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An action potential is a brief regenerative excursion of membrane potential, produced by changing electrical resistance and conductance through voltage-gated ion channels. In a typical fast neuronal action potential, sodium entry raises membrane potential, activating further sodium channels. This feedback produces the rapid rising phase. Inactivation of sodium channels and increased conductance to potassium then lower membrane potential again; persisting potassium conductance can produce an undershoot below the resting level. See Purves and colleagues: the ionic basis of action potentials.

For an illustrative electrical calculation, write inward sodium electric current as $I_{\mathrm{Na}}=g_{\mathrm{Na}}(E_{\mathrm{Na}}-V)$. At $V=-50\mathrm{mV}$, taking $E_{\mathrm{Na}}=60\mathrm{mV}$ and $g_{\mathrm{Na}}=10\mathrm{nS}$ gives $I_{\mathrm{Na}}=1.1\mathrm{nA}$ inward. A potassium current $I_{\mathrm{K}}=g_{\mathrm{K}}(E_{\mathrm{K}}-V)$ with $E_{\mathrm{K}}=-80\mathrm{mV}$ and $g_{\mathrm{K}}=20\mathrm{nS}$ gives $-0.6\mathrm{nA}$, outward. These illustrative values expose opposing driving forces; a waveform requires the conductances to evolve with membrane potential and time, as in the Hodgkin-Huxley model.

An action potential propagates along an axon because local electric currents bring neighboring regions of cell membrane into the regime where their voltage-gated ion channels regenerate the signal. It is a traveling pattern of excitation, not a packet of sodium ions traversing the entire axon. Regeneration allows an action potential to travel without the passive attenuation of a small local voltage change. See Ion Channels and the Electrical Properties of Membranes.

The neuronal refractory period constrains how soon another action potential can follow. Under comparable conditions, successive action potentials have roughly stereotyped shapes, making event count and timing useful for neural coding; waveform details can nevertheless change with channel state and conditions. The leaky integrate-and-fire model abstracts each action potential to a threshold event and reset. Its reset jump is a mathematical rule, not the actual regenerative waveform produced by sodium and potassium currents.

The cathode is the electrode at which the net electrode chemical reaction is reduction: the reacting chemical species gains electrons. This definition is independent of terminal sign. During Daniell cell discharge, ${\mathrm{Cu}}^{2+}$ cations accept electrons arriving at the copper cathode and become neutral copper. The cathode is then the positive terminal. In an externally driven electrolytic cell, the source's negative terminal supplies electrons to the negative cathode. See Pingarrón et al., §3.4: cathode and Daniell cell.

An ion carrying electric current need not undergo reduction at the cathode. For example, in the ideal Daniell cell charge-balance picture, potassium cations arriving from a salt bridge remain dissolved while ${\mathrm{Cu}}^{2+}$ cations are consumed. Follow the half-reaction to identify the reacting species; follow electric charge conservation to account for the other moving ions.

An availability change associated with the outer pore and selectivity filter of certain potassium ion channels. Its kinetics and structural origin differ from ball-and-chain inactivation, although the two processes can interact.

Cytosol dialysis is exchange between the cytosol and pipette solution through the opening used in conventional whole-cell recording. Diffusion can change ion concentrations and dilute soluble regulators of ion channels. A diminishing response can therefore reflect the recording's alteration of the biological cell, rather than the experimental treatment.

A direct motivating example is the 1988 article Muscarinic activation of ionic currents measured by a new whole-cell recording method. In rat lacrimal gland biological cells, the acetylcholine response in conventional whole-cell recording lasted about five minutes. With a pore-forming substance in the patch pipette instead of open break-in, the response remained undiminished after one hour. The readout was activation of calcium-activated potassium and ${\mathrm{Cl}}^{-}$ ion electric currents; preserving the response supported a role for retained cytoplasmic components. The authors also tested the substance extracellularly and observed reversible increases in cation electrical conductance. This comparison motivates perforated patch recording, but does not show that every intracellular constituent or every ion channel response is preserved. ^[ref]

Practical controls are matched pipette and bath compositions, recording elapsed time after break-in, time-matched untreated preparations, and tracking both patch-clamp series resistance and baseline leakage. Comparing conventional whole-cell recording with perforated patch recording can separate loss of soluble components from an intended treatment effect, but only if electrical access is characterized in both. These are controls suggested by the mechanisms above, not a new set of measured results.

A Daniell cell uses the zinc/${\mathrm{Zn}}^{2+}$ and ${\mathrm{Cu}}^{2+}$/copper pairs. In the separated-compartment teaching version, a zinc electrode contacts an aqueous chemical solution containing ${\mathrm{Zn}}^{2+}$, and a copper electrode contacts one containing ${\mathrm{Cu}}^{2+}$. A salt bridge supplies an ionic connection; a wire and load supply an electronic connection. During discharge,The zinc electrode loses material and copper is deposited at the cathode. Each half-reaction conserves chemical atom counts and electric charge: the first has net charge zero on each side, the second $+2e-2e=0$ on the left and zero on the right. The net reaction has $+2e$ on both sides, with no electrons left in its chemical equation. The Zn/Cu teaching cell and these half-reactions are described in Florida State University, Redox Reactions in Voltaic Cells: Construction of a Potential Series, lab background.

Creating one mole of ${\mathrm{Zn}}^{2+}$ adds $2F$ of positive electric charge to the anode compartment's ionic inventory; consuming one mole of ${\mathrm{Cu}}^{2+}$ removes $2F$ of positive electric charge from the cathode compartment. Here $F$ is the Faraday constant. In an ideal bookkeeping example using a potassium nitrate salt bridge, two moles of nitrate anions entering the anode compartment compensate the first change, and two moles of potassium cations entering the cathode compartment compensate the second. Other ions in the cell can share the actual transport. The two compensating inventory changes do not mean that $4F$ flowed through the load: the same series electric current transports $2F$ through each cross-section of the circuit per mole of net reaction. See salt bridge.

Under standard-state conditions near $298\mathrm{K}$, tabulated reduction potentials give a cell electromotive force of approximately $1.10\mathrm{V}$. This is a reversible reference value, not a promised loaded reading; actual composition matters through thermodynamic activity. The tabulated copper and zinc values and their subtraction are given in Purdue University, Electrochemical Reactions: standard-state reduction potentials. For the net chemical equation as written, the molar Gibbs free energy change obeysThus $\mathcal{E}=1.10\mathrm{V}$ corresponds to about $-212\mathrm{kJ}\mathrm{mo}{\mathrm{l}}^{-1}$ of net reaction. At fixed temperature and pressure, $-{\Delta }_{r}G$ is the maximum reversible electrical work per mole for this cell reaction. It is not automatically all the heat released by a finite-current cell. See 17.4 Potential, Free Energy, and Equilibrium (§17.4: cell potential and free energy).

A galvanic cell supplies electrical work from a spontaneous redox chemical reaction under the specified conditions. In discharge through a passive load, oxidation occurs at its negative anode and reduction at its positive cathode. Separating the reacting compartments makes the electrons take an external route, where their transport can deliver useful work. See Flowers et al., Chemistry 2e, §17.2: separated reactions and electrical work.

In the metallic external electrical circuit, electrons move from anode to cathode, while conventional current goes from cathode through the load to anode. Inside the cell, net ionic conventional current closes the loop from the anode compartment toward the cathode compartment. Oppositely moving cations and anions can both contribute to that direction; see electrolyte for the signed current density calculation. A cell can maintain a nonzero terminal electric potential difference near open circuit while delivering almost no power; the Daniell cell voltage and load experiment makes this distinction concrete.

Immanuel Estermann, O. C. Simpson and Otto Stern used gravitational deflection to measure atomic speeds. Stern describes scanning a hot-wire surface ionization detector through a cesium beam and recording ion electric current.^[ref] Their 1947 paper reports potassium and cesium beams; a deficit of slow arrivals increased with oven pressure, supporting a source-slit collision explanation.^[ref]

First consider an original point-launch model, with horizontal speed $v>0$, zero initial vertical velocity, flight distance $L$, and uniform gravitational acceleration $g$. Downward displacement $y$ follows from flight time $t=L/v$:Slow particles fall farther. However, a detector scan counts arrivals per interval of height, not per interval of speed. Change of variables for probability densities supplies the Jacobian determinant:Here $g(v)$ denotes the effusive beam speed distribution; the unadorned constant $g$ in $C$ denotes gravitational acceleration. The integral of $p_y$ is one: substituting $u=b/y$ reduces it to ${\int }_0^{\infty }u{e}^{-u}du=1$. Its mode is $y=b/3$. Simply mapping the most probable arrival speed into a fall distance instead gives $2b/3$. The peaks differ because equal height bins cover unequal speed intervals.

For those chosen parameters, $b\simeq 176.54\mu \mathrm{m}$, so the detector-height probability density peaks near $58.85\mu \mathrm{m}$. A detector covering only $0<y<Y$ accepts the fractionAt $Y=0.80\mathrm{mm}$ this is about $97.9\%$, even before allowing for imperfect detection. Discarding the remainder changes the observed normalization.

Real slits transmit a range of launch heights and vertical velocities. Their geometrical response must be combined with the gravitational deflection and detector width; the point-launch formula is not an exact reduction of the historical apparatus. In the point-launch model, an initial vertical velocity $w$ would add $wL/v$ to $y$. Source collisions, detector efficiency and alignment can also distort a profile. Varying oven pressure helps distinguish such source losses from an incorrect thermal distribution; inferring a source temperature from the peak alone ignores both selection and the detector's coordinate transformation.

A conductance-based Hodgkin-Huxley model couples membrane potential to voltage-dependent channel-gating variables. It explains generation of action potentials through regenerative and opposing ionic electric currents, while its parameters and channel assumptions determine its biological domain of validity.

In the classical model, $m$ describes sodium activation, $h$ describes availability against sodium inactivation, and $n$ describes potassium activation. Each follows two-state ion-channel gating, with its own voltage-dependent rates. The available electrical conductances areThe barred quantities are maximum electrical conductances. The factors have the interpretation of independent permissive gates in an ion channel: three activation factors and a distinct inactivation-availability factor for sodium, and four identical activation factors for potassium. Large $h$ means availability; small $h$ means inactivation. These are model assumptions, not a literal structural description of every ion channel. See Gerstner, Kistler, Naud and Paninski, Neuronal Dynamics (2014), §2.2: model definition and stochastic opening.

With inward-positive electric current, a single-compartment form isHere $C$ is membrane capacitance, $I_{\mathrm{ext}}$ is imposed inward electric current, $g_L$ is leak electrical conductance, and each $E$ is a reversal potential. Use consistent units, and either whole-compartment quantities throughout or quantities per membrane area throughout. Opening changes electrical conductance; the reversal potential and present membrane potential determine the associated electric current. Coupling this equation to the voltage-dependent gates makes a generally nonlinear system of ordinary differential equations; a gate's fixed-voltage limit alone does not specify its evolving state during an action potential.

The original quantitative account is ^[ref]. The contrast with the leaky integrate-and-fire model is useful: here an action potential emerges from evolving ionic electric currents, whereas the simpler model records a threshold event and imposes a reset.

In 1939, Alan Hodgkin and Andrew Huxley reported intracellular action potential recordings from squid giant axons at Plymouth.^[ref]

Alan Hodgkin's later account describes advancing a capillary electrode from a cut end into intact axon, avoiding scraping the cell membrane. Its Figure 3 uses a seawater-filled capillary internally, with external seawater as zero: the readout is internal relative to external electric potential. This supports a voltage across the surface cell membrane. As a separate ionic control, the account reports that raising external potassium toward its internal concentration reversibly abolished resting voltage; this was later work, not a control asserted for the 1939 recording. Injury and electrode-solution junction potentials limit interpretation. Voltage recording alone does not identify every conducting ion. A voltage clamp additionally uses feedback to impose voltage and measures the required electric current.^[ref]

In the schematic, connect the intracellular electrode to the positive input and the external reference electrode to the negative input of a voltage recorder. After electrode-offset correction, a negative reading means ${\varphi }_{\mathrm{inside}}<{\varphi }_{\mathrm{outside}}$. A useful baseline check is to compare both electrodes in the same external chemical solution before insertion; this is a measurement check, not an additional historical observation claimed here. Swapping inputs reverses the readout sign without changing the biological cell's membrane potential.

An ion channel is a membrane protein that provides a selective pathway for ions across a cell membrane. An open pore permits passive transport down the relevant electrochemical gradient; it does not supply the free energy for uphill transport as a pump involved in active transport does. Two things are needed for a net electric current: an available pathway and an electrochemical potential difference. Opening a pore alone need not produce a net electric current. See Ion Channels and the Electrical Properties of Membranes.

The selective permeability of an ion channel depends on interactions between its pore and the passing ions, not simply on a hole's diameter. Some ion channels strongly favor potassium over sodium; others admit several kinds of positively charged ions. Thus selective does not necessarily mean exclusive to one ion species. See Purves et al., Neuroscience, 2nd edition (2001): molecular structure of ion channels and the mixed-channel example in Purves et al.: principles derived from studies of the neuromuscular junction.

Gating is the opening and closing of an ion channel's pathway. A voltage-gated ion channel responds to membrane potential; an ionotropic receptor can respond to a bound ligand. Gating changes the available electrical conductance, while the electrochemical gradient supplies the drive for passive transport. For a fixed reversal potential in the simple model below, opening more identical ion channels increases the magnitude of the electric current at a fixed nonzero drive, without choosing its sign independently of membrane potential. The two-state ion-channel gating model describes how the open fraction can change. See the Alberts reference above.

For a worked approximation, hold an open population's electrical conductance at $g=10\mathrm{nS}$ and its reversal potential at $E_{\mathrm{rev}}=-80\mathrm{mV}$. Use $V=V_{\mathrm{inside}}-V_{\mathrm{outside}}$ for membrane potential and inward-positive conventional current:At $V=-100,-80,-60\mathrm{mV}$, respectively, the electric currents are $+200,0,-200\mathrm{pA}$, since $1\mathrm{nS}\times 1\mathrm{mV}=1\mathrm{pA}$. Positive electric current means net positive electric charge entering, or net negative electric charge leaving; it does not mean that every ion moves inward. For a pore passing only positive ions, the three results mean net inward passage, no net passage, and net outward passage. These stipulated values describe an illustrative Ohmic approximation, not measured properties of a particular ion channel; see reversal potential for the current plot and limitations.

The useful connection is between a molecular gate and a controllable electric current. A ligand can change electrical conductance through an ionotropic receptor, or membrane potential can change it through a voltage-gated ion channel, connecting recognition and electrical signaling. In a historical landmark, Erwin Neher and Bert Sakmann reported currents from individual ion channels in frog muscle membranes in 1976. See Neher and Sakmann, Single-channel currents recorded from membrane of denervated frog muscle fibres, Nature 260, 799–802 (1976).

An ionotropic receptor is a receptor in which binding of a ligand directly gates an ion channel within the same protein complex. The binding site detects the chemical signal; the pore supplies a path across the cell membrane. At a chemical synapse, a neurotransmitter therefore changes synaptic conductance without an obligatory intervening G protein or second messenger. ^[ref]

A familiar example is the nicotinic acetylcholine receptor of skeletal muscle: acetylcholine binding opens a pore passing cations, including sodium and potassium. The muscarinic acetylcholine receptor instead uses intracellular signal transduction; the same neurotransmitter can engage different mechanisms. Direct gating does not mean that an ionotropic receptor pumps ions: electrochemical gradients drive passage through the open ion channel. Nor does “ionotropic” specify excitation. The reversal potential, initial membrane potential and other conductances determine whether the effect favors an action potential, causes hyperpolarization, or supplies shunting inhibition. ^[ref]

A concrete electrical approximation separates opening from drive. Let $N$ identical ion channels each have open-channel electrical conductance $\gamma$ and opening probability $p(t)$. At fixed membrane potential $V$, with common reversal potential $E_{\mathrm{rev}}$, the expected value of inward-positive electric current isFor stipulated values $N=100$, $\gamma =20\mathrm{pS}$, $p=0.2$, $V=-60\mathrm{mV}$ and $E_{\mathrm{rev}}=0$, the mean open count is $20$, the population electrical conductance is $0.4\mathrm{nS}$ and $I_{\mathrm{in}}=24\mathrm{pA}$. One open ion channel carries $1.2\mathrm{pA}$. These are illustrative values, not measurements. At $V=E_{\mathrm{rev}}$, the net electric current vanishes despite open ion channels; neither binding nor opening alone determines the readout. The approximation omits changes in ion concentrations and voltage-dependent open-channel electrical conductance.

A motivating experiment made the elementary electrical events visible. As Bert Sakmann recounts, chronically denervated frog muscle fibers had acetylcholine-sensitive receptors spread beyond the original nerve contact. Mild enzyme treatment exposed the cell membrane; a polished glass pipette sealed over a small patch to reduce background noise. Two intracellular electrodes held the local membrane potential through voltage clamp, while the patch pipette recorded tiny electric currents. Applying suberyldicholine, a ligand that activates the acetylcholine receptor and prolongs openings, revealed abrupt, approximately rectangular current events. Their amplitudes agreed reasonably with estimates from whole-membrane current fluctuations. This established discrete opening and closing events; it did not make every ligand response instantaneous. Background noise and finite recording bandwidth concealed sufficiently small or brief events.^[ref]

Recording an intact membrane patch alone does not exclude intracellular relays. Tank, Huganir, Greengard and Webb supplied a complementary isolation test in 1983: they purified nicotinic acetylcholine receptors from an electric ray's electric organ, incorporated them into artificial lipid membranes, and fused small vesicles into larger vesicles by freezing and thawing. Sealed glass-pipette recordings from isolated membrane patches resolved functional ion channels with properties resembling those in muscle. Removing the intact cytoplasm and its signaling machinery supports the sufficiency of the receptor complex for channel function; an artificial lipid environment still cannot reproduce every native regulatory interaction.^[ref]

Direct gating supports millisecond communication at many chemical synapses. Response duration also depends on neurotransmitter clearance, binding and channel-state transitions. Continued ligand exposure can prolong activity. Classify an ionotropic receptor by its direct connection between recognition and pore gating, rather than a universal duration cutoff. ^[ref]

A membrane potential can coexist with near electroneutrality in the bulk cytosol and external chemical solution. The small imbalance producing the voltage lies near the cell membrane; most positive and negative electric charges balance in the bulk.^[ref]

For a separate original capacitor model, choose a total membrane capacitance $C=5\mathrm{pF}$ and $V_m=-70\mathrm{mV}$. These are stipulated parameters, not measured properties of a particular biological cell, and this voltage is not asserted to equal the preceding $E_{\mathrm{K}}$. Model the separated electric charge relative to an uncharged reference byUsing the elementary charge $e=1.602176634\times 10^{-19}\mathrm{C}$, this representsexcess monovalent negative-charge equivalents inside. These can represent a deficit of positive ions, rather than the arrival of that many negative ions.

Independently choose an internal reservoir volume $\mathcal{V}=1\mathrm{pL}=10^{-12}\mathrm{L}$ containing $140\mathrm{mM}=0.140\mathrm{mol}{\mathrm{L}}^{-1}$ potassium, with balancing negative electric charge. With the Avogadro constant $N_A=6.02214076\times 10^{23}\mathrm{mo}{\mathrm{l}}^{-1}$, its potassium inventory isThus, if charging were entirely due to outward monovalent potassium transport, about one in $38600$ of these potassium ions would suffice. This is a comparison with the chosen potassium inventory, not a fraction of all charged particles or a measurement of spatial charge density. No shape, surface area or thickness has been inferred from the chosen capacitance and volume. The calculation illustrates why substantial voltage does not require a strongly charged bulk cytosol.

A membrane potential is an electric potential difference across a cell membrane. We use the conventionTaking the external electric potential as zero makes $V_m<0$ mean that the inside is at lower electric potential. “Negative inside” describes a difference, not an absolute electric potential, and does not imply that the entire cytosol has a large net negative electric charge.

Consider a cell membrane permeable only to potassium ions, with higher potassium concentration inside. Diffusion initially favors outward transport. If balancing negative ions cannot follow, that loss of positive electric charge produces a small inner excess of negative electric charge and an outer positive excess. The resulting electric field favors inward potassium transport. At the Nernst equilibrium potential, chemical and electrical contributions to electrochemical potential balance; ions still cross both ways, with zero net transport.^[ref]

In living biological cells, several ions can permeate and pumps maintain their concentration differences through active transport. Pumps transporting net electric charge also contribute electric current. Thus $V_m=E_{\mathrm{K}}$ is a special limit, not a universal rule; membrane potential need not always be negative.^[ref] The existing reversal potential example shows how opposing electric currents can balance without each ion reaching thermodynamic equilibrium. This makes selective permeability a way to convert chemical differences into electrical signals: changing the available ion channels changes which electrochemical gradients influence the voltage.

A metabotropic receptor couples ligand recognition to intracellular signal transduction, which can regulate a separate ion channel, alter enzyme activity or change gene expression. In the usual neurotransmitter context, metabotropic receptors are G protein-coupled receptors: receptor activation is relayed by a G protein. There need not be a change in membrane potential at all. ^[ref]

Two routes should be distinguished. An activated G protein can regulate an ion channel locally at the cell membrane, without an obligatory diffusible second messenger. Alternatively, it can regulate an enzyme that changes the availability of a second messenger, such as cAMP or inositol trisphosphate. Downstream proteins then change channel opening, phosphorylation or other cellular activities. The receptor, G protein, second messenger and final target are distinct components; an activated G protein is a relay protein, rather than itself a small-molecule second messenger.^[ref]

Do not turn this useful chemical synapse classification into the claim that every receptor is a GPCR, or that every indirect response must pass through a G protein. For example, the insulin receptor is an enzyme-linked cell-surface receptor whose intracellular catalytic activity initiates protein phosphorylation. Intracellular receptors supply another category. “Metabotropic” commonly names the GPCR branch in neuroscience; the broader idea of biochemical coupling does not make all non-channel receptors structurally identical. ^[ref]

Separating recognition from execution allows signal amplification and branching. A persistently activated receptor can activate several relay proteins; a regulated enzyme can produce many second messenger molecules. As an explicitly invented count example, suppose one activated receptor activates four relay proteins during one interval, and each relay activates a distinct enzyme that produces fifteen second messenger molecules during the next interval. With sufficient substrates and no loss, this gives $4\times 15=60$ molecules. Those counts do not specify a physiological gain or response duration. A directly gated ion channel also passes many ions while open, so amplification is not an exclusive property of metabotropic receptors: always name the input and output being compared. ^[ref]

A particularly instructive electrophysiology experiment separated a chemical trigger from the ion channel carrying its eventual electric current. In 1987, Hirono, Ito and Sugiyama injected messenger RNA from rat brain into frog egg cells, then tested acquired responses to neurotensin and muscarinic acetylcholine stimulation. Under voltage clamp at $-60\mathrm{mV}$, neurotensin elicited transient, oscillatory inward electric currents after a delay of several tens of seconds. This delay refers to that response and preparation. Reversal potential measurements implicated increased permeability to chloride anions, rather than a pore specific to the applied ligand. Both neurotensin and acetylcholine responses were inhibited by pertussis toxin, which interferes with susceptible G proteins, and by intracellular EGTA, which binds free calcium. Injecting inositol trisphosphate mimicked the responses; a large prior dose of inositol trisphosphate reduced subsequent responses to either extracellular signal. These interventions implicate a shared intracellular relay and calcium-dependent channel opening.^[ref]

The informative comparison with the nicotinic acetylcholine receptor experiment is mechanistic: an extracellular ligand can produce an inward electric current either by directly gating the pore or by mobilizing an intracellular second messenger and stored calcium that activate another pore. Intracellular inositol trisphosphate bypasses reception, whereas EGTA tests the need for free calcium. However, neither inhibition nor mimicry alone identifies every molecular connection: a perturbation can affect several targets, and an injected mediator can activate a pathway without proving that it is the only natural route. The egg cell's endogenous machinery and the mixed messenger RNA preparation also limit extrapolation to an intact neuron. The experiment establishes functional coupling in its preparation, rather than the exact molecular composition or timing of every metabotropic receptor.

Even G protein-dependent channel regulation need not involve a lengthy second messenger cascade. Pfaffinger and colleagues reported in 1985 that acetylcholine-evoked potassium channel activation in embryonic chick atrial cells required intracellular GTP, a guanine-containing nucleotide, and was abolished by pertussis-toxin pretreatment. Changes in cyclic nucleotides, including cAMP, did not account for the channel response. The report discusses intrinsic activation delays of roughly $30$–$100\mathrm{ms}$, illustrating relatively rapid metabotropic receptor action. These observations support a G protein coupling step without cyclic-nucleotide second messengers; they do not by themselves exclude every possible intermediary or prove the specific subunit-channel interaction.^[ref]

A small timing model makes the extra steps visible without inventing an experimental trace. Let $u(t)$ jump from zero to one at $t=0$ and remain on. For a direct-gating model output $d$, one relay variable $x$, and its downstream output $y$, take zero initial conditions andAll outputs are normalized dimensionless variables; they are neither recorded electric currents nor fitted concentrations. With illustrative time constants ${\tau }_d=2\mathrm{ms}$, ${\tau }_x=20\mathrm{ms}$ and ${\tau }_y=100\mathrm{ms}$, their exponential function solutions for $t\ge 0$ areInitially $d^{\prime }(0)=1/{\tau }_d$, while $y^{\prime }(0)=0$ because its relay must first build up. Both outputs eventually approach one. Equal normalized final values do not imply equal biological amplitudes or absence of signal amplification; normalization deliberately removes that question.

The model's useful feature is the delayed buildup created by sequential relaxation, not its arbitrary numbers. Actual kinetics also depend on ligand delivery, relay deactivation, neurotransmitter clearance and the final target. A local G protein route can act promptly, while an ionotropic receptor can remain active during continued exposure or feed a longer-lasting intracellular response. The beauty of metabotropic receptor coupling is its flexibility: the same recognition event can adjust electrical responsiveness and other cellular tasks through different targets. To classify an observed response, combine timing with molecular identity and controlled perturbations.

A neuronal refractory period is the change in excitability following an action potential: recent firing changes whether, and how readily, a neuron can fire again. The absolute neuronal refractory period prevents a second regenerative action potential; during the relative neuronal refractory period, some stimuli that work after full recovery still fail. These are useful distinctions, but their durations are not universal constants. The preparation, temperature, starting membrane potential, stimulation protocol and criterion for detecting an action potential must accompany a measured interval.

The mechanism continues the opposing sodium and potassium electric currents described under action potential and the Hodgkin-Huxley model. After a spike, ion-channel inactivation leaves fewer sodium-selective voltage-gated ion channels available for regenerative depolarization, while persisting potassium electrical conductance opposes that depolarization. In the Hodgkin-Huxley model, recovery of $h$ restores sodium availability and relaxation of $n$ reduces potassium electrical conductance. Closed but available channels differ from inactivated channels: opening and recovery from ion-channel inactivation are different processes.^[ref]

This short memory matters for spike trains: a stimulus-only Poisson process can predict very short interspike intervals that a refractory neuron cannot produce. Neuronal paired-pulse recovery makes that memory visible. The phenomenological paired-pulse recovery example below separates a chosen recovery rule, pulse strength and event readout; refractory limits on neuronal firing then shows why an absolute bound is not a prediction of sustained firing rate.

Alan Hodgkin and Andrew Huxley recorded the membrane potential directly between the inside of a squid axon and the external solution. The crucial result was an action potential that passed through zero: the interior became positive, rather than merely losing its negative resting membrane potential. A theory in which excitation simply abolishes membrane selectivity and shorts out the resting membrane potential cannot account for that reversal. Their original report establishes the historical interpretation independently of the unavailable examination picture.^[ref]

The later Hodgkin-Huxley model explains the rising phase through increased sodium permeability and the falling phase through sodium ion-channel inactivation and increased potassium permeability. Distinct Nernst equilibrium potentials make a selective conductance change capable of reversing the membrane potential. The recording established the phenomenon; it did not by itself reveal individual ion channel structures or all their gating kinetics.

Source illustration TODO: the source page's recording is missing in both the held PDF and its archive parent. No amplitudes, time intervals, or trace layout are reconstructed here; the surviving historical request is answered above.

Here $V_m$ is the inside-minus-outside membrane potential, $V_K$ is the potassium Nernst equilibrium potential, and ${\bar{g}}_K$ is the maximum potassium conductance, or conductance per area if $I_K$ is a current density. The factor $n\in [0,1]$ is the permissive-state probability of an activation gate. Four independent permissive gates in an ion channel give the open fraction $n^4$, henceThe model assumes identical independent gating units, additive currents from many ion channels, an approximately ohmic open-pore current, and fixed ionic activities setting $V_K$. Outward positive electric current is obtained for $V_m>V_K$. The original delayed-rectifier term omits rapid ion-channel inactivation. The fourth power is a successful phenomenological gating description, rather than a deduction of the molecular structure from this equation alone.

Fast ion-channel inactivation would reduce the outward potassium electric current just when it normally repolarizes the axon. Since $C_m{\dot{V}}_m=I_{\mathrm{applied}}-I_{\mathrm{Na}}-I_K-I_{\mathrm{leak}}$, a reduction of positive $I_K$ makes the falling slope less negative. With other mechanisms unchanged, the action potential is generally broader and its after-hyperpolarization is weaker. A plateau or slow return is possible until sodium ion-channel inactivation, leakage, or another outward conductance restores the resting membrane potential. The precise trace depends on those remaining currents; rapid potassium inactivation alone does not determine a unique waveform.

The left panel is a qualitative sketch of this comparison, not a fit or a reconstruction of the missing historical recording.

In classical ball-and-chain inactivation, a cytoplasmic N-terminal part of the voltage-gated potassium channel acts as a tethered blocking particle. Once the pore opens, this particle reaches and occludes its intracellular entrance. The flexible connecting segment allows access; removal of the block permits recovery. Thus opening and subsequent loss of conduction can occur even while the activating voltage remains applied.

Several independent observations support this mechanism. Removing or disrupting the N-terminal inactivation segment suppresses fast ion-channel inactivation while leaving activation possible. An appropriate soluble peptide applied from the cytoplasmic side restores an open-channel block in otherwise noninactivating channels. Changes in the blocking segment alter block kinetics, while changing its access or tether can alter how rapidly it finds the pore. Rescue in trans is particularly informative: the blocking particle need not remain covalently attached to produce the effect.^[ref][ref]

This mechanism is N-type inactivation. It should not be generalized to every potassium ion channel: C-type inactivation instead involves changes associated with the outer pore and selectivity filter.

Full dissociation gives bulk concentrations in $\mathrm{mM}$ of $155$ for sodium, $5$ for potassium, $2$ for calcium, $114$ for chloride, and $25$ for hydrogen phosphate. The positive and negative charge concentrations are both $164\mathrm{mM}$, so the bulk is electrically neutral. At $T=298.15\mathrm{K}$,The Boltzmann distribution then givesFor completeness the coion concentrations are $114e^{-\nu }=6.65196\mathrm{mM}$ and $25e^{-2\nu }=0.0851195\mathrm{mM}$. They are depleted, not zero. Using $1\mathrm{mM}=1\mathrm{mol}{\mathrm{m}}^{-3}$ and multiplying molar concentrations by the Avogadro constant in the Grahame equation givesThis calculation retains every species. Since $|{\varphi }_0|/V_T=2.84$, a linear Debye–Hückel approximation is not justified. The large accumulation, especially of divalent counterions, follows from the valence in the Boltzmann factor. However, multi-molar local concentrations also warn that point-ion mean-field theory neglects finite ion size, hydration, specific adsorption, correlations, and changes in local permittivity. These are predictions of the stated idealized model, not precise measured interfacial concentrations.