The Resting Potential
−70 mV — the electrochemical baseline
Before an action potential can fire, the neuron must maintain a resting membrane potential of approximately −70 mV (inside negative relative to outside). This potential is established and maintained by the unequal distribution of ions across the plasma membrane and the selective permeability of the membrane to those ions.
The key ion gradients: Na⁺ is high outside (145 mM) and low inside (12 mM) — both the concentration gradient and the electrical gradient (negative inside) drive Na⁺ in, but the membrane at rest is relatively impermeable to Na⁺. K⁺ is high inside (140 mM) and low outside (5 mM) — the concentration gradient drives K⁺ out, but the electrical gradient (negative inside attracts positive K⁺) drives it in. At rest, K⁺ permeability is much higher than Na⁺ permeability. The K⁺ equilibrium potential (~−90 mV) and the Na⁺ equilibrium potential (~+60 mV) are balanced by the Na⁺/K⁺ ATPase pump (3 Na⁺ out, 2 K⁺ in) at −70 mV.
💡 All-or-Nothing Law and Coding of Signal Intensity
The action potential obeys the all-or-nothing law: once threshold is reached, the action potential fires at full amplitude regardless of how strong the stimulus is. A suprathreshold stimulus does not produce a larger action potential than a threshold stimulus.
If action potentials are all the same size, how does the nervous system encode stimulus intensity? Through frequency coding: a stronger stimulus causes the neuron to fire action potentials more rapidly (higher frequency). A weak but suprathreshold stimulus might produce 10 action potentials per second; a strong stimulus might produce 100 per second. The brain interprets higher frequency as a stronger signal.
Population coding also contributes: a strong stimulus recruits more neurons (lower threshold neurons fire first, higher threshold neurons added as stimulus increases), so signal intensity is also encoded by how many neurons are firing simultaneously.
Ph1
Depolarization — Na⁺ rushes in
When a stimulus depolarizes the membrane to threshold (~−55 mV), voltage-gated Na⁺ channels open rapidly. Na⁺ floods into the cell down its steep electrochemical gradient → membrane potential rises rapidly from −55 mV toward +30 mV (the peak of the action potential). This is a positive feedback process — depolarization opens more Na⁺ channels, which causes more depolarization, which opens more channels (the Hodgkin cycle). The rising phase is extremely rapid (less than 1 millisecond).
The action potential rises toward but never quite reaches the Na⁺ equilibrium potential (+60 mV) because Na⁺ channels begin inactivating before full equilibrium is reached.
Memory trick: Depolarization = Na⁺ IN. Threshold opens voltage-gated Na⁺ channels → Na⁺ floods in → inside becomes positive. 'De-' means removing the negative — Na⁺ rushing in makes the inside positive.
Ph2
Repolarization — K⁺ rushes out
At the peak of the action potential (+30 mV), two things happen simultaneously: voltage-gated Na⁺ channels inactivate (the inactivation gate closes, preventing further Na⁺ entry — this is distinct from the activation gate that opened during depolarization) and voltage-gated K⁺ channels open (they open more slowly than Na⁺ channels — this delay is why depolarization precedes repolarization). K⁺ rushes out of the cell down its concentration gradient → membrane potential falls back toward the resting level. This is repolarization.
Memory trick: Repolarization = K⁺ OUT. Na⁺ channels inactivate, K⁺ channels open → K⁺ rushes out → inside returns to negative. 'Re-' means restoring the original polarity.
Ph3
Hyperpolarization and the refractory period
K⁺ channels remain open slightly longer than needed to restore −70 mV → K⁺ continues to leave → membrane hyperpolarizes briefly to approximately −80 mV (closer to K⁺ equilibrium potential). This is the afterhyperpolarization.
During the absolute refractory period (the duration of Na⁺ channel inactivation), no stimulus can trigger another action potential — the Na⁺ channels are inactivated and cannot open again until repolarization returns them to their resting (closed but available) state. During the relative refractory period (afterhyperpolarization), a stronger-than-normal stimulus can fire an action potential because the membrane is hyperpolarized (further from threshold).
The refractory period ensures that action potentials travel in one direction (cannot travel backward, because the membrane just behind the advancing wavefront is refractory) and limits the maximum firing frequency of neurons.
Memory trick: Hyperpolarization = overshooting the return (K⁺ channels slow to close). Absolute refractory = impossible to fire (Na⁺ channels inactivated). Relative refractory = possible but harder. Refractory = unidirectional propagation.
🔬 Clinical Scenario — Local Anesthetics and Ion Channels
Local anesthetics work by directly blocking voltage-gated Na⁺ channels:
A
Mechanism of local anesthetics. Local anesthetics (lidocaine, bupivacaine, procaine) are weak bases that enter the axon in their uncharged form, then become protonated inside the axon and bind to the inner surface of the voltage-gated Na⁺ channel. Binding blocks the channel → Na⁺ cannot flow → action potentials cannot propagate → no signal reaches the brain → no pain sensation.
B
Use-dependent block. Local anesthetics bind more effectively to Na⁺ channels that are open or inactivated (channels that have recently been firing). Frequently firing C-fibers (pain fibers) are blocked more easily than less active A-β fibers (touch). This is why a dental injection numbs pain before it fully numbs touch — pain fibers fire more and are blocked first.
C
Differential nerve block and fiber diameter. Smaller diameter, unmyelinated C-fibers (pain, temperature) are blocked at lower anesthetic concentrations than larger myelinated A-α fibers (proprioception, motor). This explains why epidural anesthesia in labor can eliminate pain while preserving some motor function if the concentration is carefully titrated.
D
Cardiac arrhythmias — Na⁺ channel mutations. Brugada syndrome is caused by loss-of-function mutations in SCN5A (the cardiac voltage-gated Na⁺ channel gene) → reduced Na⁺ current → abnormal ventricular depolarization → ventricular fibrillation → sudden cardiac death. Long QT syndrome type 3 is caused by gain-of-function SCN5A mutations → persistent late Na⁺ current → prolonged action potential duration → arrhythmia. Both illustrate how Na⁺ channel function is critical beyond the nervous system.
📌 Exam Application
Action potential questions test phases, ion movements, and clinical connections:
1. Four phases in order: Depolarization (Na⁺ in, threshold to +30 mV), Repolarization (K⁺ out, +30 mV back to −70 mV), Hyperpolarization (K⁺ channels slow to close, overshoots to −80 mV), Recovery (return to −70 mV, Na⁺ channels reset).
2. Ion movements: Depolarization = Na⁺ IN. Repolarization = K⁺ OUT. Na⁺/K⁺ pump restores gradients (not needed for individual action potential — the gradients are barely disturbed by one AP).
3. Refractory periods: Absolute (Na⁺ channels inactivated, no AP possible). Relative (hyperpolarized, stronger stimulus needed). Both ensure unidirectional propagation.
4. All-or-nothing law: Action potential amplitude is constant — intensity coded by frequency and number of active neurons.
5. Local anesthetics: Block voltage-gated Na⁺ channels from inside. Use-dependent. Block small pain fibers before large motor fibers.
⚠️ The Most Common Action Potential Mistakes
Na⁺ channels have TWO gates — activation and inactivation. Students often describe the refractory period simply as 'the channel is closed.' But there are two gates: the activation gate (opens during depolarization, closes during repolarization) and the inactivation gate (closes during the peak of the action potential, preventing further Na⁺ entry). During the absolute refractory period, the activation gate is closed AND the inactivation gate is closed (channel is inactivated). The channel cannot open again until repolarization causes the inactivation gate to reopen (reset) — this takes a few milliseconds. This dual-gate mechanism is why local anesthetics that bind to the inactivated state are particularly effective.
K⁺ channels open during repolarization — not depolarization. Both Na⁺ and K⁺ channels are voltage-gated, but they have different kinetics. Na⁺ channels open rapidly at threshold (fast activation). K⁺ channels open more slowly, reaching peak conductance only as the action potential peaks — which is why repolarization follows (not accompanies) depolarization.
The Na⁺/K⁺ pump is not needed for each action potential — just for long-term maintenance. Each individual action potential causes only a tiny change in ion concentrations (because so few ions move relative to the total). Neurons can fire thousands of times before ion gradients are significantly depleted. The Na⁺/K⁺ pump continuously restores gradients but is not required for the moment-to-moment action potential mechanism.
✓ Quick Self-Test
1. What is the resting membrane potential and what ion gradients maintain it?
2. Describe the ion movements during each phase of the action potential.
3. What is the absolute refractory period and why does it ensure unidirectional propagation?
4. How do local anesthetics block pain?
5. What does the all-or-nothing law mean, and how does the nervous system encode stimulus intensity?
Answers:
1. The resting membrane potential is approximately −70 mV (inside negative). Maintained by: high intracellular K⁺ (140 mM) and high extracellular Na⁺ (145 mM) established by the Na⁺/K⁺ ATPase pump; high resting K⁺ permeability (K⁺ leaks out, bringing membrane toward K⁺ equilibrium potential of −90 mV); low resting Na⁺ permeability; and electrostatic attraction keeping K⁺ inside and Cl⁻ outside.
2. Depolarization: voltage-gated Na⁺ channels open → Na⁺ rushes in → membrane goes from −70 mV to +30 mV. Repolarization: Na⁺ channels inactivate; voltage-gated K⁺ channels open → K⁺ rushes out → membrane returns toward −70 mV. Hyperpolarization: K⁺ channels slow to close → membrane overshoots to ~−80 mV. Recovery: K⁺ channels close, Na⁺ channel inactivation gates reset → membrane returns to −70 mV.
3. The absolute refractory period is the period during and immediately after an action potential when no stimulus, however strong, can trigger another AP. It occurs because Na⁺ channels are in the inactivated state (inactivation gate closed) and cannot open again until repolarization resets them. Unidirectional propagation: the membrane behind the advancing wavefront is in the absolute refractory period (just fired) and cannot be re-excited, so the action potential can only propagate forward.
4. Local anesthetics (lidocaine, bupivacaine) diffuse across the axon membrane in their uncharged form, then become protonated inside and bind to the inner surface of voltage-gated Na⁺ channels. Binding blocks Na⁺ flow through the channel → action potentials cannot be generated or propagated → pain signals do not reach the brain → no pain sensation.
5. The all-or-nothing law states that action potentials always fire at the same maximum amplitude once threshold is reached — a stronger stimulus does not produce a larger action potential. The nervous system encodes stimulus intensity through frequency coding (stronger stimulus → higher action potential firing frequency per neuron) and population coding (stronger stimulus recruits more neurons simultaneously).