The Action Potential

The action potential is a rapid (roughly 1–2 ms), large (about 100 mV), transient change in membrane potential that propagates without decrement along an excitable membrane. At rest, a typical neuron sits near -65 to -70 mV, close to the K⁺ equilibrium potential because resting membrane conductance is dominated by K⁺-selective leak channels (as the Goldman-Hodgkin-Katz equation predicts for a membrane far more permeable to K⁺ than to Na⁺). An action potential begins when some depolarizing input — synaptic current, sensory transduction current, or experimental current injection — pushes the membrane potential toward a critical value called threshold, typically around -55 mV in a mammalian neuron. Below threshold, depolarizations decay passively back to rest. At or above threshold, a runaway process begins that drives the membrane potential rapidly toward +30 to +40 mV before falling back below rest and then recovering — a stereotyped waveform whose shape and amplitude do not depend on how large the triggering stimulus was, provided it crossed threshold. This is the all-or-none principle. The key conceptual move, introduced by Hodgkin and Huxley, is to treat the membrane not as having one fixed permeability ratio but as having voltage-dependent and time-dependent permeabilities to specific ions, carried by distinct populations of channels. Two channel types dominate the action potential: voltage-gated Na⁺ channels, which open rapidly upon depolarization and then inactivate, and voltage-gated K⁺ channels, which open more slowly and do not inactivate on this timescale. The interplay of these two conductances — one fast and self-limiting, one slow and sustained — is sufficient to generate the entire spike, the undershoot that follows it, and the refractory period that follows that. Because the action potential is regenerative — depolarization opens more Na⁺ channels, which causes more depolarization — it is fundamentally different from a graded potential such as an excitatory postsynaptic potential (EPSP) or a receptor potential, which scale continuously with stimulus strength and decay with distance (a topic developed further in Action Potential Propagation and Cable Properties). The action potential trades graded information for reliability over distance: it is a digital pulse riding on an analog substrate, regenerated identically at every patch of excitable membrane it crosses.

Step 1 — Resting state. At rest, the membrane potential (V_m) sits near -65 mV. Voltage-gated Na⁺ channels are in a closed, resting (deactivated) conformation but available to open. Voltage-gated K⁺ channels are closed. The dominant resting conductance is through K⁺ leak channels, so V_m sits close to E_K (around -80 to -90 mV, pulled slightly less negative by a small resting Na⁺ permeability), consistent with the Goldman-Hodgkin-Katz relation for a membrane dominated by g_K.

Step 2 — Local depolarization and threshold. An excitatory input (synaptic current, generator potential, or injected current) depolarizes the membrane locally. As V_m rises, a small fraction of voltage-gated Na⁺ channels begins to open. If the depolarization is small, the extra Na⁺ influx is outpaced by K⁺ efflux through leak channels, and V_m relaxes back to rest — a subthreshold response. Threshold is reached when Na⁺ influx becomes self-sustaining: the rate of Na⁺ entry (which depolarizes the membrane further, opening still more Na⁺ channels) exceeds the rate of repolarizing K⁺ (and Cl⁻) efflux. Threshold is therefore not a fixed intrinsic membrane property but the voltage at which net inward current first exceeds net outward current — it depends on the local density of channels and can be shifted by prior activity, temperature, and channel-modulating drugs.

Step 3 — The rising phase (depolarization). Once threshold is crossed, voltage-gated Na⁺ channels open in a positive-feedback cascade: depolarization → channels open → Na⁺ enters (driven by both its concentration gradient, [Na⁺]out ≈ 145 mM vs [Na⁺]in ≈ 15 mM, and the negative internal potential) → more depolarization → more channels open. This regenerative loop drives V_m rapidly toward E_Na (calculated from the Nernst equation, roughly +60 mV), though it typically peaks at only +30 to +40 mV because Na⁺ channels begin inactivating and K⁺ channels begin opening before equilibrium is reached. This phase lasts under a millisecond.

Step 4 — Na⁺ channel inactivation. Each voltage-gated Na⁺ channel has two gates in series (in the classical Hodgkin-Huxley formalism): an activation gate (m) that opens quickly on depolarization, and an inactivation gate (h) that closes more slowly on depolarization. At the peak of the spike, activation gates are open but inactivation gates have swung shut, so the channel — though depolarized — carries no current. This inactivated state is distinct from the closed resting state: an inactivated channel cannot reopen until the membrane repolarizes and the inactivation gate resets, a process with its own time course, as detailed in the study of Voltage-Gated Channel Gating and Kinetics.

Step 5 — The falling phase (repolarization). Two processes cooperate to bring V_m back down: (1) Na⁺ channels inactivate, shutting off the depolarizing current, and (2) voltage-gated K⁺ channels, which activate more slowly than Na⁺ channels (hence "delayed rectifier"), open and drive K⁺ efflux, which is repolarizing because it moves V_m toward E_K (around -80 to -90 mV). The combination collapses V_m rapidly.

Step 6 — Undershoot (afterhyperpolarization). K⁺ channels close slowly, so K⁺ efflux persists briefly after V_m has returned to rest, driving the membrane transiently more negative than the resting potential — the afterhyperpolarization. As the K⁺ channels finally close and Na⁺ channels recover from inactivation, V_m returns to rest.

Step 7 — Refractory periods. During the absolute refractory period (roughly the duration of the spike and part of the undershoot), a large fraction of Na⁺ channels are inactivated, and no stimulus, however large, can trigger a second action potential. During the following relative refractory period, Na⁺ channels are progressively recovering and some K⁺ channels are still open, so a second action potential can be triggered only by a stronger-than-normal stimulus. Refractoriness limits maximum firing rate (setting an upper bound, in most neurons, on the order of a few hundred to just over a thousand Hz) and ensures that action potentials propagate in one direction along an axon rather than reflecting backward.

The mechanism above was not deduced from first principles — it was proved, ion by ion and gate by gate, by Alan Hodgkin and Andrew Huxley working on the squid giant axon at the Marine Biological Laboratory in Plymouth, England, in a series of experiments published in 1952. The squid giant axon, up to about 1 mm in diameter, was essential: it was large enough to thread with an internal wire electrode, permitting both voltage recording and later voltage control across the whole membrane, something impossible in ordinary vertebrate axons at the time. The critical technical breakthrough was the voltage clamp, developed by Kenneth Cole and refined by Hodgkin, Huxley, and Bernard Katz. Normally, if you depolarize a membrane, voltage-gated channels open, current flows, and that current further changes the voltage — the very regenerative feedback that makes the action potential explosive but that also makes the underlying currents impossible to interpret from voltage recordings alone. The voltage clamp broke this feedback loop deliberately: a feedback amplifier injects exactly the current needed to hold membrane potential at any voltage the experimenter chooses, step by step. Because voltage is held fixed, whatever current the amplifier must supply to maintain that voltage is a direct, real-time readout of the ionic current flowing through the membrane at that voltage — with the confounding voltage changes eliminated. Using the voltage clamp, Hodgkin and Huxley depolarized the squid axon membrane to a series of fixed voltages and recorded the resulting current. At depolarizing steps, they observed a characteristic two-phase current: a brief inward current followed by a sustained outward current. The key logical step was ion substitution: they repeated the experiment after replacing external Na⁺ with the impermeant cation choline. With Na⁺ removed, the early inward current vanished, leaving only the late outward current. This proved the early current was carried by Na⁺ influx and the late current by a different (K⁺) conductance — separating the two conductances experimentally, not just by inference from the total current. By subtracting the choline-substituted trace from the control trace, they could isolate the pure Na⁺ current at any voltage; the remaining late current, they showed, was carried by K⁺ (confirmed using K⁺ channel-selective manipulations and later by pharmacological blockers such as tetrodotoxin for Na⁺ channels and tetraethylammonium for K⁺ channels, tools developed by later researchers building on this framework). From these separated currents, Hodgkin and Huxley extracted the voltage- and time-dependence of the Na⁺ and K⁺ conductances: Na⁺ conductance rose quickly with depolarization and then decayed even under sustained voltage clamp (revealing inactivation as an intrinsic, voltage- and time-dependent process, not merely Na⁺ depletion), while K⁺ conductance rose more slowly and stayed elevated as long as depolarization was maintained. They fit these conductance time courses with empirical differential equations using gating variables they called m (Na⁺ activation), h (Na⁺ inactivation), and n (K⁺ activation), each obeying first-order kinetics with voltage-dependent rate constants measured directly from the clamp data. The decisive test came when they combined these empirically-derived conductances into a single mathematical model — the Hodgkin-Huxley model, developed further in its own right — and used it to simulate, without any additional free parameters, what should happen if the membrane were released from voltage clamp and allowed to respond freely to a threshold stimulus. The simulated waveform reproduced the actual action potential: its amplitude (~110 mV total swing), rising and falling phase durations, and even the conduction velocity of the propagated impulse (calculated using cable properties) — all matched the experimentally recorded action potential to within a few percent. This was the proof: the ionic currents measured in isolated, static voltage-clamp steps were sufficient, when combined, to reconstruct the entire dynamic, regenerative, propagating action potential. Hodgkin, Huxley, and John Eccles received the Nobel Prize in Physiology or Medicine in 1963 for this body of work. A further confirming line of evidence came later from Erwin Neher and Bert Sakmann's patch-clamp technique (1976 onward), which allowed recording of current through single ion channels. Patch clamp recordings directly visualized individual Na⁺ channels flickering open for about a millisecond and then closing/inactivating, and individual K⁺ channels opening with a delay and staying open longer — confirming at the single-molecule level the stochastic, voltage-dependent gating that Hodgkin and Huxley had inferred only indirectly from whole-membrane currents.

Example 1 — Predicting whether a compound stimulus reaches threshold. A cortical neuron rests at -68 mV with threshold at -54 mV. It receives two nearly simultaneous excitatory postsynaptic potentials (EPSPs) from different synapses: one produces a local depolarization of +9 mV at the trigger zone, the other +4 mV, and due to space and time constants, they summate with 80% efficiency (i.e., the combined depolarization is 0.8 × (9+4) mV rather than the full arithmetic sum, because of leak and imperfect temporal overlap). Combined depolarization = 0.8 × 13 mV = 10.4 mV. New membrane potential = -68 + 10.4 = -57.6 mV. Since -57.6 mV is still below the -54 mV threshold, no action potential fires — the inputs summate but fall short. This illustrates subthreshold summation: graded potentials add (imperfectly, due to leak) but do not themselves become all-or-none; only if their sum crosses threshold does the regenerative Na⁺ cascade engage. If a third EPSP contributing an effective +5 mV (after the same 80% summation discount, i.e. a raw ~6.25 mV) arrived within the same integration window, the total would reach -68 + 0.8×(13+6.25) ≈ -68 + 15.4 = -52.6 mV — above threshold, and a full action potential would fire, identical in shape regardless of whether the trigger was two inputs or three.

Example 2 — Reasoning through refractory period and maximum firing rate. Suppose a peripheral sensory axon has an absolute refractory period of 1.2 ms and a relative refractory period lasting a further 2.8 ms, during which the threshold is elevated according to Threshold(t) = -55 mV + 20 mV × e^(−t / 1.4 ms), where t is time (ms) since the end of the absolute refractory period. Question: What is the maximum possible firing rate if the axon fires exactly at the end of the absolute refractory period each cycle (worst case, ignoring the relative period), and, separately, what is a more realistic sustainable rate if each spike must wait until the elevated threshold has decayed to within 2 mV of normal threshold? Part A (theoretical maximum): If spikes could occur immediately after the absolute refractory period ends (t = 1.2 ms apart, ignoring that firing right at that instant would require an enormous stimulus because threshold is still elevated), the maximum rate is: Rate = 1 / 1.2 ms = 833 Hz. Part B (realistic sustainable rate): We need t such that Threshold(t) is within 2 mV of -55 mV, i.e., 20 × e^(−t/1.4) ≤ 2. e^(−t/1.4) ≤ 0.1 −t/1.4 ≤ ln(0.1) = −2.303 t ≥ 1.4 × 2.303 ≈ 3.22 ms Total interspike interval = absolute refractory period + this relative-period wait = 1.2 + 3.22 = 4.42 ms. Sustainable rate = 1 / 4.42 ms ≈ 226 Hz. This example shows why textbook "maximum firing rates" quoted near 1000 Hz are theoretical ceilings set almost entirely by the absolute refractory period, while realistic sustained firing rates in most neurons — limited by the relative refractory period and by the practical difficulty of recruiting enough depolarizing current to overcome an elevated threshold — are typically in the low hundreds of Hz or less.

Alan Lloyd Hodgkin and Andrew Fielding Huxley were both Cambridge-trained physiologists whose partnership began before World War II and resumed after it, interrupted by their separate wartime work on radar and aviation medicine. Their 1952 papers in the Journal of Physiology are considered one of the most complete and quantitatively successful mechanistic explanations in the history of biology — a rare case where a fully specified mathematical model, built from isolated component measurements, correctly predicted an emergent whole-system behavior (the propagating spike) with no additional fitting. Hodgkin was known for his instrumentation ingenuity (he helped design the differential amplifier circuits for the voltage clamp), while Huxley contributed much of the mathematical formalism and numerical integration — famously performed by hand and with a mechanical calculator, since electronic computers were not yet available to them for this work.

The ionic mechanism of the action potential is the direct pharmacological target of an enormous share of clinically used drugs. Local anesthetics (lidocaine, procaine) block voltage-gated Na⁺ channels from the inside of the membrane, preventing threshold from ever being reached and thus blocking pain-signal propagation at the site of injection — a direct, designed exploitation of the mechanism described here. Class I antiarrhythmic drugs and several anti-epileptic drugs (phenytoin, carbamazepine, lamotrigine) work by preferentially binding the inactivated state of Na⁺ channels, stabilizing inactivation and thereby damping pathologically rapid, repetitive firing in cardiac tissue or seizing cortical circuits, without much affecting normal, lower-frequency firing.

Tetrodotoxin (from pufferfish) and saxitoxin (from dinoflagellates causing red-tide shellfish poisoning) are potent, selective Na⁺ channel blockers that were instrumental research tools in dissecting Na⁺ current pharmacologically, and remain clinically and forensically relevant as causes of respiratory paralysis in poisoning cases. Inherited channelopathies — point mutations in the genes encoding voltage-gated Na⁺ or K⁺ channels — cause disorders including certain forms of epilepsy, periodic paralysis, cardiac long-QT syndrome, and some pain disorders (mutations in the Na_v1.7 channel gene cause both congenital insensitivity to pain and, in other mutations, severe chronic pain syndromes), directly linking the molecular kinetics of gating to human disease phenotypes. In neuroscience research, the ionic mechanism underlies interpretation of extracellular and intracellular electrophysiological recordings used throughout systems neuroscience, and informs the design of neurostimulation devices (cochlear implants, deep brain stimulation, spinal cord stimulators) that must deliver current sufficient to cross threshold in target neurons while avoiding damage or unwanted spread.

Ask the tutor: How does the Hodgkin-Huxley m-h-n gating formalism mathematically combine to reconstruct the full action potential waveform from separately measured Na⁺ and K⁺ conductances?