Chapter 4: The Action Potential — Comprehensive Study Notes
Introduction
The action potential (AP) is the signal that conveys information over distances in the nervous system.
Resting membrane potential (Vm) is negative inside relative to outside; during an AP, the inside briefly becomes positive.
Terminology: spike, nerve impulse, discharge.
APs generated by a patch of membrane are uniform in size and duration and do not diminish as they are conducted along the axon.
The frequency and pattern of APs constitute the neural code for transferring information.
This chapter explains mechanisms of AP generation and propagation along the axon.
Properties of the Action Potential
Universal properties shared by axons across species (from squid to humans).
Key questions: What does an AP look like? How is it initiated? How rapidly can a neuron generate APs?
AP waveform: rising phase (rapid depolarization) → overshoot (inside becomes positive) → falling phase (rapid repolarization) → undershoot or after-hyperpolarization (AHP) → restoration of resting potential.
Typical timings: AP lasts about 2 ext{ ms}.
Recording APs: intracellular measurements vs extracellular, often using an oscilloscope for voltage vs. time; intracellular measures Vm, extracellular detects transmembrane currents at membranes near the recording site.
The Ups and Downs of an Action Potential
Resting Vm ≈ -65 mV.
During AP, Vm briefly becomes positive (overshoot).
The AP has identifiable parts: rising phase, overshoot, falling phase, undershoot, and return to resting potential.
Measuring and displaying APs: oscilloscope traces of Vm over time.
The AP is an all-or-none event: once threshold is crossed, an AP is generated; further depolarization does not produce a larger initial response in a single AP.
Box 4.1: Methods of Recording Action Potentials (intracellular vs extracellular)
Intracellular recording: microelectrode impales neuron; measures potential difference between intracellular electrode and ground; high conductivity solution (often KCl); can detect currents and potentials; often displayed with an oscilloscope.
Extracellular recording: recording near the membrane; measures potential difference between recording electrode and ground; reflects current flow across the membrane when AP passes by.
Each method has distinct scales and interpretations; intracellular tends to show larger voltage changes than extracellular.
The Generation of an Action Potential
AP initiation begins when a nerve ending’s membrane is stretched (a mechanical stimulus) or when depolarization reaches a threshold.
Threshold is the critical depolarization needed to trigger an AP.
In interneurons, depolarization can be due to Na+ entry via channels activated by neurotransmitters; other neurons can be depolarized by injected current via a microelectrode.
Analogy: threshold is like a camera shutter; crossing threshold triggers an action (AP).
The AP is an all-or-none event due to the voltage-gated Na+ channels’ properties and the threshold phenomenon.
Box 4.2: Path of Discovery — Channelrhodopsins and Optogenetics (Georg Nagel et al.)
Channelrhodopsin-2 (ChR2) is a light-gated cation channel permeable to Na+ and Ca2+; opens rapidly in response to blue light (≈460 nm).
Halorhodopsin is a light-activated Cl− pump; used as a hyperpolarizer with yellow light (≈580 nm).
Discovery enabled optogenetics: control of neuronal firing with light by expressing light-gated channels in neurons.
ChR2 originally characterized in Frankfurt; subsequent work with ChR2-YFP allowed visualization of expression and experiments in C. elegans and mammalian neurons.
The box highlights the evolution of optogenetics from discovery to toolkit expansion and therapeutic potential.
Optogenetics: Controlling Neural Activity with Light (continuation)
Neurons can be depolarized (via ChR2) or hyperpolarized (via halorhodopsin) with light, enabling precise, noninvasive control of firing rates.
This approach transformed neuroscience by enabling causal tests of neuronal function and behavior.
The Action Potential, in Theory
The AP is a dramatic redistribution of electrical charge across the membrane: depolarization via Na+ influx, repolarization via K+ efflux.
Membrane currents and conductances:
Idealized neuron with Na+/K+ pumps, K+ channels, and Na+ channels.
Ion gradients: assume K+ concentrated inside (- inside/outside distribution) and Na+ concentrated outside.
Nernst potentials at 37°C: EK \,=-80\text{ mV},\quad E{Na} \,=+62\text{ mV}. (From the text; E values are used to compute driving forces.)
If only K+ channels are open (gK > 0, gNa = 0), Vm moves toward EK (≈ -80 mV).
Driving force and current relation (Ohm's law for ions):
Three core relationships:
1) The net K+ current is a function of conductance and driving force: IK = gK (Vm - EK).
2) More generally: I{ion} = g{ion} (Vm - E{ion}).
3) The driving force on an ion is the difference between the membrane potential and its equilibrium potential: Vm - E{ion}.
The action potential can be explained by switching dominant membrane permeability from K+ to Na+ (depolarization) and back to K+ (repolarization).
Rising phase explained by transient increase in g_Na and Na+ influx driving Vm toward ENa; falling phase explained by inactivation of Na+ channels and continued K+ conductance.
The model predicts the key temporal sequence: Na+ channels open rapidly, then inactivate; K+ channels open with a delay (~1 ms) and drive Vm back toward EK.
The patch-clamp breakthroughs enabled precise measurement of conductances and currents, validating the Na+/K+ mechanism.
The Action Potential, in Reality
True AP dynamics: brief transient Na+ conductance increase (gNa) with rapid Na+ influx; brief channel opening and inactivation; transient K+ conductance increase (gK) leading to K+ efflux and repolarization.
The role of the Na+ and K+ channels explains threshold, rising phase, overshoot, falling phase, and refractoriness.
The Voltage-Gated Sodium Channel
Structure: a single polypeptide with four homologous domains I–IV; each domain contains six transmembrane segments S1–S6.
The four domains come together to form the pore; gating is voltage-dependent.
The Na+ selectivity filter makes the channel ~12-fold more permeable to Na+ than to K+; ions pass with partial dehydration and water molecules act as a chaperone.
The voltage sensor resides in the S4 segment, which contains regularly spaced positively charged residues; depolarization moves S4 and opens the channel gate.
Functional properties (from patch-clamp studies):
Opening occurs with little delay upon depolarization beyond threshold.
Open state lasts ~1 ms, then inactivation occurs.
After inactivation, channels cannot be opened again until membrane potential returns to a negative value (deinactivation).
A single channel’s conductance is unitary; thousands of channels operate in parallel to generate the full AP.
The short open time and inactivation explain the brief AP and the absolute refractory period.
Box 4.3: The Patch-Clamp Method
Patch-clamp enables recording currents through single channels by forming a gigaseal (~10^9 ohms) between a glass pipette and a patch of membrane and then applying suction.
Patch can be held at a set membrane potential; current through the patch is measured; single-channel openings produce characteristic unitary currents.
Patch-clamp revealed two-state behavior: open vs closed for most channels.
The Effects of Toxins on the Sodium Channel
Tetrodotoxin (TTX) blocks the Na+ pore by binding to a site on the outside; blocks all Na+-dependent APs and is often fatal if ingested.
Saxitoxin (from dinoflagellates) similarly blocks Na+ channels and can accumulate in shellfish during red tides.
Batrachotoxin (frogs) forces channels open at more negative potentials and can prolong opening, scrambling AP signaling.
Veratridine and aconitine have similar actions; scorpion and sea anemone toxins can disrupt Na+ channel inactivation.
Toxins are useful experimental tools and have aided structure-function understanding of Na+ channels.
Voltage-Gated Potassium Channels
Hodgkin and Huxley showed that the falling phase involves a transient increase in g_K and K+ efflux after Na+ channels inactivate.
They proposed potassium gates that open with depolarization, but with a delay (~1 ms) relative to Na+ gates.
Four-subunit potassium channels form a pore that opens in response to voltage changes, enabling K+ efflux to restore the resting Vm.
Putting the Pieces Together (key properties of the AP)
Threshold: the membrane potential at which enough voltage-gated Na+ channels open to favor Na+ over K+ conductance.
Rising phase: inward Na+ current depolarizes the cell.
Overshoot: Vm approaches ENa, which is positive relative to 0 mV.
Falling phase: Na+ channels inactivate and K+ channels open, causing K+ efflux.
Undershoot: Vm hyperpolarizes toward EK due to continued K+ permeability.
Absolute refractory period: Na+ channels inactivate; another AP cannot be generated until deinactivation occurs when Vm becomes sufficiently negative.
Relative refractory period: after the absolute period, a stronger depolarizing input can elicit an AP until the membrane returns to baseline thresholds and channels close.
The Na+/K+ pump continues to maintain concentration gradients in the background, contributing to the steady-state conditions that allow repetitive APs.
Action Potential Conduction
After generation, the AP must propagate along the axon to reach the synapse; this is like a burning fuse.
Propagation mechanism: depolarization at one patch of membrane spreads to the adjacent patch, triggering Na+ channels there to open and generate the next segment AP.
Directionality: normally orthodromic (soma to terminal) because the patch just behind the AP is refractory due to Na+ channel inactivation; antidromic conduction (from terminal back toward soma) is possible experimentally, but not typical physiologically.
AP conduction velocities vary; a typical velocity is about 10 ext{ m/s}. The AP lasts about 2 ext{ ms}, so an AP traveling at 10 m/s traverses roughly 2 imes 10^{-2} ext{ m} = 2 ext{ cm} of axon during the event.
Key factors influencing conduction velocity:
Axonal diameter: larger diameter reduces internal resistance and increases conduction speed.
Membrane leak: more leaks (more open channels) dissipate current, slowing conduction.
Myelination: increases speed dramatically by reducing membrane capacitance and forcing current to jump between nodes (saltatory conduction).
Box 4.4: Local Anesthesia (special interest)
Local anesthetics (e.g., lidocaine) block action potentials by binding to voltage-gated Na+ channels, preventing Na+ influx.
Binding site identified as the S6 alpha-helix of domain IV; access requires crossing the membrane and entering the open channel gate.
Smaller axons (which require fewer channels to conduct a given signal) are blocked at lower concentrations, making them more susceptible to local anesthetics.
Box 4.5: Myelin and Saltatory Conduction (special interest)
Myelin insulation (formed by Schwann cells in the PNS and oligodendroglia in the CNS) increases conduction velocity by reducing current leakage and capacitance.
Nodes of Ranvier are gaps in the myelin where voltage-gated Na+ channels are concentrated; APs jump from node to node (saltatory conduction).
Distances between nodes typically range from 0.2 to 2.0 mm depending on axon size.
Box 4.4 and Box 4.5 illustrate clinical relevance: demyelinating diseases (e.g., Multiple Sclerosis, Guillain–Barré syndrome) slow or disrupt saltatory conduction, highlighting myelin’s role in rapid signaling.
Axon anatomy and the spike-initiation zone
The spike-initiation zone is typically located at the axon hillock, where high densities of voltage-gated Na+ channels enable AP initiation.
In many sensory neurons, the spike-initiation zone is at the peripheral sensory nerve endings.
Dendrites generally do not generate Na+-driven APs; their signaling is typically via graded potentials and synaptic inputs.
Box 4.6: The Eclectic Electric Behavior of Neurons
Neurons vary in electrical behavior: some neurons fire at steady rates, others adapt, burst, or show rhythmic bursting.
The diversity arises from the variety and distribution of ion channels across neuronal membranes; interactions among many ion channel types produce different firing patterns and responses to stimuli.
The Experimental Toolbox and Real-World Relevance
Box 4.3: The Patch-Clamp Method (revisited)
A technical breakthrough enabling measurement of currents through single ion channels.
Key idea: seal a recording electrode onto a patch of membrane; measure currents under controlled voltages to infer conductance and channel kinetics.
Toxins and disease as windows into channel function
Toxins reveal channel architecture and gating mechanics and can be used to block or modify signaling in experiments.
Channelopathies are diseases arising from dysfunctional ion channels (e.g., some epilepsies linked to Na+ channel mutations).
Optogenetics: a synthesis of genetics and optics enabling precise control of neural activity with light (ChR2, halorhodopsin) and has revolutionized neuroscience research and potential therapies.
Concluding Remarks and Synthesis
The AP is governed by the orchestrated opening and closing of voltage-gated Na+ and K+ channels, governed by membrane voltage and channel kinetics.
Ion pumps (Na+/K+ ATPase) maintain ionic gradients, enabling the driving forces that power APs.
AP conduction depends on axon properties (diameter, myelination) and can be modulated by disease, pharmacology, or genetic differences in channel proteins.
Neuronal signaling is not a single process but a network of ion channel dynamics, conduction, and synaptic transmission, which together underlie brain function and information processing.
Key Concepts and Equations (summary)
Resting membrane potential: V_m^{rest} \approx -65 \,\text{mV}.
Action potential peaks and phases: rising phase, overshoot, falling phase, undershoot, restoration.
Threshold: the depolarization level at which enough voltage-gated Na+ channels open to trigger the AP.
Peak values: typical overshoot near E_{Na} \,= 62\text{ mV}.
Driving forces and currents:
General current: I{ion} = g{ion} (Vm - E{ion}).
Specific ions: IK = gK (Vm - EK), I{Na} = g{Na} (Vm - E{Na}).
Refractory periods:
Absolute refractory period: roughly ~1 ms; Na+ channels inactivated and cannot be reopened until deinactivation.
Relative refractory period: after absolute, higher depolarizing current needed to reach threshold due to hyperpolarization.
Ion channels and gating concepts:
Voltage-gated Na+ channel structure: four domains (I–IV), each with S1–S6; S4 as the voltage sensor; selectivity filter.
Activation and inactivation gates account for rapid opening, brief open time (~1 ms), and inactivation.
Patch clamp: technique to measure single-channel and multi-channel currents; gigaohm seal; unitary currents; patch allows measurement of conductance and kinetics.
Toxins and pharmacology:
TTX and saxitoxin block Na+ channels; batrachotoxin and related toxins modify gating to alter opening/closing.
Local anesthetics (e.g., lidocaine) block Na+ channels by binding to S6 in domain IV from inside the channel, with higher efficacy on active fibers.
Myelination and saltatory conduction:
Myelin insulation speeds conduction by reducing capacitance and leakage; APs propagate via nodes of Ranvier; conduction velocity depends on myelination and axon diameter.
Spike-initiation zone:
High density of Na+ channels at axon hillock or sensory nerve endings defines where the AP starts.
Optogenetics:
ChR2: blue-light-activated cation channel permits depolarization to trigger APs.
Halorhodopsin: yellow-light-activated Cl− pump that hyperpolarizes and inhibits AP firing.
Connections to Foundational Principles
The AP illustrates core neurophysiology concepts: neurons encode information in spike rate and pattern, not just the presence of a depolarization.
The balance of ionic gradients and ion channel properties underpins all electrical signaling in excitable membranes.
Experimental methods (voltage clamp, patch clamp, optogenetics) provide causal links between ion channel behavior and neuronal outputs.
Clinical relevance: demyelinating diseases disrupt saltatory conduction; local anesthetics exploit Na+ channel properties to block nociceptive signaling; channelopathies illustrate the importance of ion channels for normal brain function.
Practice and Review Questions (from the chapter's prompts)
Define membrane potential (Vm) and Na+ equilibrium potential (E_Na). Which changes during an AP?
Which ions carry the early inward and late outward currents during the AP?
Why is the AP described as an “all-or-none” event?
What would happen if delayed rectifier K+ channels opened much later than normal?
If tetrodotoxin (TTX) labels a neuron, which parts would be labeled and what would be the consequence of applying TTX?
How does AP conduction velocity vary with axonal diameter? Explain the mechanism.
References and Further Reading
Nagel G, Szellas T, Huhn W, et al. 2003. Channelrhodopsin-2, a directly light-gated cation-selective membrane channel. Proc. Natl. Acad. Sci. USA 100:13940–13945.
Boyden ES, Zhang F, Bamberg E, Nagel G, Deisseroth K. 2005. Millisecond-timescale, genetically targeted optical control of neural activity. Nature Neuroscience 8:1263–1268.
Hille B. 1992. Ionic Channels of Excitable Membranes, 2nd ed. Sunderland, MA: Sinauer.
Neher E., Sakmann B. 1992. The patch-clamp technique. Scientific American 266:28–35.
Nicholls J., Martin AR., Fuchs PA., Brown DA, Diamond ME, Weisblat D. 2011. From Neuron to Brain, 5th ed. Sunderland, MA: Sinauer.
Boxed Highlights (short summaries)
Box 4.1: Recording action potentials—intracellular vs extracellular methods.
Box 4.2: Channelrhodopsins and the birth of optogenetics; ChR2 and halorhodopsin as tools to control neuronal activity with light.
Box 4.3: Patch-clamp method and single-channel recordings; unitary conductance.
Box 4.4: Local anesthesia and the S6 domain IV binding site of lidocaine; small fibers are more susceptible to block.
Box 4.5: Myelin and saltatory conduction; MS and Guillain–Barré syndrome illustrate conduction deficits.
Box 4.6: The diverse electrical behaviors of neurons arise from a repertoire of ion channels and their interactions.
Note: This study guide summarizes major concepts, mechanisms, and numerical benchmarks from the chapter to support exam preparation. Numbers, symbols, and equations are provided in LaTeX where indicated. If you want any section expanded into a more detailed sub-notes format or want diagrams translated into descriptive text, tell me which parts to elaborate.