Action Potential

An action potential (also termed a nerve impulse or spike) is a rapid, transient, all-or-none, self-regenerating reversal of the transmembrane electrical potential (V_m) that propagates along the plasma membrane of excitable cells. While present in all animal neurons, skeletal myocytes, cardiac myocytes, and neuroendocrine cells—as well as in specialized plant tissues such as the mechanosensory traps of Dionaea muscipula and the giant internodal cells of charophyte algae (Chara corallina)—action potentials serve as the universal biophysical currency for rapid long-distance information transmission and excitation–contraction coupling. Unlike passive electrotonic potentials, which decay exponentially with distance due to membrane current leak and axial cytoplasmic resistance, an action potential regenerates its full amplitude (~100–120 mV in vertebrate neurons) as it travels along an axon, preserving signal fidelity over distances ranging from micrometers to several meters.

The bioelectrical nature of nerve signaling was first investigated by Luigi Galvani in 1791 and measured quantitatively by Emil du Bois-Reymond in 1848, who detected the "negative variation" (negatives Schwankung) of active frog sciatic nerve fibers. In 1850, Hermann von Helmholtz measured the conduction velocity of the frog nerve impulse at ~27 m s⁻¹, demonstrating that neural signaling obeys finite physical kinetics rather than instantaneous optical propagation. In 1902, Julius Bernstein proposed the membrane hypothesis, suggesting that resting cells are selectively permeable to K⁺ ions and undergo a transient breakdown of selective permeability during excitation.

Bernstein's hypothesis was refined in 1939 and 1949 when Alan Hodgkin and Andrew Huxley, together with Kenneth Cole and Howard Curtis, inserted intracellular glass microelectrodes into the giant axon (~0.5–1.0 mm diameter) of the longfin inshore squid (Doryteuthis pealeii). They discovered that the membrane potential does not merely collapse to 0 mV during an impulse, but overshoots zero to reach +40 to +55 mV. Using the voltage-clamp technique and selective substitution of extracellular Na⁺, Hodgkin and Huxley published a set of four coupled nonlinear differential equations in 1952 that quantitatively explained the action potential as a sequential, voltage-dependent change in membrane conductance to Na⁺ and K⁺ ions across the cell membrane, work for which they shared the 1963 Nobel Prize in Physiology or Medicine.

The Na+/K+-ATPase and Nernst Equilibrium

Before an excitable cell can generate an action potential, it must maintain a polarized resting membrane potential (V_rest, typically −65 to −85 mV inside negative relative to the extracellular fluid). Active transport by the electrogenic Na⁺/K⁺-ATPase pump hydrolyzes one molecule of ATP to extrude 3 Na⁺ ions into the extracellular space in exchange for importing 2 K⁺ ions into the cytosol. In a typical mammalian neuron, this establishes steep transmembrane concentration gradients:

• [Na⁺]_out ≈ 145 mM vs. [Na⁺]_in ≈ 12 mM
• [K⁺]_out ≈ 4 mM vs. [K⁺]_in ≈ 140 mM
• [Cl⁻]_out ≈ 110 mM vs. [Cl⁻]_in ≈ 4–10 mM
• [Ca²⁺]_out ≈ 1.5–2.0 mM vs. [Ca²⁺]_in ≈ 10⁻⁴ mM (100 nM)

For any single permeant ion species X with valence z, the electrical potential difference that exactly balances the diffusive flux driven by its concentration gradient is given by the Nernst equation, derived from thermodynamic equilibrium (standard electrode potential and the Boltzmann distribution):

E_X = (RT / zF) ln([X]_out / [X]_in)

where R is the universal gas constant (8.314 J mol⁻¹ K⁻¹), T is absolute temperature in kelvins, and F is the Faraday constant (96,485 C mol⁻¹). At physiological mammalian body temperature (37 °C = 310.15 K), the prefactor 2.303(RT/F) equals 61.5 mV, yielding Nernst equilibrium potentials of E_K ≈ −95 mV, E_Na ≈ +67 mV, E_Cl ≈ −70 to −85 mV, and E_Ca ≈ +125 mV.

The Goldman–Hodgkin–Katz Voltage Equation

Because the resting plasma membrane is simultaneously permeable to multiple ions—predominantly K⁺ via constitutively open two-pore-domain K⁺ (K_2P) leak channels and inwardly rectifying K⁺ (K_ir) channels, with minor resting permeability to Na⁺ and Cl⁻—the steady-state resting potential is governed by the Goldman–Hodgkin–Katz (GHK) voltage equation:

V_m = (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) )

At rest, the relative membrane permeability ratio is approximately P_K : P_Na : P_Cl = 1.0 : 0.04 : 0.45. Because P_K dominates, V_rest sits close to E_K at approximately −70 mV. Conversely, during the peak of an action potential, the permeability ratio shifts to P_K : P_Na : P_Cl = 1.0 : 20 : 0.45, driving V_m toward E_Na.

Equivalent Circuit and Ionic Conductances

Hodgkin and Huxley modeled a patch of excitable membrane as an electrical circuit containing a lipid bilayer capacitance (C_m ≈ 1.0 μF cm⁻²) in parallel with three ionic conductance pathways: a voltage-dependent sodium conductance (g_Na), a voltage-dependent potassium conductance (g_K), and a constant background leak conductance (g_L). The total transmembrane current density I_m is the sum of the capacitive current and the individual ionic currents, each driven by its electrochemical driving force (V − E_ion):

I_m = C_m (dV/dt) + ḡ_Na m³ h (V − E_Na) + ḡ_K n⁴ (V − E_K) + g_L (V − E_L)

Here, ḡ_Na (~120 mS cm⁻² in squid axon) and ḡ_K (~36 mS cm⁻²) represent maximal conductances when all corresponding ion channels are open, while m, h, and n are dimensionless gating variables ranging between 0 and 1 that describe the probability of independent gating particles occupying permissive conformations:

• m (Na_V activation gate): Represents three rapid activation gates per voltage-gated sodium channel; depolarization increases m with a sub-millisecond time constant (τ_m ≈ 0.1–0.5 ms), producing the positive-feedback Hodgkin cycle.
• h (Na_V inactivation gate): Represents a single slower inactivation gate (τ_h ≈ 1–2 ms) that closes upon depolarization, terminating Na⁺ influx via a cytoplasmic "ball-and-chain" or hinged-lid occlusion mechanism (mediated by the intracellular loop between domains III and IV containing the conserved IFM motif in eukaryotic Na_V channels).
• n (K_V activation gate): Represents four slow activation subunits (τ_n ≈ 2–5 ms) of the delayed-rectifier voltage-gated potassium channel, which open with a delay after depolarization to repolarize the membrane.

Each gating variable x ∈ {*m*, h, *n*} obeys first-order relaxation kinetics governed by voltage-dependent forward (α_x) and backward (β_x) rate constants:

dx/dt = α_x(V)(1 − x) − β_x(V)*x* = (x_∞(V) − x) / τ_x(V)

Phases of the Neuronal Action Potential and Refractory Periods

A canonical neuronal action potential progresses through five sequential phases:

1. Threshold Depolarization: Graded excitatory postsynaptic potentials (EPSPs) or sensory receptor currents depolarize the axon initial segment (AIS). If V_m remains below threshold (typically −55 to −50 mV), outward K⁺ and leak currents exceed inward Na⁺ current and the potential decays passively. Once V_m crosses threshold, the inward Na⁺ current I_Na exceeds outward K⁺ current, initiating a regenerative positive-feedback loop (depolarization → increased m → increased g_Na → inward Na⁺ flux → further depolarization).
2. Rising Phase (Depolarization) and Overshoot: Rapid opening of Na_V1.1–1.6 channels increases Na⁺ conductance 500-fold, driving dV/dt up to 200–500 V s⁻¹. V_m crosses 0 mV (overshoot) and peaks at +35 to +50 mV, approaching E_Na.
3. Falling Phase (Repolarization): Near the peak, two processes reverse the membrane trajectory: Na_V channels enter the fast-inactivated state (h → 0), and delayed-rectifier K_V channels open (n⁴ → 1), driving rapid K⁺ efflux down both its concentration and electrical gradients.
4. Afterhyperpolarization (Undershoot): Because K_V channels close slowly (τ_n > τ_m), g_K temporarily remains elevated above its resting value after Na_V channels have closed, pulling V_m closer to E_K (−80 to −90 mV) before relaxing back to V_rest.
5. Absolute and Relative Refractory Periods: During the rising, falling, and early undershoot phases (~1–2 ms), virtually all Na_V channels are either already open or locked in the inactivated state (h ≈ 0); no stimulus, regardless of magnitude, can elicit a second spike (absolute refractory period). This limits maximal neuronal firing frequencies to ~500–1,000 Hz and guarantees unidirectional orthodromic propagation from the axon hillock to the synaptic terminal. During the subsequent relative refractory period (~2–5 ms), a fraction of Na_V channels have recovered from inactivation (h > 0) while g_K remains elevated, requiring a suprathreshold stimulus to trigger an action potential.

Passive Electrotonic Spread and Space/Time Constants

Action potential propagation along an cylindrical axon of radius a relies on local circuit currents flowing longitudinally through the axoplasm (specific intracellular resistivity R_i ≈ 30–100 Ω·cm) to depolarize adjacent downstream membrane segments. In a passive unmyelinated cylinder, subthreshold voltage V(x, t) obeys the one-dimensional cable equation:

λ² (∂²V / ∂*x*²) − τ_m (∂*V* / ∂*t*) − V = 0

where the membrane time constant τ_m = R_mC_m governs the temporal rate of voltage charging, and the length (space) constant λ determines the spatial distance over which a steady-state voltage decays exponentially to 1/e (~37%) of its initial value according to V(x) = V₀ exp(−*x*/λ):

λ = √(r_m / r_i) = √( (R_m a) / (2 R_i) )

Because λ scales with the square root of axon radius (√*a*), invertebrates evolved giant unmyelinated axons—such as the 0.5–1.0 mm squid giant axon or crustacean medial giant fibers—to reduce internal axial resistance r_i and achieve conduction velocities of 20–35 m s⁻¹.

Myelination and Nodes of Ranvier

Vertebrates achieved rapid conduction within compact nervous systems by wrapping axons in concentric layers of lipid-rich myelin produced by oligodendrocytes in the central nervous system (CNS) and Schwann cells in the peripheral nervous system (PNS). Up to 150 compact membrane lamellae insulate the internodal axon segment, increasing specific transmembrane resistance R_m ~100-fold and reducing effective membrane capacitance C_m ~100-fold. Consequently, the internodal space constant λ increases several-fold while the charging time constant τ_m drops sharply.

Voltage-gated Na_V1.6 channels are clustered at densities of ~1,000–2,000 channels μm⁻² exclusively at 1-μm gaps in the myelin sheath called nodes of Ranvier (spaced 0.5–2.0 mm apart), whereas internodal membranes contain <25 channels μm⁻². Depolarizing current generated at one node flows rapidly through the low-capacitance myelinated internode to ignite the next node—a process termed saltatory conduction (from the Latin saltare, "to leap"). Myelination increases conduction velocity from v ∝ √*a* in unmyelinated fibers (0.5–2.0 m s⁻¹ in mammalian C-fibers) to a linear scaling v ∝ a in myelinated fibers, reaching 80–120 m s⁻¹ in 15–20 μm mammalian Aα motor and Ia proprioceptive axons while reducing the metabolic ATP cost of Na⁺/K⁺-ATPase ion restoration by >95%.

Not all action potentials rely exclusively on Na⁺ influx or exhibit millisecond durations. In mammalian ventricular cardiomyocytes, a rapid phase 0 upstroke mediated by Na_V1.5 channels is followed by a prolonged phase 2 plateau lasting 200–350 ms, maintained by balanced inward Ca²⁺ influx through L-type voltage-gated calcium channels (Ca_V1.2) and outward K⁺ currents (I_Ks, I_Kr). This extended duration prolongs the absolute refractory period to match the mechanical systole of the heart, preventing tetanic summation and cardiac fibrillation. In sinoatrial (SA) node pacemaker cells, which lack a stable resting potential, spontaneous diastolic depolarization is driven by hyperpolarization-activated cyclic nucleotide-gated (HCN4) "funny" currents (I_f, permeant to Na⁺ and K⁺), and the action potential upstroke is mediated entirely by T-type (Ca_V3.1) and L-type (Ca_V1.3) Ca²⁺ channels.

In photosynthetic organisms such as the Venus flytrap (Dionaea muscipula) and charophyte green algae (Chara), where extracellular fluid is dilute and resting potentials are maintained at −150 to −200 mV by plasma-membrane P-type H⁺-ATPases, mechanical or electrical stimulation triggers cytosolic Ca²⁺ influx that opens Ca²⁺-activated Cl⁻ channels. Because intracellular Cl⁻ is actively accumulated above electrochemical equilibrium, Cl⁻ efflux carries negative charge out of the cell, generating a 1–5 second depolarizing action potential that coordinates leaf closure or cytoplasmic streaming arrest.

Why is an action potential described as "all-or-none"?

Once a membrane depolarization crosses the voltage threshold (~−55 mV), the inward Na⁺ current exceeds outward K⁺ current, initiating a regenerative positive-feedback cycle that opens all available voltage-gated Na⁺ channels until the membrane approaches the Na⁺ Nernst potential. Consequently, the peak amplitude and waveform of an action potential are intrinsic properties of the membrane's ion channel densities and electrochemical gradients, entirely independent of the strength of the suprathreshold stimulus; stronger stimuli are encoded by higher firing frequencies (rate coding) rather than larger spikes.

How many ions actually cross the membrane during a single action potential?

Changing the transmembrane potential of a 1-μm diameter axon by Δ*V* = 100 mV across a specific membrane capacitance of C_m = 1 μF cm⁻² requires transferring a surface charge density of Q = C_mΔ*V* = 10⁻⁷ C cm⁻², corresponding to roughly 6,000 monovalent Na⁺ ions per square micrometer of membrane. In a 1-μm axon, this influx alters bulk intracellular Na⁺ concentration by less than 0.002%, allowing a neuron to fire hundreds of thousands of action potentials even if the Na⁺/K⁺-ATPase is pharmacologically blocked.

Why do action potentials only travel in one direction along an axon?

When an action potential is initiated at the axon initial segment, local circuit currents spread passively in both directions along the axoplasm. However, as the spike advances orthodromically toward the axon terminal, the upstream membrane segment immediately behind the wavefront contains voltage-gated Na⁺ channels locked in their fast-inactivated conformation (h ≈ 0) alongside open delayed-rectifier K⁺ channels. This trailing refractory zone prevents backward (antidromic) re-excitation during normal physiological firing.

1. Hodgkin, A. L., & Huxley, A. F. (1952). "A quantitative description of membrane current and its application to conduction and excitation in nerve." The Journal of Physiology, 117(4), 500–544. https://doi.org/10.1113/jphysiol.1952.sp004764
2. Bean, B. P. (2007). "The action potential in mammalian central neurons." Nature Reviews Neuroscience, 8(6), 451–465. https://doi.org/10.1038/nrn2148
3. Catterall, W. A., Raman, I. M., Robinson, H. P. C., Sejnowski, T. J., & Paulsen, O. (2012). "The Hodgkin-Huxley heritage: from channels to circuits." The Journal of Neuroscience, 32(41), 14064–14073. https://doi.org/10.1523/JNEUROSCI.3403-12.2012
4. Nave, K.-A., & Werner, H. B. (2014). "Myelination of the nervous system: mechanisms and functions." Annual Review of Cell and Developmental Biology, 30, 503–533. https://doi.org/10.1146/annurev-cellbio-100913-013101