Resting Membrane Potential

The steady electrical potential difference across an unstimulated cell membrane (inside negative relative to outside). For a typical mammalian neuron it is about −70 mV; for skeletal muscle about −90 mV. It is the baseline from which every action potential, synaptic event and receptor response is generated, so it is foundational physiology.

Definition and the core idea

The resting membrane potential (RMP) is the voltage measured inside a living cell, by convention referenced to the extracellular fluid set at 0 mV. Because the cell interior is electronegative, RMP values are written as negative numbers (−70, −90 mV, etc.).

Two facts must be held together:

1. The membrane is selectively permeable — at rest it is far more permeable to K⁺ than to Na⁺ (roughly 50–100:1 for K⁺ over Na⁺).
2. There are standing ionic concentration gradients set up and maintained by the Na⁺-K⁺ ATPase.

High-yield: RMP exists because the resting membrane is dominantly permeable to potassium, so the membrane potential sits close to (but not exactly at) the potassium equilibrium potential (E_K ≈ −90 mV).

The RMP is not the equilibrium potential of any single ion. It is a weighted average dominated by K⁺, dragged slightly positive (less negative) by a small leak of Na⁺.

Typical ionic concentrations (mammalian neuron)

Ion	Intracellular (mM)	Extracellular (mM)	Ratio (out:in)	Nernst potential (37 °C)
K⁺	140	4	~1:35	−94 mV
Na⁺	14	142	~10:1	+60 mV
Cl⁻	4–10	103–110	~10–25:1	−70 to −90 mV
Ca²⁺	0.0001 (free)	1.2–2.5	very high	+120 to +140 mV
A⁻ (organic anions/proteins)	155	5	—	impermeant (trapped inside)

High-yield: Large intracellular organic anions (proteins, phosphates, sulphates) cannot cross the membrane. They contribute to interior negativity and to the Gibbs–Donnan effect.

Ionic basis and pathophysiology of the potential

1. The Nernst equation (single-ion equilibrium potential)

The Nernst equation gives the membrane voltage at which the electrical force exactly balances the concentration (diffusion) force for one ion, so net flux is zero — the equilibrium potential.

At body temperature (37 °C) for a univalent ion the simplified form is:

E_ion = (61 / z) × log₁₀ ([ion]_out / [ion]_in) (mV)

• z = valency (+1 for Na⁺/K⁺, −1 for Cl⁻, +2 for Ca²⁺)
• 61 mV is the constant at 37 °C (it is 58–59 mV at room temperature ~20–25 °C; the classic textbook value at 37 °C is ~61.5 mV).

Worked logic for K⁺: high inside, low outside → K⁺ diffuses out, leaving the inside negative until the build-up of negativity stops further net efflux. That balance point is E_K ≈ −90 to −94 mV.

For Na⁺: high outside → Na⁺ would diffuse in; equilibrium needs the inside to be strongly positive, so E_Na ≈ +60 mV.

High-yield: The Nernst equation handles one ion at a time and tells you its equilibrium (reversal) potential. If RMP were set by K⁺ alone, it would equal E_K. The small gap between observed RMP (−70) and E_K (−90) is explained by Na⁺ leak.

2. The Goldman–Hodgkin–Katz (GHK) equation (multi-ion)

The actual RMP is determined by all permeant ions weighted by their permeabilities (P). The GHK constant-field equation:

V_m = 61 × log₁₀ ( [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 Cl⁻ flips (in over out) because it is an anion.

• When P_K ≫ P_Na, V_m → E_K (the resting state).
• During an action potential, P_Na transiently rises ~600-fold, so V_m → E_Na (depolarisation toward +60 mV).

High-yield: GHK = "weighted Nernst." The ion with the highest permeability dominates the membrane potential. The membrane potential always moves toward the equilibrium potential of whichever ion has just become most permeable.

Flow of how RMP is established:

Na⁺-K⁺ ATPase builds gradients → K⁺ high inside, Na⁺ high outside → membrane mostly K⁺-permeable (leak channels open) → K⁺ diffuses out down its gradient → interior becomes negative → negativity opposes further K⁺ exit → near-equilibrium reached close to E_K → small steady Na⁺ leak inward makes RMP slightly less negative than E_K → steady −70 mV.

3. The Na⁺-K⁺ ATPase (sodium pump)

A P-type ATPase that hydrolyses 1 ATP to pump 3 Na⁺ out and 2 K⁺ in per cycle. Because it moves 3 positive charges out for every 2 brought in, it is electrogenic — it directly contributes a few millivolts (about −4 to −11 mV) of extra negativity.

Two roles:

• Indirect (major): maintains the Na⁺ and K⁺ gradients that the leak channels and the GHK relationship depend on. Without it, gradients run down and RMP collapses toward 0.
• Direct (minor): electrogenic contribution to the resting voltage.

High-yield: The pump is inhibited by cardiac glycosides (digoxin, ouabain). Inhibition → rise in intracellular Na⁺ → less Na⁺/Ca²⁺ exchange → intracellular Ca²⁺ rises → positive inotropy. This links RMP physiology to cardiac pharmacology, a favourite exam bridge.

Mnemonic — pump stoichiometry "3 out, 2 in, OUT-numbered makes it electrogenic": 3 Na⁺ OUT, 2 K⁺ IN; the extra cation leaving keeps the inside negative.

4. The Gibbs–Donnan equilibrium

Impermeant intracellular anions (proteins) attract diffusible cations and repel diffusible anions, producing an unequal but predictable distribution of permeant ions and an osmotic tendency to swell. The product of diffusible ion concentrations is equal on the two sides at Donnan equilibrium ([K⁺]_in × [Cl⁻]_in = [K⁺]_out × [Cl⁻]_out). The Na⁺ pump counteracts the Donnan-driven osmotic swelling — the "pump-leak" or double-Donnan hypothesis of cell volume control.

High-yield: Gibbs–Donnan explains why, even before metabolic pumping is considered, the membrane potential is non-zero and why cells would swell and burst if the Na⁺ pump failed (e.g., in hypoxia/ischaemia).

Factors that change the resting membrane potential

Change	Effect on RMP	Mechanism / exam relevance
↑ Extracellular K⁺ (hyperkalaemia)	Depolarises (less negative)	Reduces K_out:K_in ratio → E_K less negative → RMP rises toward threshold; sustained depol inactivates Na⁺ channels → cardiac arrest, peaked T waves
↓ Extracellular K⁺ (hypokalaemia)	Hyperpolarises (more negative)	Higher K⁺ ratio → E_K more negative; cells harder to excite, U waves, arrhythmia
Na⁺-K⁺ ATPase block (digoxin, hypoxia, ouabain)	Gradual depolarisation	Gradients run down
↑ Membrane K⁺ permeability (e.g., ACh on SA node via GIRK)	Hyperpolarises	Moves V_m closer to E_K
Acidosis/hypoxia	Depolarises	ATP depletion → pump fails

High-yield: RMP is far more sensitive to extracellular K⁺ than to extracellular Na⁺, because resting permeability to K⁺ dominates the GHK equation. This is why hyperkalaemia is rapidly cardiotoxic but modest sodium changes are not membrane-lethal.

Clinical / functional correlates

• Excitability and threshold: A neuron fires when depolarised from −70 to about −55 mV (threshold). The distance between RMP and threshold sets excitability. Hyperkalaemia narrows the gap initially (hyperexcitable), then inactivates Na⁺ channels (inexcitable, paralysis/arrest).
• Driving force: The electrochemical driving force on an ion = (V_m − E_ion). At rest, Na⁺ has a huge inward driving force (−70 − (+60) = −130 mV) but tiny permeability, so little flows.
• Cardiac tissue: Ventricular myocytes have a stable RMP (~−90 mV) maintained by I_K1 (inward rectifier). Pacemaker (SA/AV) cells lack a true stable RMP — they have the funny current (I_f, HCN channels) causing slow diastolic depolarisation, hence automaticity.
• Skeletal vs smooth muscle: Skeletal muscle ~−90 mV (stable); smooth muscle ~−50 to −60 mV (less negative, less K⁺-dominant, often unstable with slow waves).

High-yield: Inward rectifier K⁺ channels (Kir/I_K1) are chiefly responsible for setting and holding the resting potential in cardiac and skeletal muscle. "Leak"/two-pore-domain K⁺ channels (K2P, e.g., TASK/TREK) do the same in neurons.

Diagnosis / how RMP is measured (investigation of choice)

• Intracellular microelectrode (sharp glass micropipette) referenced to a bath electrode — the classical method; gives a direct mV reading.
• Patch-clamp (whole-cell configuration) — modern gold standard for membrane potential and single-channel currents; Neher and Sakmann, Nobel Prize 1991.
• Voltage-sensitive dyes / optical mapping — for tissue-level relative changes.

High-yield (eponym): Hodgkin & Huxley (squid giant axon, voltage clamp) elucidated the ionic basis of RMP and the action potential — Nobel Prize 1963 (with Eccles).

Management / "drug-of-choice" links

There is no "treatment" for a normal RMP, but exam questions test agents that act through it:

• Hyperkalaemia (RMP depolarised, cardiotoxic): IV calcium gluconate is first to stabilise the myocardial membrane (raises threshold, restoring the RMP–threshold gap) — it does not lower K⁺. Then insulin + glucose, salbutamol (shift K⁺ in via Na⁺-K⁺ ATPase stimulation), and finally removal (diuretics, dialysis, binders).
• Digoxin: therapeutic Na⁺ pump inhibition for inotropy/rate control; toxicity worsened by hypokalaemia (less competition for the pump's K⁺ site).
• Local anaesthetics / antiarrhythmics: act on Na⁺ channels, but their effect depends on the RMP-determined fraction of channels in resting vs inactivated states (state-dependent block — relevant to Class I antiarrhythmics).

Complications / consequences of deranged RMP

• Hyperkalaemic cardiac arrest: sustained depolarisation → Na⁺ channel inactivation → wide QRS → sine wave → asystole/VF.
• Periodic paralysis: hyper- and hypokalaemic periodic paralyses — channelopathies altering RMP and excitability.
• Ischaemic depolarisation: ATP loss → pump failure → cell swelling, Ca²⁺ overload, anoxic depolarisation in stroke.
• Hypocalcaemia (tetany): low extracellular Ca²⁺ destabilises Na⁺ channels lowering the firing threshold (membrane "leakier"/more excitable) — note this is a threshold effect, RMP itself changes little.

Key differentials / concept confusions

Concept	What it is	Common confusion
Equilibrium potential (Nernst)	Voltage where one ion's net flux = 0	Not the RMP; RMP ≠ E_K exactly
Resting membrane potential (GHK)	Weighted steady potential of all permeant ions	Dominated by K⁺, not equal to any single E_ion
Threshold potential	Voltage at which an AP is triggered (~−55 mV)	Different from RMP; gap = excitability
Reversal potential	V_m at which current through a channel reverses direction	Equals E_ion for a single-ion channel
Action potential	Transient large reversal of V_m	Caused by sudden ↑P_Na (V_m → E_Na)

High-yield: When only one ion is permeant, RMP = that ion's Nernst potential. When multiple ions are permeant, use GHK. Examiners love asking which equation applies — the trigger word is "permeable to several ions" (GHK) vs "equilibrium potential of X" (Nernst).

Recently asked / exam angle

• Direct recall: "Resting membrane potential of a neuron is about?" → −70 mV (skeletal muscle −90 mV; SA node has no stable RMP).
• Mechanism MCQ: "RMP is mainly determined by?" → K⁺ permeability / K⁺ diffusion potential, maintained by Na⁺-K⁺ ATPase.
• Equation identification: A stem giving permeabilities of K⁺, Na⁺ and Cl⁻ → answer is Goldman (GHK) equation; a stem asking the potential for a single ion → Nernst.
• Pump stoichiometry: "Na⁺-K⁺ ATPase transports?" → 3 Na⁺ out, 2 K⁺ in, electrogenic, inhibited by ouabain/digoxin.
• Clinical bridge: "Effect of hyperkalaemia on RMP?" → partial depolarisation (RMP less negative); ECG peaked T waves; treat with IV calcium gluconate first for membrane stabilisation.
• Channel question: "Channel responsible for maintaining cardiac RMP?" → inward rectifier K⁺ channel (I_K1); neuronal resting leak → K2P channels.
• Calculation: Given [K]_in 150, [K]_out 5, compute E_K → 61 × log(5/150) = 61 × log(0.0333) = 61 × (−1.477) ≈ −90 mV.
• Temperature trap: the Nernst constant is ~61 mV at 37 °C but ~58–59 mV at room temperature — watch which the stem specifies.

Rapid revision

1. Neuronal RMP ≈ −70 mV; skeletal muscle −90 mV; SA/AV node has no stable RMP (I_f/HCN drive automaticity).
2. RMP is set chiefly by K⁺ permeability and sits near, but slightly positive to, E_K (−90 mV) due to Na⁺ leak.
3. Nernst = equilibrium potential of one ion; GHK/Goldman = weighted potential of all permeant ions (K⁺, Na⁺, Cl⁻).
4. Nernst at 37 °C: E = (61/z) log([out]/[in]) → E_K ≈ −90, E_Na ≈ +60, E_Ca ≈ +120 to +140 mV.
5. Na⁺-K⁺ ATPase: 3 Na⁺ out / 2 K⁺ in per ATP; electrogenic; maintains gradients; blocked by digoxin/ouabain.
6. Inward rectifier K⁺ (I_K1) holds cardiac/skeletal RMP; K2P leak channels hold neuronal RMP.
7. RMP is far more sensitive to extracellular K⁺ than Na⁺; hyperkalaemia depolarises, hypokalaemia hyperpolarises.
8. Hyperkalaemia → RMP less negative → Na⁺ channel inactivation → cardiac arrest; treat with IV calcium gluconate first (stabilises membrane).
9. Gibbs–Donnan: impermeant intracellular proteins cause unequal ion distribution and osmotic swelling, opposed by the Na⁺ pump (pump-leak hypothesis).
10. Membrane potential always moves toward the E_ion of whichever ion is most permeable at that moment.
11. Hodgkin–Huxley (squid axon, voltage clamp, Nobel 1963); patch-clamp Neher–Sakmann (Nobel 1991) is the gold-standard measurement.
12. Threshold ≈ −55 mV; the RMP-to-threshold gap defines excitability — not the same thing as the resting potential itself.