Action Potential

The action potential (AP) is the rapid, transient, self-propagating reversal of membrane potential that allows excitable tissues (nerve, skeletal muscle, cardiac muscle, smooth muscle) to signal over distance. It is governed by voltage-gated ion channels obeying the all-or-none law, and forms the physiological substrate behind arrhythmias and antiarrhythmic drug action — a recurring NEET PG theme.

Definition & basic concepts

An action potential is a brief (~1 ms in nerve) all-or-none electrical signal generated when the membrane potential is depolarised to a threshold, triggering regenerative opening of voltage-gated Na⁺ (or Ca²⁺) channels.

Key baseline values to memorise:

Parameter	Typical value (neuron)	Notes
Resting membrane potential (RMP)	−70 mV	Set mainly by K⁺ (closest to E_K −90 mV)
Threshold	≈ −55 mV	Firing level; "point of no return"
Peak (overshoot)	+30 to +35 mV	Approaches E_Na (+60 mV)
Equilibrium potential E_Na	+60 mV	Per Nernst equation
Equilibrium potential E_K	−90 mV	Per Nernst equation
AP duration (nerve)	~1 ms	vs 200–300 ms in cardiac ventricle

The RMP is set by the high resting K⁺ permeability (leak K⁺ channels) and maintained by the Na⁺-K⁺ ATPase (3 Na⁺ out : 2 K⁺ in; electrogenic, contributes ~−4 mV directly). The ionic gradients themselves, however, are not consumed during a single AP — only a tiny fraction of ions cross.

High-yield: RMP is closest to the K⁺ equilibrium potential because resting membrane is most permeable to K⁺. The actual reversal/peak of the AP approaches E_Na because Na⁺ permeability transiently rises ~600-fold.

Phases of the nerve action potential

A stepwise sequence (flow):

Resting state (−70 mV) → Subthreshold depolarisation (local/graded potentials) → Threshold (−55 mV) reached → Rapid depolarisation/upstroke (voltage-gated Na⁺ channels open, Na⁺ influx) → Overshoot/peak (+30 mV) → Repolarisation (Na⁺ channels inactivate + voltage-gated K⁺ channels open, K⁺ efflux) → After-hyperpolarisation (undershoot) (delayed K⁺ channel closure, briefly < RMP) → Return to RMP.

Ionic conductance changes

1. Upstroke (depolarisation): Fast voltage-gated Na⁺ channels open. Na⁺ has two gates — an activation (m) gate that opens rapidly on depolarisation and an inactivation (h) gate that closes more slowly. The rapid opening of m-gates produces explosive Na⁺ influx (positive feedback → regenerative). Conductance g_Na rises sharply.
2. Repolarisation: Two events — (a) Na⁺ channel inactivation (h-gate closes), stopping influx, and (b) delayed opening of voltage-gated K⁺ channels (slow to open), driving K⁺ efflux. g_K rises as g_Na falls.
3. After-hyperpolarisation: K⁺ channels close sluggishly, so K⁺ permeability briefly exceeds resting levels, pushing V_m transiently towards E_K (more negative than RMP).

High-yield: Na⁺ channel has activation + inactivation gates; K⁺ (delayed rectifier) channel has only an activation gate. This single difference explains both the upstroke→repolarisation transition and the refractory periods.

All-or-none law & threshold

Once threshold is reached, the AP fires with a constant amplitude and shape regardless of stimulus strength — increasing stimulus strength does not increase AP size. Subthreshold stimuli produce only graded local potentials that decay. Information about stimulus intensity is therefore coded by frequency of firing (rate coding) and recruitment, not amplitude.

Feature	Graded (local) potential	Action potential
Amplitude	Variable (graded with stimulus)	Fixed (all-or-none)
Summation	Yes (temporal & spatial)	No
Propagation	Decremental (decays)	Non-decremental (regenerative)
Channels	Ligand/mechanical-gated	Voltage-gated
Refractory period	Absent	Present
Direction	Can be depolarising or hyperpolarising	Depolarising

Refractory periods

• Absolute refractory period (ARP): During upstroke and most of repolarisation. No stimulus, however strong, can elicit a second AP because Na⁺ channels are inactivated (h-gate shut) and cannot reopen until the membrane repolarises. Determines the maximum firing frequency and ensures unidirectional propagation.
• Relative refractory period (RRP): During late repolarisation/after-hyperpolarisation. A stronger-than-normal stimulus can trigger an AP because some Na⁺ channels have recovered, but K⁺ permeability is still high (membrane hyperpolarised). The resulting AP has a higher threshold and smaller amplitude.

High-yield: The ARP is due to Na⁺ channel inactivation, not closure. Recovery from inactivation requires repolarisation — this is why the refractory period prevents tetanic fusion in cardiac muscle and limits re-entry.

High-yield: ARP underlies the all-or-none + unidirectional conduction and sets the upper limit on impulse frequency.

Propagation & conduction velocity

In unmyelinated fibres the AP propagates by continuous (local circuit) conduction — local currents depolarise the adjacent membrane to threshold. In myelinated fibres, conduction is saltatory — the AP "jumps" between nodes of Ranvier (where Na⁺ channels are concentrated), greatly increasing speed and energy efficiency.

Factors increasing conduction velocity:

• Myelination (saltatory conduction)
• Larger fibre diameter (lower internal resistance)
• Higher temperature (up to a point)

High-yield: Conduction velocity ∝ fibre diameter and is dramatically increased by myelination. Demyelination (e.g. multiple sclerosis, Guillain–Barré) slows or blocks conduction.

Cardiac action potentials — the most tested comparison

Fast-response (ventricular/atrial myocyte, Purkinje) — 5 phases

• Phase 0 (upstroke): Fast Na⁺ influx (rapid depolarisation).
• Phase 1 (initial repolarisation): Transient outward K⁺ current (I_to) + Na⁺ inactivation.
• Phase 2 (plateau): Ca²⁺ influx via L-type (long-lasting) Ca²⁺ channels balanced by K⁺ efflux. This plateau is the hallmark of cardiac muscle and accounts for the long AP, long refractory period (prevents tetany) and electromechanical coupling.
• Phase 3 (repolarisation): K⁺ efflux (delayed rectifier I_Kr, I_Ks) dominates as Ca²⁺ channels close.
• Phase 4 (resting): Stable RMP maintained by I_K1 (inward rectifier).

Slow-response (SA node, AV node — pacemaker) — 3 phases

• Phase 4 (pacemaker potential / slow diastolic depolarisation): "Funny" current I_f (Na⁺ influx through HCN channels) + decreasing K⁺ → gradual drift to threshold. No stable resting potential — this gives automaticity.
• Phase 0 (upstroke): Ca²⁺ influx via L-type Ca²⁺ channels (slow), NOT Na⁺. Hence a slower, smaller upstroke.
• Phase 3 (repolarisation): K⁺ efflux.

Feature	Nerve / Skeletal	Cardiac ventricle (fast)	SA node (slow/pacemaker)
Phase 0 ion	Na⁺	Na⁺	Ca²⁺ (L-type)
Plateau (phase 2)	Absent	Present (Ca²⁺)	Absent
RMP/phase 4	Stable (−70/−90 mV)	Stable (−90 mV)	Unstable (pacemaker, ~−60 mV)
Duration	~1 ms	~200–300 ms	Intermediate
Automaticity	No	No	Yes (I_f funny current)
Refractory period	Short	Long (plateau)	Long

High-yield: SA/AV nodal phase 0 = L-type Ca²⁺ influx (slow channels) → explains why Ca²⁺ channel blockers (verapamil, diltiazem) slow nodal conduction. Pacemaker phase 4 = I_f funny current (HCN channel) → target of ivabradine (selective heart-rate reduction without affecting contractility).

Smooth muscle action potentials

Smooth muscle shows variable behaviour: some exhibit spike potentials, others slow waves (basal electrical rhythm) with superimposed spikes, and some show plateau-type potentials. The upstroke depends largely on Ca²⁺ influx (L-type Ca²⁺ channels) rather than Na⁺. Many visceral smooth muscles are spontaneously active (pacemaker activity via interstitial cells of Cajal in the gut). Latch-bridge mechanism allows sustained tone at low energy cost.

Effect of ion changes & drugs (clinical correlation)

Disturbance	Effect on excitable membrane
Hyperkalaemia	RMP less negative (partial depolarisation) → initial increased excitability, then Na⁺ channel inactivation → decreased excitability / cardiac arrest (peaked T waves → sine wave)
Hypokalaemia	Hyperpolarisation, prolonged repolarisation → U waves, arrhythmia risk
Hypocalcaemia	Lowers threshold → increased excitability (tetany, perioral tingling)
Hypercalcaemia	Raises threshold → decreased excitability, shortened QT
Hyponatraemia	Reduced AP amplitude (less Na⁺ available for upstroke)

High-yield: Calcium stabilises the membrane by raising the threshold (less excitable). Hence hypocalcaemia → hyperexcitability/tetany — counter-intuitive but a favourite MCQ.

Channel-blocking toxins & drugs

• Tetrodotoxin (TTX, pufferfish) & saxitoxin → block voltage-gated Na⁺ channels from outside → no AP.
• Tetraethylammonium (TEA) → blocks voltage-gated K⁺ channels → prolonged repolarisation.
• Local anaesthetics (lignocaine) → block Na⁺ channels (use-dependent), preferring the inactivated state.
• Class I antiarrhythmics → Na⁺ channel blockers; Class III (amiodarone, sotalol) → K⁺ blockers (prolong AP/QT); Class IV (verapamil/diltiazem) → Ca²⁺ blockers (nodal); Class II (β-blockers) → reduce phase 4 slope.

Mnemonic for Vaughan–Williams antiarrhythmics: "Some Block Potassium Channels" → Sodium (I), Beta-blocker (II), Potassium (III), Calcium (IV).

Excitation–contraction coupling (link to AP)

In skeletal muscle, the AP travels down T-tubules, activating dihydropyridine receptors (DHPR, voltage sensors) which are mechanically coupled to ryanodine receptors (RyR1) on the sarcoplasmic reticulum → Ca²⁺ release. In cardiac muscle, the plateau Ca²⁺ entry triggers calcium-induced calcium release (CICR) via RyR2 — extracellular Ca²⁺ is essential (unlike skeletal muscle).

High-yield: Skeletal muscle contraction does not require extracellular Ca²⁺ (mechanical DHPR–RyR coupling); cardiac muscle does (CICR). Classic distinguishing point.

Key differentials / things often confused

• Activation vs inactivation of Na⁺ channel: activation gate (m) opens fast on depolarisation; inactivation gate (h) closes slowly → terminates upstroke and causes ARP.
• Repolarisation vs hyperpolarisation: repolarisation returns towards RMP; after-hyperpolarisation overshoots below RMP due to persistent K⁺ efflux.
• Threshold vs firing level vs RMP: RMP −70, threshold/firing level −55, peak +30.
• Absolute vs relative refractory period (cause = inactivation vs partial recovery + raised threshold).
• Fast-response vs slow-response cardiac AP (Na⁺ vs Ca²⁺ phase 0).

Recently asked / exam angle

• Ion responsible for phase 0 of SA node AP → answer: Ca²⁺ (L-type), not Na⁺ (extremely common trap).
• Funny current (I_f) channel = HCN channel, drug = ivabradine.
• Cause of absolute refractory period → Na⁺ channel inactivation.
• RMP closest to which ion's equilibrium potential → K⁺.
• Plateau phase ion in ventricular myocyte → Ca²⁺ influx (L-type) balanced by K⁺.
• Hypocalcaemia → increased neuromuscular excitability (tetany) — explain via threshold lowering.
• TTX mechanism → voltage-gated Na⁺ channel blockade.
• Saltatory conduction site → nodes of Ranvier; basis = high Na⁺ channel density at nodes.
• Why cardiac muscle cannot be tetanised → long ARP due to plateau.
• Effect of hyperkalaemia on cardiac AP / ECG → peaked T waves, conduction block.

Rapid revision

1. RMP −70 mV, threshold −55 mV, peak +30 mV; nerve AP lasts ~1 ms.
2. Upstroke = voltage-gated Na⁺ influx; repolarisation = Na⁺ inactivation + delayed K⁺ efflux.
3. Na⁺ channel has activation + inactivation gates; K⁺ channel has only activation gate.
4. Absolute refractory period = Na⁺ channel inactivation → ensures all-or-none + unidirectional conduction.
5. Relative refractory period = stronger stimulus needed; membrane partly hyperpolarised.
6. RMP closest to E_K (−90); peak approaches E_Na (+60); Na⁺-K⁺ ATPase 3:2, electrogenic.
7. Myelinated fibres conduct by saltatory conduction at nodes of Ranvier; velocity ∝ diameter.
8. Ventricular AP: phase 2 plateau = L-type Ca²⁺ influx; gives long refractory period (no tetany).
9. SA node phase 0 = Ca²⁺ (slow); phase 4 pacemaker = I_f funny current (HCN) → ivabradine target.
10. Calcium raises threshold → hypocalcaemia causes hyperexcitability/tetany.
11. TTX/saxitoxin block Na⁺ channels; TEA blocks K⁺ channels; lignocaine blocks Na⁺ (use-dependent).
12. Skeletal muscle E-C coupling = mechanical DHPR–RyR1; cardiac = CICR needing extracellular Ca²⁺.