Neuron Structure and Action Potentials - Anatomy and Physiology

SECTION 1

Historical Context & Motivation

The question of how the nervous system communicates information has captivated scientists for centuries. Early anatomists recognized that nerves connected the brain to the rest of the body, but the mechanism of signal transmission remained elusive until advances in microscopy, electrophysiology, and biochemistry converged to reveal the neuron as the fundamental signaling unit. Understanding the structure of neurons and the electrical events that propagate signals along them—known as action potentials—is essential for grasping how the nervous system integrates sensory input, coordinates motor output, and supports higher cognitive functions. The history of this understanding is a story of incremental discoveries, each building on the last, that transformed neuroscience from philosophical speculation into a rigorous experimental discipline.

1791 • Galvani's Bioelectricity

Luigi Galvani demonstrated that electrical stimulation caused frog leg muscles to contract, providing the first evidence that animal tissues generate and respond to electricity—a concept he termed 'animal electricity.'

1888 • Ramón y Cajal's Neuron Doctrine

Santiago Ramón y Cajal used Golgi staining to argue that the nervous system is composed of discrete individual cells rather than a continuous reticulum, establishing the neuron doctrine that underpins modern neuroscience.

1939 • Hodgkin & Huxley Begin Squid Axon Work

Alan Hodgkin and Andrew Huxley began recording electrical signals from the giant axon of the squid Loligo, exploiting its large diameter (~1 mm) to insert electrodes and measure transmembrane voltage changes directly.

1952 • The Hodgkin–Huxley Model

Hodgkin and Huxley published their landmark quantitative model describing ionic conductance changes during the action potential, earning them the 1963 Nobel Prize in Physiology or Medicine.

1976 • Patch Clamp Technique

Erwin Neher and Bert Sakmann developed the patch clamp method, enabling the recording of currents through single ion channels, confirming that discrete channel proteins mediate membrane conductance.

These discoveries collectively answered a fundamental question: how does a nerve cell encode and transmit information across distances that can span more than a meter? The answer lies in the interplay between the neuron's specialized anatomy and the precisely orchestrated opening and closing of voltage-gated ion channels that generate action potentials. In the sections that follow, we will dissect both the structural and electrochemical foundations of this process.

SECTION 2

Core Principles & Definitions

Before exploring the detailed anatomy and physiology of neurons, it is important to establish a set of foundational principles that govern how nerve cells operate. Neurons are excitable cells—meaning they respond to stimuli by generating rapid, transient changes in membrane voltage. These voltage changes depend on the asymmetric distribution of ions across the cell membrane, the selective permeability of that membrane, and the properties of specialized protein channels embedded within it. The following core concepts provide the scaffolding on which a deeper mechanistic understanding can be built.

Resting Membrane Potential

At rest, a typical neuron maintains a voltage of approximately −70 mV across its plasma membrane (inside negative relative to outside). This resting potential arises primarily from the selective permeability of the membrane to K⁺ ions and the activity of the Na⁺/K⁺-ATPase pump.

Electrochemical Gradients

Ions are driven across the membrane by two forces: the concentration gradient (diffusion from high to low concentration) and the electrical gradient (attraction toward opposite charge). Together, these constitute the electrochemical gradient.

Threshold & All-or-None Firing

If a stimulus depolarizes the membrane to approximately −55 mV (threshold), an action potential is triggered. Once initiated, the action potential proceeds to completion at full amplitude regardless of stimulus strength—the all-or-none principle.

Voltage-Gated Ion Channels

The action potential depends on voltage-gated Na⁺ channels (which open rapidly upon depolarization) and voltage-gated K⁺ channels (which open more slowly to repolarize the membrane). Their sequential gating produces the characteristic spike.

Saltatory Conduction

In myelinated neurons, the action potential 'jumps' between nodes of Ranvier—gaps in the myelin sheath—dramatically increasing conduction velocity. This mechanism, called saltatory conduction, can reach speeds exceeding 100 m/s.

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KEY TAKEAWAY

Think of the neuron's resting membrane potential like a loaded spring: the Na⁺/K⁺-ATPase and leak channels establish a state of stored electrochemical energy. When threshold is reached, it is as though the spring is released—the action potential fires automatically and completely, propagating like a row of dominoes falling along the axon. The energy was already stored in the ion gradients; the stimulus merely triggers its release.

SECTION 3

Visual Explanation — Neuron Anatomy

A neuron's anatomy is exquisitely adapted to its dual functions of receiving input and transmitting output over long distances. The diagram below illustrates the major structural regions of a typical multipolar neuron, the most common type found in the central nervous system. Each region plays a distinct role in the generation and propagation of electrical signals.

A multipolar neuron showing the dendrites (input receivers), soma with its nucleus, axon hillock (integration zone), myelinated axon interrupted by nodes of Ranvier, and axon terminals that release neurotransmitters at synapses.

The dendrites are highly branched extensions that receive synaptic input from other neurons, transducing chemical signals into small, graded changes in membrane potential called postsynaptic potentials. These graded potentials spread passively toward the soma (cell body), which houses the nucleus and the bulk of the cell's biosynthetic machinery. The graded potentials converge at the axon hillock, a specialized region with a particularly high density of voltage-gated Na⁺ channels. If the sum of all incoming signals depolarizes the axon hillock to threshold, an action potential is initiated and propagated along the axon to the axon terminals (synaptic boutons), where neurotransmitter vesicles are released into the synaptic cleft to communicate with downstream cells.

In many neurons of the peripheral and central nervous systems, the axon is wrapped in a myelin sheath—layers of lipid-rich membrane produced by Schwann cells in the PNS and oligodendrocytes in the CNS. The myelin acts as an electrical insulator, confining ion flux to the small unmyelinated gaps called nodes of Ranvier. This arrangement enables saltatory conduction, in which the action potential effectively leaps from node to node, dramatically increasing conduction speed while conserving metabolic energy.

SECTION 4

The Ionic Basis of the Action Potential

The action potential can be understood quantitatively through two foundational equations that relate ionic concentrations and membrane permeability to voltage. These equations allow us to predict the equilibrium potential for any given ion and the net membrane potential when multiple ions contribute.

NERNST EQUATION

E_ion = (RT / zF) × ln([ion]_outside / [ion]_inside)

Where E_ion is the equilibrium potential for the ion, R is the universal gas constant (8.314 J·mol⁻¹·K⁻¹), T is absolute temperature in kelvins, z is the valence of the ion, and F is the Faraday constant (96,485 C·mol⁻¹). At 37 °C, this simplifies to approximately E = (61.5 mV / z) × log₁₀([ion]ₒ / [ion]ᵢ) using common logarithms.

GOLDMAN–HODGKIN–KATZ (GHK) EQUATION

V_m = (RT/F) × ln( (P_K[K⁺]_o + P_Na[Na⁺]_o + P_Cl[Cl⁻]_i) / (P_K[K⁺]_i + P_Na[Na⁺]_i + P_Cl[Cl⁻]_o) )

The GHK equation extends the Nernst equation by accounting for the relative permeabilities (P) of multiple ions. Note that Cl⁻ concentrations are inverted (inside in the numerator, outside in the denominator) because of its negative charge. At rest, $P_K$ dominates, pulling V_m toward E_K (≈ −90 mV). During the action potential peak, P_Na transiently dominates, driving V_m toward E_Na (≈ +60 mV).

Phases of the Action Potential

An action potential proceeds through five distinct phases. During the resting state, the membrane sits at approximately −70 mV with most voltage-gated Na⁺ and K⁺ channels closed. A depolarization phase begins when a stimulus brings the membrane to threshold (≈ −55 mV), triggering the rapid opening of voltage-gated Na⁺ channels and a massive influx of Na⁺ that drives the membrane potential toward +30 to +40 mV. The repolarization phase follows as Na⁺ channels inactivate and voltage-gated K⁺ channels open fully, allowing K⁺ efflux that returns the membrane potential toward negative values. Because K⁺ channels close slowly, the membrane briefly hyperpolarizes beyond the resting potential (the undershoot or after-hyperpolarization). Finally, during the return to resting state, leak channels and the Na⁺/K⁺-ATPase restore the original ion distributions and voltage.

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Refractory Periods

Following an action potential, the neuron enters an absolute refractory period during which Na⁺ channels are inactivated and no new action potential can be generated regardless of stimulus strength. This is followed by a relative refractory period during which a stronger-than-normal stimulus is required because the membrane is hyperpolarized and some Na⁺ channels remain inactivated. These refractory periods enforce unidirectional propagation and set an upper limit on firing frequency.

SECTION 5

The Action Potential Waveform

The action potential is most commonly visualized as a plot of membrane potential (in millivolts) against time (in milliseconds). The following diagram depicts a typical action potential waveform recorded from a mammalian neuron, with each phase labeled and the ionic conductance changes annotated. Understanding this graph is essential for interpreting electrophysiological recordings and predicting how pharmacological agents or diseases might alter neuronal signaling.

An action potential waveform: the membrane begins at resting potential (−70 mV), rapidly depolarizes past threshold (−55 mV) due to Na⁺ influx, overshoots to ~+30 mV, then repolarizes as K⁺ efflux restores negative potential. A brief hyperpolarization (undershoot) occurs before return to rest.

Phase	Voltage Range	Dominant Ion Movement	Key Channel State
Resting	≈ −70 mV	K⁺ leak outward	Na⁺ & K⁺ voltage-gated channels closed
Depolarization	−55 mV → +30 mV	Rapid Na⁺ influx	Na⁺ activation gates open
Repolarization	+30 mV → −70 mV	K⁺ efflux	Na⁺ inactivation gates close; K⁺ channels open
Hyperpolarization	−70 mV → −90 mV	Continued K⁺ efflux	K⁺ channels slow to close
Return to Rest	−90 mV → −70 mV	Na⁺/K⁺-ATPase restores gradients	All voltage-gated channels reset to closed

Summary of action potential phases with ionic and channel dynamics

SECTION 6

Worked Example — Calculating Equilibrium Potential

Let us apply the Nernst equation to calculate the equilibrium potential for potassium (K⁺) in a typical mammalian neuron at body temperature (37 °C). The intracellular K⁺ concentration is approximately 140 mM, and the extracellular K⁺ concentration is approximately 5 mM.

Nernst Equilibrium Potential for K⁺

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Step 1 — Identify Given Values

We are given the following: [K⁺]_outside = 5 mM, [K⁺]_inside = 140 mM, T = 37 °C = 310 K, z = +1 (K⁺ is monovalent), R = 8.314 J·mol⁻¹·K⁻¹, F = 96,485 C·mol⁻¹.

All values identified and converted to SI units.
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Step 2 — Apply the Simplified Nernst Equation at 37 °C

At 37 °C, the Nernst equation simplifies to: E_K = (61.5 mV / z) × log₁₀([K⁺]_o / [K⁺]_i). Substituting: E_K = (61.5 mV / 1) × log₁₀(5 / 140).

E_K = 61.5 mV × log₁₀(0.0357)
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Step 3 — Evaluate the Logarithm

log₁₀(0.0357) = log₁₀(5/140) = log₁₀(5) − log₁₀(140) ≈ 0.699 − 2.146 = −1.447.

log₁₀(0.0357) ≈ −1.447
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Step 4 — Calculate the Final Equilibrium Potential

E_K = 61.5 mV × (−1.447) ≈ −89.0 mV. This value is close to the commonly cited equilibrium potential for K⁺ of approximately −90 mV. Since the resting membrane potential (≈ −70 mV) is more positive than E_K, there is a net driving force pushing K⁺ outward at rest—consistent with the known K⁺ leak current that contributes to the resting potential.

$E_K$ ≈ −89 mV

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INTERPRETING EQUILIBRIUM POTENTIALS

The Nernst potential tells you where the membrane voltage would settle if the membrane were permeable to only that single ion. The resting membrane potential lies between E_K (≈ −90 mV) and E_Na (≈ +60 mV), weighted by relative permeability—just as the temperature of a room falls between the settings of two competing thermostats, weighted by how 'loudly' each one runs.

SECTION 7

Continuous vs. Saltatory Conduction

Action potential propagation differs fundamentally between unmyelinated and myelinated axons. The table below contrasts these two modes of conduction, highlighting the trade-offs in speed, metabolic cost, and anatomical investment.

Feature	Continuous Conduction (Unmyelinated)	Saltatory Conduction (Myelinated)
Speed	0.5 – 2 m/s (C fibers)	Up to 120 m/s (Aα fibers)
Mechanism	Sequential depolarization of every patch of membrane	Current jumps between nodes of Ranvier via local circuits
ATP Cost	Higher—Na⁺/K⁺-ATPase must restore ions across the entire axon length	Lower—ion exchange confined to small nodal regions
Axon Diameter	Speed increases with diameter (larger = faster)	Myelination allows high speed at smaller diameters
Examples	Visceral pain fibers, olfactory nerves	Motor neurons, proprioceptive sensory fibers
Clinical Vulnerability	Less affected by demyelinating diseases	Multiple sclerosis and Guillain-Barré syndrome disrupt myelin, slowing or blocking conduction

Comparison of unmyelinated and myelinated axon conduction

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WHY MYELINATION MATTERS

Myelination is the nervous system's engineering solution to a fundamental constraint: increasing axon diameter is metabolically expensive and consumes space. By insulating segments of the axon, myelination achieves conduction velocities that would otherwise require axon diameters of several centimeters—an anatomical impossibility in the human body. This is analogous to fiber-optic versus copper cables: the insulating cladding around a fiber-optic line allows signals to travel much faster and farther without amplification, compared to bare copper wire.

SECTION 8

Connection to Advanced & Clinical Neuroscience

The principles of neuron structure and action potential physiology form the basis for understanding numerous clinical conditions and advanced neuroscience topics. Disorders of ion channel function (channelopathies), demyelinating diseases, and pharmacological manipulations of neural excitability all stem directly from the concepts introduced in this lesson. The table below highlights how foundational concepts connect to more advanced topics.

Foundational Concept	Advanced / Clinical Extension
Voltage-gated Na⁺ channel gating	Local anesthetics (e.g., lidocaine) block Na⁺ channels, preventing action potential initiation in sensory neurons
Myelin sheath integrity	Multiple sclerosis: autoimmune demyelination causes conduction block, producing motor and sensory deficits
Resting membrane potential	Hyperkalemia raises [K⁺]ₒ, depolarizing the resting potential and potentially causing cardiac arrhythmias and muscle weakness
Refractory periods	Anti-epileptic drugs (e.g., carbamazepine) prolong Na⁺ channel inactivation, extending the refractory period to reduce seizure frequency
Synaptic transmission at axon terminals	Neuromuscular junction pharmacology: botulinum toxin blocks vesicle fusion, curare blocks nicotinic receptors
Hodgkin–Huxley model	Computational neuroscience: HH-type models serve as building blocks for simulating neural circuits and brain function

Bridging foundational neurophysiology to clinical and advanced topics

As you progress into courses on neuroscience, pharmacology, and pathophysiology, you will find that virtually every topic revisits the ionic and structural principles introduced here. The Hodgkin–Huxley formalism, for instance, has been extended into sophisticated computational models that simulate entire neural networks, forming the mathematical backbone of modern computational neuroscience. Similarly, understanding how channel mutations produce inherited epilepsies, periodic paralyses, and long QT syndrome requires a firm grasp of the voltage-dependent gating mechanisms covered in this lesson.

SECTION 9

Practice Problems

Question 1: CONCEPTUAL

Explain why the resting membrane potential of a neuron (≈ −70 mV) is closer to the equilibrium potential for K⁺ (≈ −90 mV) than to the equilibrium potential for Na⁺ (≈ +60 mV). What would happen to the resting potential if the membrane suddenly became equally permeable to Na⁺ and K⁺?

Show answer

At rest, the membrane is approximately 50–75 times more permeable to K⁺ than to Na⁺ because K⁺ leak channels are far more abundant than Na⁺ leak channels. According to the Goldman–Hodgkin–Katz equation, V_m is a weighted average of the equilibrium potentials, weighted by permeability. Since P_K dominates, V_m sits much closer to E_K. If P_Na were made equal to P_K, V_m would shift to roughly the midpoint between E_K and E_Na, approximately −15 mV, a significantly depolarized state.

Question 2: BASIC CALCULATION

Using the simplified Nernst equation at 37 °C (E = 61.5 mV / z × log₁₀([ion]ₒ/[ion]ᵢ)), calculate the equilibrium potential for Na⁺ given [Na⁺]ₒ = 145 mM and [Na⁺]ᵢ = 12 mM.

Show answer

E_Na = (61.5 mV / 1) × log₁₀(145/12) = 61.5 × log₁₀(12.08) = 61.5 × 1.082 ≈ +66.6 mV. This is consistent with the commonly cited value of approximately +60 to +67 mV for E_Na. The positive value indicates that the equilibrium for Na⁺ strongly favors Na⁺ entry into the cell, which explains the rapid depolarization during the action potential when Na⁺ channels open.

Question 3: INTERMEDIATE

A patient with hyperkalemia has a serum [K⁺] of 8 mM (normal ≈ 4–5 mM). Using the simplified Nernst equation at 37 °C and [K⁺]ᵢ = 140 mM, calculate the new E_K and predict how the resting membrane potential and neuronal excitability would be affected.

Show answer

E_K = 61.5 × log₁₀(8/140) = 61.5 × log₁₀(0.0571) = 61.5 × (−1.243) ≈ −76.4 mV. Compared to the normal E_K of ≈ −89 mV, this represents a depolarization of about 13 mV. Since the resting potential tracks E_K closely, V_m would shift from ≈ −70 mV to ≈ −60 mV, closer to threshold. Initially, this makes neurons more excitable (smaller stimulus needed to reach threshold). However, sustained depolarization can inactivate Na⁺ channels, paradoxically reducing excitability—a phenomenon relevant to the muscle weakness and cardiac arrhythmias seen in hyperkalemia.

Question 4: APPLIED

A neurologist is studying a patient with suspected multiple sclerosis. Nerve conduction velocity (NCV) testing of a motor nerve reveals a conduction velocity of 15 m/s (normal for that nerve: 50–60 m/s). Explain the physiological basis for this reduction in terms of the concepts covered in this lesson, and predict what the NCV might look like if demyelination were complete.

Show answer

In multiple sclerosis, autoimmune destruction of the myelin sheath disrupts saltatory conduction. Normally, local currents generated at one node of Ranvier spread rapidly through the high-resistance, low-capacitance myelinated internodal segments to depolarize the next node. With partial demyelination, current leaks across the damaged internode, slowing propagation and reducing NCV from the expected 50–60 m/s to the observed 15 m/s. The waveform may also show temporal dispersion (broadening) because different axons are affected to varying degrees. If demyelination were complete, the axon would need to conduct action potentials continuously rather than via saltatory conduction, lowering NCV to the range typical of unmyelinated fibers (0.5–2 m/s)—or conduction could fail entirely if the now-exposed axonal membrane has insufficient density of Na⁺ channels in the internodal regions.

Question 5: CRITICAL THINKING

The Na⁺/K⁺-ATPase pumps 3 Na⁺ out and 2 K⁺ in per cycle, making it electrogenic—it contributes roughly −3 to −5 mV to the resting potential. Some textbooks simplify by stating it 'maintains' the resting potential while others say it 'contributes' to it. Construct an argument for why the pump is necessary for a sustained resting potential but insufficient on its own to explain it. What would happen if you acutely inhibited the pump with ouabain?

Show answer

The resting membrane potential is primarily an equilibrium phenomenon determined by ion concentration gradients and differential permeability, as described by the GHK equation. The pump is essential because it continuously restores the Na⁺ and K⁺ concentration gradients that are slowly dissipated by leak channels and by the ionic fluxes associated with action potentials. Without the pump, the gradients would eventually collapse and V_m would approach 0 mV. However, the pump itself contributes only about −3 to −5 mV directly (due to the 3:2 stoichiometry creating a net outward positive current). Thus the pump 'maintains' the resting potential indirectly by sustaining the gradients, but the voltage arises primarily from the passive diffusion of K⁺ through leak channels. Acute ouabain application would initially produce little effect because the ion gradients are large reservoirs, but over minutes the gradients would diminish, the resting potential would slowly depolarize, and eventually the neuron would be unable to fire action potentials.

SUMMARY

Lesson Summary

Summary

Neurons are the fundamental signaling units of the nervous system, structurally organized into dendrites that receive input, a soma that integrates signals, an axon hillock that serves as the trigger zone, a myelinated axon for rapid signal conduction, and axon terminals that transmit information to downstream cells via synaptic neurotransmitter release. The resting membrane potential of approximately −70 mV arises from the selective permeability of the membrane to K⁺ (described by the Nernst and Goldman–Hodgkin–Katz equations) and is actively maintained by the Na⁺/K⁺-ATPase.

When a stimulus depolarizes the membrane to the threshold of approximately −55 mV, an action potential is generated in an all-or-none fashion: rapid Na⁺ influx drives depolarization to ~+30 mV, followed by K⁺ efflux that repolarizes and briefly hyperpolarizes the membrane. Refractory periods enforce unidirectional propagation. In myelinated axons, saltatory conduction between nodes of Ranvier achieves velocities up to 120 m/s, and disruption of myelin—as in multiple sclerosis—profoundly impairs neural communication. Mastering these structural and electrochemical principles provides the foundation for pharmacology, clinical neuroscience, and computational modeling of the nervous system.