This means the resting membrane's permeability ratio strongly favors K⁺: a typical estimate is that resting P_K : P_Na : P_Cl is roughly 1 : 0.04 : 0.45 (values vary by cell type and are famously derived from Hodgkin and Katz's analysis of the squid axon).

Step 3 — K⁺ diffuses down its gradient, generating a separation of charge. Because K⁺ is concentrated inside, and K⁺ channels are open, K⁺ ions diffuse outward down their concentration gradient. Each K⁺ ion that leaves carries one positive charge out, leaving behind an uncompensated negative charge (from impermeant intracellular anions — proteins, organic phosphates) on the inner membrane face. This creates an electrical field across the membrane that opposes further K⁺ efflux: the growing internal negativity attracts K⁺ back inward electrostatically even as the concentration gradient continues pushing it outward.

Step 4 — Equilibrium for a single ion is reached at its Nernst potential. For K⁺ alone, net flux stops when the electrical force exactly balances the diffusional force. The voltage at which this balance occurs is the potassium equilibrium potential, E_K, given by the Nernst equation: E_K = (RT/zF) · ln([K⁺]_out / [K⁺]_in) With [K⁺]_out = 5 mM, [K⁺]_in = 140 mM, z = +1, and RT/F ≈ 26.7 mV at human body temperature (37°C), this gives E_K ≈ −91 mV. Using the simplified form at room temperature (58 mV/decade, log base 10) gives a similar estimate near −90 mV.

Step 5 — Because the membrane is not perfectly K⁺-selective, Vₘ sits somewhat positive of E_K. If the membrane were permeable only to K⁺, Vₘ would equal E_K exactly. But a small resting Na⁺ permeability lets Na⁺ leak in continuously, dragging Vₘ away from E_K toward E_Na (which is strongly positive, around +60 mV given [Na⁺]_out = 145, [Na⁺]_in = 15). Chloride, often near its own equilibrium passively, contributes further. The Goldman-Hodgkin-Katz (GHK) equation combines all permeant ions weighted by their relative permeabilities: Vₘ = (RT/F) · ln [ (P_K[K⁺]_out + P_Na[Na⁺]_out + P_Cl[Cl⁻]_in) / (P_K[K⁺]_in + P_Na[Na⁺]_in + P_Cl[Cl⁻]_out) ] (Note chloride terms are inverted relative to cations because Cl⁻ carries negative charge.) Plugging in typical values and P_K : P_Na : P_Cl ≈ 1 : 0.04 : 0.45 yields Vₘ ≈ −65 to −70 mV, matching experimental measurements far better than the K⁺-only Nernst prediction.

Step 6 — The system is a steady state, not a true equilibrium. Because Na⁺ continuously leaks in and K⁺ continuously leaks out, the concentration gradients would slowly run down if left unchecked. The Na⁺/K⁺ pump continuously counteracts this leak, actively re-exporting the Na⁺ that entered and re-importing the K⁺ that left. The resting potential is therefore a dynamic steady state sustained by ongoing ATP expenditure — not a passive equilibrium the cell would reach and stay at forever without energy input. Blocking the pump (e.g., with the cardiac glycoside ouabain) does not instantly collapse Vₘ, but the gradients slowly dissipate and the resting potential eventually decays toward zero.

The resting potential's ionic basis was not established by armchair reasoning; it required precise electrical recordings from single cells, which was extraordinarily difficult before the mid-twentieth century because neurons are microscopic. The breakthrough came from an unusual animal: the squid giant axon, discovered to be suitable for electrophysiology by J. Z. Young in the 1930s. This axon, which controls the squid's escape jet response, can be up to 1 mm in diameter — roughly 100 times wider than a typical mammalian axon — because giant axon diameter increases conduction velocity, and large diameter made it possible to insert a wire electrode directly down the inside of the axon.

Cole and Curtis (1939) and, working independently in England, Hodgkin and Huxley (1939), inserted fine glass or wire electrodes longitudinally into the giant axon of the squid Loligo while it was bathed in seawater, and measured the voltage between the internal electrode and a reference electrode in the bathing fluid. They recorded a stable resting potential of roughly −60 to −70 mV, inside negative — the first direct intracellular measurement of a resting membrane potential in an excitable cell. This confirmed, for the first time with a real number rather than inference, that living axon membranes hold a substantial steady voltage even when not conducting impulses. The second crucial piece of evidence came from Alan Hodgkin and Bernard Katz (1949), who tested whether this resting voltage behaved as predicted by ionic theory. They systematically varied the external sodium and potassium concentrations bathing the squid axon and measured the resulting change in resting (and action) potential. Key findings:

• Raising external K⁺ concentration made the resting potential less negative (depolarized), in close quantitative agreement with the Nernst prediction for K⁺ — strong evidence that resting Vₘ tracks E_K.
• The relationship was not perfectly linear with the K⁺ Nernst prediction at very low external K⁺, deviating in the direction expected if a small Na⁺ permeability were also present — exactly what the GHK equation, which Hodgkin, Katz, and David Goldman (1943, theoretical derivation) predicted.
• Reducing external Na⁺ had little effect on the resting potential (confirming low resting P_Na) but dramatically reduced the action potential overshoot, showing Na⁺ was responsible for the depolarizing spike rather than the resting state.

Together these experiments — direct intracellular recording plus systematic ion-substitution — established the two pillars of the resting potential: that a real, sizable transmembrane voltage exists, and that it is quantitatively predictable from ionic concentration gradients weighted by relative membrane permeability, exactly as the Nernst and Goldman equations describe. This body of work, along with the subsequent voltage-clamp experiments of Hodgkin and Huxley (1952) dissecting the action potential itself, earned Hodgkin and Huxley the 1963 Nobel Prize in Physiology or Medicine (shared with John Eccles). A complementary, later line of evidence came from patch-clamp recording, developed by Erwin Neher and Bert Sakmann in the late 1970s, which allowed direct measurement of current flowing through single ion channels. Patch-clamp studies confirmed that resting membranes contain open K⁺-selective leak channels conducting steady outward current at rest, directly visualizing the very channels the ionic theory had inferred indirectly decades earlier. Neher and Sakmann received the 1991 Nobel Prize for this technique.

Example 1 — Calculating E_K and comparing it to measured Vₘ. A cortical pyramidal neuron has [K⁺]_in = 140 mM and [K⁺]_out = 4 mM, and is held at physiological temperature (37°C, so RT/F = 26.7 mV, and the base-10 form uses 61.5 mV per decade). Using the Nernst equation: E_K = 61.5 mV × log₁₀(4/140) = 61.5 × log₁₀(0.0286) = 61.5 × (−1.544) ≈ −95 mV Suppose the neuron's actual measured resting potential is −70 mV, some 25 mV positive of E_K. This gap is the signature of the small but nonzero Na⁺ (and Cl⁻) permeability pulling Vₘ away from a pure-K⁺ equilibrium. Using the GHK equation with [Na⁺]_in = 15 mM, [Na⁺]_out = 145 mM, and a resting P_Na/P_K ratio of about 0.04: Vₘ = 61.5 × log₁₀[ (145 × 0.04 + 4) / (15 × 0.04 + 140) ] = 61.5 × log₁₀[ (5.8+4)/(0.6+140) ] = 61.5 × log₁₀(9.8/140.6) = 61.5 × log₁₀(0.0697) = 61.5 × (−1.157) ≈ −71 mV This is very close to the measured −70 mV, illustrating why the GHK equation (which incorporates multiple ions and their relative permeabilities) predicts real resting potentials far better than the Nernst equation for K⁺ alone.

Example 2 — Clinical scenario: hyperkalemia and cardiac risk. A patient in renal failure has serum K⁺ elevated from the normal ~4 mM to 8 mM (hyperkalemia), while intracellular K⁺ remains near 140 mM (intracellular stores are large and change slowly). What happens to cardiac muscle cell resting potential, and why is this dangerous? Using the Nernst equation at 37°C: E_K (normal) = 61.5 × log₁₀(4/140) ≈ −95 mV E_K (hyperkalemic) = 61.5 × log₁₀(8/140) = 61.5 × log₁₀(0.0571) = 61.5 × (−1.243) ≈ −76 mV Raising external K⁺ from 4 to 8 mM shifts E_K by about +19 mV, making the resting potential substantially less negative (depolarized) — because a smaller outward K⁺ concentration gradient means less electrical force is needed to balance it. Since resting Vₘ tracks E_K closely, cardiac cell resting potential depolarizes similarly, from roughly −90 mV toward −70 mV. This partial depolarization is clinically dangerous for a non-obvious reason: it does not simply make cells "more excitable." Persistent depolarization instead inactivates a large fraction of voltage-gated Na⁺ channels (which require repolarization to recover from inactivation), reducing the number of channels available to fire the next action potential. The result is slowed cardiac conduction, widened QRS complexes on ECG, and risk of life-threatening arrhythmias or asystole — precisely why hyperkalemia is treated urgently with calcium gluconate (to stabilize the membrane), insulin/glucose, and dialysis (to actually remove excess K⁺).

Alan Lloyd Hodgkin was a Cambridge physiologist whose meticulous, quantitative approach to nerve function transformed a qualitative idea — "the membrane is a battery" — into a precise, testable mathematical theory. Working with the squid giant axon at the Marine Biological Laboratory in Plymouth, Hodgkin combined careful electrode craftsmanship with rigorous physical reasoning, treating the axon membrane as a genuine electrical circuit with measurable conductances and capacitance. His long collaboration with Andrew Huxley, interrupted by wartime radar research, resumed after 1945 and culminated in the voltage-clamp experiments that dissected the ionic basis of both the resting and action potentials.

The resting membrane potential is not a historical curiosity confined to squid axons — it is a live variable in modern medicine, pharmacology, and biotechnology. Local anesthetics (lidocaine, procaine) work by blocking voltage-gated Na⁺ channels, but their efficacy depends on the resting potential setting the baseline from which channels can be reached and inactivated. Cardiac arrhythmia management depends heavily on resting potential physiology: potassium-sparing diuretics, ACE inhibitors, and dialysis all risk perturbing serum K⁺ and therefore E_K and resting Vₘ, with direct arrhythmia consequences as shown in the hyperkalemia example above. General anesthetics and antiepileptic drugs frequently act by enhancing K⁺ leak conductance or GABA-mediated Cl⁻ conductance, hyperpolarizing neurons toward E_K or E_Cl to dampen excitability. In neurodegeneration and stroke research, the collapse of resting potential during ischemia (as ATP runs out and the Na⁺/K⁺ pump fails) triggers "anoxic depolarization," a cascade implicated in excitotoxic cell death; drugs targeting this cascade are active areas of stroke therapeutics. In biotechnology, optogenetic and chemogenetic tools (channelrhodopsins, DREADDs) are engineered specifically to shift Vₘ away from or toward rest, hijacking the same ionic logic described here to control neurons experimentally. In agriculture and toxicology, pesticides and natural toxins (tetrodotoxin, batrachotoxin, various plant alkaloids) target the very channels that set resting permeability, informing both pest control chemistry and antidote design. Understanding the resting potential is foundational preparation for Ion Channels and Selective Permeability and The Nernst Equation and Equilibrium Potentials, the concepts that explain, respectively, which channels are open at rest and how each ion's own equilibrium voltage is calculated — together completing the machinery behind every subsequent electrical signal a neuron produces.

Ask the tutor: How does the resting potential set the stage for the depolarizing phase of an action potential, and why does raising external K⁺ affect resting Vm so much more than raising external Na⁺?