The Neuronal Action Potential: From Resting Membrane to Propagation
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Voltage-gated sodium and potassium channels, the Nernst and Goldman equations made simple, refractory periods, saltatory conduction, and the axonal pathologies that disrupt nerve impulse propagation.
- The resting membrane potential (−70 mV) is determined primarily by K⁺ efflux through leak channels — the Goldman equation predicts it from multiple ion permeabilities.
- Action potentials are ALL-OR-NONE events: once threshold (−55 mV) is reached, the positive feedback loop of Na⁺ channel activation ensures a full action potential.
- The absolute refractory period is due to Na⁺ channel inactivation — it limits maximum firing frequency to ~500–1000 Hz and ensures unidirectional propagation.
- Saltatory conduction in myelinated axons increases conduction velocity 10–100× while reducing metabolic cost by >90% because only nodes of Ranvier depolarise.
- Demyelinating disease (e.g., canine distemper virus, coonhound paralysis) slows or blocks conduction by exposing internodal membrane with insufficient Na⁺ channel density.
- Acute flaccid tetraplegia with preserved mentation → consider acute polyradiculoneuritis (coonhound paralysis) — a demyelinating and axonopathic disease targeting ventral roots.
- Tick paralysis (Ixodes holocyclus in Australia, Dermacentor in North America) → toxin blocks ACh release at the NMJ by inhibiting presynaptic Ca²⁺ entry, not by blocking Na⁺ channels. Differentiate from botulism.
- Acute cluster seizures or status epilepticus → neuronal Na⁺ channel inactivation failure → uncontrolled repetitive firing. First-line: benzodiazepines (enhance GABA-A); second-line: levetiracetam or phenobarbital.
Introduction: The Universal Language of the Nervous System
Every thought, every sensation, every movement, every autonomic adjustment — all depend on the action potential, a brief, propagated change in membrane potential that travels along axons at speeds up to 120 m/s (in the largest mammalian myelinated fibres). The neuronal action potential is one of the most thoroughly understood phenomena in all of biology, described quantitatively by the Hodgkin-Huxley equations in 1952 — work that earned the Nobel Prize and remains the foundation of modern electrophysiology.
This article builds from the resting membrane potential through the Nernst and Goldman equations, the sequential opening and closing of voltage-gated Na⁺ and K⁺ channels, refractory periods, and the remarkable efficiency of saltatory conduction. We close with clinical correlations — how local anaesthetics work, why demyelination causes conduction block, and what happens when neuronal excitability goes awry in epilepsy and neuropathic pain.
The Resting Membrane Potential: Why Cells Are Negative Inside
The Nernst Equation — Equilibrium Potential for a Single Ion
The resting membrane potential (RMP) of a typical mammalian neuron is approximately −70 mV (inside negative relative to outside). This potential arises from two factors: (1) the concentration gradients of ions across the membrane (high K⁺ inside, high Na⁺ and Cl⁻ outside), maintained by the Na⁺/K⁺-ATPase pump, and (2) the selective permeability of the resting membrane to K⁺ (via leak channels) with very low permeability to Na⁺.
For any single ion, the equilibrium potential (the membrane voltage at which there is no NET movement of that ion) is given by the Nernst equation:
| Ion | Intracellular [mM] | Extracellular [mM] | E_X (mV at 37°C) | Direction of passive flux at RMP (−70 mV) |
|---|---|---|---|---|
| K⁺ | 140 | 4 | −94 | OUTWARD (RMP less negative than E_K → K⁺ leaves) |
| Na⁺ | 12 | 145 | +66 | INWARD (strong driving force — both electrical and chemical gradients favour Na⁺ entry) |
| Cl⁻ | 4 | 120 | −89 | Passively distributes; often near RMP. Inward at −70 mV. |
| Ca²⁺ | 0.0001 (100 nM) | 1.2 | +125 | INWARD (enormous driving force — critical for neurotransmitter release) |
The Goldman-Hodgkin-Katz Equation — Multiple Ions, One Potential
Real membranes are permeable to multiple ions simultaneously. The Goldman equation predicts the resting membrane potential from the concentration gradients AND relative permeabilities (P) of all permeant ions:
The Action Potential: A Five-Act Molecular Drama
1. Resting State (Phase 4)
Membrane at −70 mV. Voltage-gated Na⁺ channels: closed (m gate closed, h gate open — 'closed but available'). Voltage-gated K⁺ channels: closed (n gate closed). Na⁺/K⁺-ATPase maintains ion gradients.
2. Threshold and Rising Phase (Phase 0)
A depolarising stimulus (synaptic input, sensory receptor potential, or electrotonic spread from an adjacent region) raises the membrane potential toward threshold (approximately −55 mV). At threshold, a critical density of voltage-gated Na⁺ channels activates (m gates open rapidly) → Na⁺ conductance increases → Na⁺ influx → further depolarisation → more Na⁺ channels activate → POSITIVE FEEDBACK → the membrane depolarises explosively toward E_Na (+66 mV).
This positive feedback loop — the Hodgkin cycle — is the molecular basis of the ALL-OR-NONE property of action potentials. Once threshold is crossed, the action potential proceeds to completion regardless of the stimulus strength. Subthreshold stimuli produce only passive, local potentials that decay with distance.
3. Repolarisation (Phase 3)
Two processes terminate the action potential: (1) Na⁺ channel INACTIVATION — the h gate closes (slower than m gate opening) after ~0.5 ms, stopping Na⁺ influx. Inactivated channels CANNOT reopen until the membrane repolarises and the h gate resets. (2) Voltage-gated K⁺ channel ACTIVATION — the n gate opens (slower still, ~1–2 ms delay), allowing K⁺ efflux, which drives the membrane potential back toward E_K (−94 mV).
4. Afterhyperpolarisation
Because K⁺ channels are slow to close, the membrane potential briefly overshoots the resting potential, becoming transiently MORE negative than −70 mV (afterhyperpolarisation, or 'undershoot'). During this period, the neuron is in the relative refractory period — a stronger-than-normal stimulus is required to reach threshold because the membrane is further from threshold (hyperpolarised) and some Na⁺ channels are still inactivated.
5. Restoration of Gradients
After a single action potential, the Na⁺ and K⁺ that moved across the membrane are negligible — fewer than 1 in 100,000 ions — and the Na⁺/K⁺-ATPase restores the concentration gradients over the longer term. A neuron can fire thousands of action potentials before ion gradients become significantly depleted.
RESTING (−70 mV): m CLOSED, h OPEN → 'closed but available'
ACTIVATED (−55 mV): m OPEN, h OPEN → channel OPEN (Na⁺ flows in)
INACTIVATED: m OPEN, h CLOSED → channel blocked (cannot reopen until repolarised)
RECOVERY (repol.): m CLOSED, h OPEN → returns to resting state
K⁺ channel (n gate = activation):
RESTING (−70 mV): n CLOSED → channel closed
ACTIVATED (depol.): n OPEN → channel OPEN (K⁺ flows out) — DELAYED by ~1–2 ms
Refractory Periods: Why Action Potentials Only Go One Way
The refractory period is the defining feature that makes the action potential a regenerative, propagating signal rather than a decaying local potential. It ensures unidirectional propagation and limits the maximum firing frequency.
| Period | Mechanism | Stimulus needed | Max firing frequency |
|---|---|---|---|
| Absolute refractory period | Na⁺ channels are either OPEN (activated) or INACTIVATED — no channels are available. No stimulus, however strong, can elicit another AP. | Infinite — impossible | Limits max frequency: ~500–1000 Hz for mammalian neurons |
| Relative refractory period | Some Na⁺ channels have recovered (h gate reopened) but K⁺ conductance is still elevated (membrane hyperpolarised). Stronger stimulus needed. | Greater than normal | N/A — AP can be elicited |
| Supranormal period (rare, brief) | Membrane is slightly closer to threshold as K⁺ conductance decays | Less than normal | AP may fire more easily — risk of repetitive firing |
Saltatory Conduction: The Myelin Leap
Why Myelinate? The Speed and Energy Problem
An unmyelinated axon conducts at ~0.5–2 m/s — fine for autonomic fibres but impossibly slow for a spinal reflex that must travel 1.5 metres (C1 → pelvic limb → C1 in a large dog). Myelination increases conduction velocity 10–100×, achieving speeds up to 120 m/s in the largest mammalian axons. Equally important, it reduces energy consumption by >90% — only the nodes of Ranvier need to be depolarised and repolarised, sparing the internode from ion pumping.
The Node of Ranvier: A Dense Cluster of Na⁺ Channels
Myelin (produced by Schwann cells in the PNS and oligodendrocytes in the CNS) wraps around the axon in multiple layers, creating segments of high-resistance, low-capacitance insulation. The nodes of Ranvier — gaps in the myelin sheath approximately 1 μm wide, spaced every 0.2–2 mm — are densely packed with voltage-gated Na⁺ channels (~1,000–2,000 per μm², compared to ~25 per μm² in the internode).
When an action potential reaches a node, the influx of Na⁺ creates a local current that spreads passively (electrotonically) to the next node. Because the internode is insulated, the current decays only minimally over the 0.2–2 mm gap — sufficient to depolarise the next node to threshold. The action potential thus 'jumps' from node to node — saltatory conduction (from the Latin saltare, to leap).
Demyelinating Disease: When the Insulation Fails
Demyelination exposes the internodal membrane. Because internodal membrane has very few Na⁺ channels (~25/μm² vs ~1,500/μm² at nodes), the local current from the nearest node is rarely sufficient to depolarise the bare internode to threshold. The action potential is either BLOCKED entirely (conduction block → clinical paresis/paralysis) or SLOWED dramatically (reduced conduction velocity → delayed reflexes, temporal dispersion).
Clinical Pharmacology: How Local Anaesthetics Work
Local anaesthetics (lidocaine, bupivacaine, ropivacaine, mepivacaine) are Na⁺ channel blockers that prevent action potential generation and propagation. They are weak bases (pKa ~7.6–8.1) that exist in equilibrium between an uncharged (B, lipid-soluble) form and a charged (BH⁺, water-soluble) form at physiological pH.
- The uncharged form (B) crosses the axonal membrane.
- Inside the cell, the lower pH (7.0 vs 7.4 extracellular) shifts the equilibrium toward the charged form (BH⁺).
- The charged form enters the Na⁺ channel from the intracellular side and binds to a receptor site in the S6 segment of domain IV, physically occluding the pore.
- Binding is use-dependent — the channel must OPEN for the drug to access its binding site. This is why local anaesthetics block rapidly firing pain fibres (small, unmyelinated C fibres) before they block larger, less active motor fibres (Aa fibres).
Differential blockade: C fibres (pain, unmyelinated, 0.5–2 μm, high firing rate) are blocked first. Aδ fibres (sharp pain, temperature, thinly myelinated, 2–5 μm) are blocked second. Aα and Aβ fibres (motor, proprioception, large myelinated, 12–20 μm) are blocked last. This is the basis of the 'differential block' used in epidural anaesthesia — pain sensation is lost while motor function may be partially or fully preserved, depending on the concentration of local anaesthetic used.
Clinical Neurophysiology: From Channelopathies to Neuropathic Pain
Inherited Channelopathies in Veterinary Neurology
Ion channel mutations — 'channelopathies' — are increasingly recognised in veterinary patients. Episodic falling syndrome in Cavalier King Charles Spaniels (hyperekplexia): a mutation in the BCAN gene encoding brevican, an extracellular matrix protein that anchors postsynaptic receptors. Clinical signs: episodic muscle hypertonicity triggered by exercise/excitement. Myotonia congenita in Miniature Schnauzers: a mutation in the CLCN1 gene encoding the skeletal muscle Cl⁻ channel (ClC-1). Reduced Cl⁻ conductance → decreased resting membrane stability → afterdischarges following voluntary contraction → delayed muscle relaxation (myotonia) — the classic 'stiffness that warms out' with exercise. This is the same gene mutated in human Thomsen and Becker myotonia. The goat 'fainting' phenotype is also a CLCN1 mutation.
Chronic Pain and Central Sensitisation
Persistent nociceptive input produces plastic changes in the spinal cord dorsal horn — 'central sensitisation.' The NMDA receptor (a glutamate-gated Ca²⁺ channel normally blocked by Mg²⁺ at resting potentials) becomes unblocked when the postsynaptic membrane is sufficiently depolarised by sustained C-fibre input. Ca²⁺ influx through NMDA receptors activates Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) → phosphorylation of AMPA receptors → increased AMPA conductance → amplified synaptic responses to subsequent stimuli → hyperalgesia and allodynia. This is the molecular basis of 'wind-up' — the progressive increase in dorsal horn neuron firing with repeated C-fibre stimulation at >0.5 Hz. Ketamine (NMDA antagonist) and gabapentin (reduces glutamate release) target this cascade at different points.
Electrodiagnostics: What EMG and Nerve Conduction Studies Tell Us
Electromyography (EMG) records electrical activity in muscle. In denervated muscle (LMN disease), spontaneous activity appears after 5–7 days: fibrillation potentials (regular, brief, low-amplitude — individual muscle fibre action potentials) and positive sharp waves (similar origin, but triggered by needle movement). Nerve conduction studies measure conduction velocity and amplitude. Demyelination → reduced conduction velocity and temporal dispersion. Axonopathy → reduced amplitude (fewer axons firing) with relatively normal conduction velocity — until severe loss affects the largest, fastest fibres. Together, EMG and NCS distinguish primary muscle disease (myopathy), neuromuscular junction disease (decremental response to repetitive stimulation = MG), demyelinating neuropathy, and axonal neuropathy — guiding the diagnostic workup.
Synaptic Transmission: From Action Potential to Post-Synaptic Response
An action potential is only useful if it communicates something to the next cell. This communication occurs at synapses — specialised junctions where an electrical signal (the presynaptic action potential) is converted into a chemical signal (neurotransmitter release) and then back into an electrical signal (the postsynaptic potential). This conversion is the site of action for most neuroactive drugs in veterinary medicine.
The Quantal Nature of Neurotransmitter Release
Neurotransmitter release is QUANTAL — it occurs in discrete packets (quanta), each corresponding to the contents of a single synaptic vesicle (~5,000–10,000 neurotransmitter molecules). At the neuromuscular junction, a single presynaptic action potential triggers the release of 100–300 quanta, producing an end-plate potential (EPP) of ~30–50 mV — far above the ~15 mV threshold for the postsynaptic muscle action potential (the 'safety factor' of ~3–5×). At central synapses, each action potential typically releases only 1–10 quanta, producing postsynaptic potentials of 0.2–2 mV — below threshold individually, but summating with inputs from many synapses to trigger an action potential (spatial and temporal summation).
Ionotropic vs Metabotropic Receptors — Speed vs Modulation
- IONOTROPIC RECEPTORS: Ligand-gated ion channels. The receptor IS the channel. Fast (millisecond) responses. Examples: nicotinic AChR (Na⁺/Ca²⁺ influx → EPSP), GABA-A receptor (Cl⁻ influx → IPSP), AMPA and NMDA glutamate receptors (Na⁺/Ca²⁺ influx → EPSP). Target of: benzodiazepines (enhance GABA-A — increase Cl⁻ channel opening frequency), propofol/alfaxalone (enhance GABA-A), ketamine (NMDA antagonist).
- METABOTROPIC RECEPTORS: G-protein coupled receptors (GPCRs). Slower (seconds to minutes), longer-lasting. Modulate cellular function through second messengers (cAMP, IP3/DAG). Examples: muscarinic AChR (M1–5), adrenergic receptors (α1, α2, β1, β2, β3), dopamine receptors, opioid receptors. Target of: atropine/glycopyrrolate (M2 antagonist → increased HR), medetomidine/dexmedetomidine (α2 agonist → reduced NE release → sedation), dobutamine (β1 agonist → increased contractility).
EPSPs, IPSPs, and Integration — The Neuron as a Decision Maker
A typical CNS neuron receives 1,000–10,000 synaptic inputs (some excitatory, some inhibitory) distributed across its dendritic tree. The neuron integrates these inputs both SPATIALLY (inputs arriving simultaneously at different locations summate) and TEMPORALLY (inputs arriving in rapid succession at the same synapse summate). The integrated signal propagates passively to the axon hillock — the site with the highest density of voltage-gated Na⁺ channels and the lowest threshold. If the summed potential at the axon hillock reaches threshold → action potential initiated. If not → no output. This integration is the fundamental computational operation of the nervous system.
Neurotransmitter Systems: The Chemical Languages of the Nervous System
Glutamate — The Workhorse Excitatory Transmitter
Glutamate is the principal excitatory neurotransmitter in the CNS — it mediates fast synaptic transmission at >80% of CNS synapses. Glutamate is synthesised from α-ketoglutarate (a TCA cycle intermediate) or glutamine (the 'glutamate-glutamine cycle' — astrocytes take up synaptically released glutamate, convert it to glutamine via glutamine synthetase, and export glutamine for neuronal reuptake and re-conversion to glutamate). Glutamate acts at: (1) AMPA receptors — fast Na⁺ influx → EPSP; (2) NMDA receptors — Ca²⁺ influx (requires co-agonist glycine + depolarisation to relieve Mg²⁺ block); (3) kainate receptors — similar to AMPA. Excessive glutamate release ('excitotoxicity') in ischaemia → uncontrolled Ca²⁺ influx via NMDA receptors → mitochondrial Ca²⁺ overload → cell death — a mechanism of neuronal death in stroke, traumatic brain injury, and possibly epilepsy.
GABA — The Brake Pedal
Gamma-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the CNS. It is synthesised from glutamate by glutamic acid decarboxylase (GAD). Two receptor types: (1) GABA-A — ligand-gated Cl⁻ channel → Cl⁻ influx → hyperpolarisation (IPSP). Target of benzodiazepines (enhance GABA binding → increase Cl⁻ channel opening FREQUENCY), barbiturates (increase channel opening DURATION), propofol/alfaxalone (directly activate GABA-A at high concentrations). (2) GABA-B — GPCR → Gi → inhibits adenylyl cyclase, activates K⁺ channels → slow, prolonged inhibition. Target of baclofen (GABA-B agonist → reduces spasticity in UMN disease). Defects in GABAergic inhibition are implicated in epilepsy, anxiety disorders, and neuropathic pain.
Dopamine and Norepinephrine — The Modulatory Amines
Dopamine (DA) and norepinephrine (NE) are catecholamine neurotransmitters with widespread modulatory roles. DA — synthesised from tyrosine → L-DOPA → dopamine → (further → NE). DA acts at D1-like (Gs → cAMP ↑) and D2-like (Gi → cAMP ↓) receptors. Functions: motor control (nigrostriatal pathway — degeneration → Parkinson's in humans; rare in dogs), reward/motivation (mesolimbic pathway), prolactin inhibition (tuberoinfundibular pathway). NE — acts at α1 (Gq → IP3/DAG), α2 (Gi → cAMP ↓), β1 and β2 (Gs → cAMP ↑). NE from the locus coeruleus projects diffusely to the entire forebrain → regulates arousal, attention, and the sleep-wake cycle. Drugs targeting these systems: acepromazine (D2 antagonist → sedation), medetomidine/dexmedetomidine (α2 agonist → sedation + analgesia), dobutamine (β1 agonist → inotrope), and phenylpropanolamine (α1 agonist → urethral sphincter tone → urinary incontinence management).
- The Hodgkin-Huxley model of the squid giant axon (1952) remains the foundation of all neural electrophysiology — the same principles apply to canine and feline neurons.
- Local anaesthetics (lidocaine, bupivacaine) block Na⁺ channels from the INTRACELLULAR side — they must cross the membrane in their uncharged form, then become charged and trapped inside the channel (the 'hydrophilic pathway').
- Hyperkalemia makes neurons MORE excitable initially (membrane closer to threshold), then LESS excitable as Na⁺ channels become inactivated by sustained partial depolarisation — the same biphasic effect seen in cardiac muscle.
Frequently asked questions
Self-check quiz
Test yourself. Answers are below each question — cover them first if you are studying.
- It becomes more negative
- It becomes less negative (depolarised)
- It stays the same
- It reverses polarity
Show answer
Answer: It becomes less negative (depolarised)
E_K = 61.5 × log₁₀([K⁺]ₒ / [K⁺]ᵢ). At 4 mM: 61.5 × log₁₀(4/140) = −94 mV. At 8 mM: 61.5 × log₁₀(8/140) = −76 mV. The equilibrium potential has DEPOLARISED by 18 mV. This is the electrophysiological basis of hyperkalemia-induced membrane depolarisation.
- K⁺ channel activation
- Na⁺ channel inactivation
- Na⁺/K⁺-ATPase pump activity
- Myelin insulation
Show answer
Answer: Na⁺ channel inactivation
During the absolute refractory period, Na⁺ channels are either open (activated) or — critically — inactivated (h gate closed). Inactivated channels CANNOT reopen regardless of the membrane potential. No amount of Na⁺ channels available = no action potential possible.
- The axon diameter decreases
- The exposed internodal membrane has too few Na⁺ channels to regenerate the action potential
- K⁺ channels are overexpressed
- Myelin debris physically blocks ion flow
Show answer
Answer: The exposed internodal membrane has too few Na⁺ channels to regenerate the action potential
Internodal membrane has ~25 Na⁺ channels/μm² vs ~1,500/μm² at the nodes. The local current from the nearest node is insufficient to depolarise the bare internode to threshold. The action potential is either slowed or blocked entirely.
- Aα motor fibres (large, myelinated, slow firing)
- C fibres (small, unmyelinated, rapid firing)
- Aβ proprioceptive fibres (large, myelinated)
- B fibres (preganglionic autonomic, thinly myelinated)
Show answer
Answer: C fibres (small, unmyelinated, rapid firing)
Local anaesthetics are USE-DEPENDENT — they block open/inactivated channels preferentially. C fibres fire at high rates, exposing many channels in the open/inactivated state. Additionally, C fibres are small — the drug reaches the critical concentration for block faster. This differential block allows pain relief with relative motor preservation in epidural anaesthesia.
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