Neurons communicate using brief, self-regenerating pulses of electricity called action potentials. At rest, a neuron maintains a small voltage difference across its membrane, with the inside sitting roughly 70 millivolts more negative than the outside. When the neuron is stimulated enough, specialized protein channels snap open, ions rush across the membrane, and the voltage swings dramatically in the span of a millisecond. That pulse then races down the neuron’s long output fiber and triggers communication with the next cell. The whole system runs on a handful of ion types, a few families of channel proteins, and an energy-hungry pump that resets everything after each firing.
The Battery That Never Turns Off
Before a neuron can send a signal, it has to maintain a charged-up baseline. This resting voltage exists because the membrane separates two chemically different solutions. The fluid outside the cell is rich in sodium; the fluid inside is rich in potassium. A protein called the sodium-potassium pump constantly moves three sodium ions out while pulling two potassium ions in, both against their natural flow direction.1PubMed Central. Na+/K+-pump and neurotransmitter membrane receptors Because three positive charges leave for every two that enter, the pump itself nudges the inside of the cell slightly negative. But the bigger factor is what happens passively: the membrane has leak channels that let potassium seep out far more easily than sodium can seep in. As potassium drifts outward, it carries positive charge with it, leaving the interior even more negative. The result is the resting potential, roughly −70 mV, which is the stored energy the neuron draws on every time it fires.
Where Firing Begins
A neuron collects input from other neurons through its branching dendrites and cell body. Those inputs take the form of small local voltage shifts, some pushing the membrane toward firing and some pushing it away. If the combined input is strong enough to push the voltage past a critical threshold, the neuron fires. But it does not fire just anywhere along the cell. The action potential starts at a structure called the axon initial segment, a short stretch at the base of the axon that is packed with voltage-gated sodium channels at a higher density than almost anywhere else on the neuron.2PubMed Central. Axon initial segments: structure, function, and disease That concentration of channels makes the initial segment the most electrically excitable spot on the cell, so it reaches threshold first and launches the pulse.
The Action Potential Up Close
When the membrane at the axon initial segment reaches threshold, voltage-gated sodium channels undergo a rapid shape change that opens a pore selective for sodium ions. At rest, these channels sit in a closed state because the negative interior voltage holds them shut. The moment the voltage rises enough, the channel’s internal voltage sensor shifts, the pore opens, and sodium floods inward driven by both its concentration gradient and the electrical pull of the negative interior.3ACS Publications. Voltage-Gated Sodium Channels: Structure, Function, Pharmacology, and Clinical Indications This inrush of positive charge drives the membrane voltage from −70 mV all the way to about +30 or +40 mV in less than a millisecond. The whole swing is called depolarization.
Almost as quickly, two things shut the process down. The sodium channels themselves transition into an inactivated state within milliseconds, slamming a molecular “gate” that blocks further sodium entry even though the channel’s main pore opened.3ACS Publications. Voltage-Gated Sodium Channels: Structure, Function, Pharmacology, and Clinical Indications Meanwhile, voltage-gated potassium channels, which are slower to open, now reach full conductance and let potassium rush out. That outward flow of positive charge pulls the voltage back down, repolarizing the membrane.4PubMed Central. Potassium conductances underlying repolarization and after-hyperpolarization in rat CA1 hippocampal interneurones The potassium channels stay open a beat longer than necessary, briefly driving the voltage below the resting level (a phase sometimes called the undershoot or after-hyperpolarization) before everything settles back to baseline.
Because the sodium channels are inactivated for a short window after firing, the neuron cannot fire a second action potential during that interval. This refractory period limits how fast a neuron can fire and, just as importantly, ensures that the action potential travels in one direction along the axon rather than bouncing backward.
How the Signal Travels Down the Axon
An action potential at one spot on the axon creates local currents that depolarize the adjacent patch of membrane, pushing it past threshold and triggering a fresh action potential there. The pulse effectively regenerates itself point by point along the length of the fiber, never losing strength. In bare, unmyelinated axons, this process is continuous and relatively slow.
Many axons in the vertebrate nervous system are wrapped in myelin, a fatty insulating sheath produced by supporting cells. Myelin dramatically speeds up signal travel by forcing the action potential to jump between small exposed gaps called nodes of Ranvier. The insulation prevents current from leaking out across the covered stretches, so the local currents shoot ahead to the next node, where a fresh cluster of sodium channels fires a new action potential. This jumping pattern, called saltatory conduction, accelerates impulse propagation well beyond what a bare axon of the same diameter could manage.5PubMed Central. Saltatory Conduction along Myelinated Axons Involves a Periaxonal Nanocircuit Voltage imaging of myelinated fibers confirms that rapid nodal potentials travel ahead of slower, attenuated waves in the insulated segments between nodes.6Cell. Biophysics of Action Potential Propagation in Myelinated Axons Revealed by High-Speed Voltage Imaging
Axon diameter also matters. Thicker axons have lower internal resistance, so local currents spread farther and faster.7PubMed Central. Signal transmission between gap-junctionally coupled passive cables is most effective at an optimal diameter Invertebrates like squid, which lack myelin, evolved giant axons to achieve high conduction speed through sheer diameter. Vertebrates found a more space-efficient solution in myelin, achieving comparable speed with axons a fraction of the width.
What Happens at the Synapse
When the action potential reaches the end of the axon, the electrical signal has to cross a gap to reach the next cell. At a chemical synapse, the arriving pulse opens voltage-gated calcium channels in the presynaptic terminal.8PubMed Central. Functions of Presynaptic Voltage-gated Calcium Channels Calcium floods in, and the rise in calcium concentration triggers tiny sacs (vesicles) filled with chemical neurotransmitters to fuse with the membrane and spill their contents into the synaptic cleft. The neurotransmitter drifts across the gap, binds to receptor proteins on the receiving cell, and opens ion channels there, producing a new electrical signal in the target neuron.
The relationship between calcium entry and transmitter release is impressively sensitive. Research at single presynaptic terminals has shown that even the opening of a single calcium channel, admitting fewer than 200 calcium ions, can be enough to trigger the release of one packet of neurotransmitter.9Neuron. Single calcium channels and acetylcholine release at a presynaptic nerve terminal This reflects the tight physical coupling between calcium channels and the vesicle release machinery: the release apparatus is essentially tethered right next to the calcium channel, so even a tiny puff of calcium at close range can do the job.
Interestingly, the timing of calcium channel activation during the action potential is not straightforward. Most presynaptic calcium channels open during the repolarization phase rather than the peak of the action potential, because the channels keep activating as the voltage swings back down. By the time the membrane has returned near its resting level, each remaining open channel is letting in more calcium per channel because the electrical driving force on calcium is stronger at negative voltages.10Frontiers in Synaptic Neuroscience. Presynaptic Calcium Channel Open Probability and Changes In Calcium Influx Throughout the Action Potential Determined Using AP-Waveforms So the tail end of the action potential contributes more to neurotransmitter release than you might expect.
How a Neuron Adds Up Its Inputs
A single neuron in the brain can receive thousands of synaptic inputs, some excitatory (pushing the voltage toward threshold) and some inhibitory (pushing it away). The cell body acts like a calculator, summing all these inputs to determine whether the axon initial segment reaches threshold. This is not a simple addition. In pyramidal neurons, the combined output at the cell body can be approximated as the excitatory input plus the inhibitory input plus a nonlinear interaction term that captures how inhibition “shunts” excitation.11PubMed Central. An arithmetic rule for spatial summation of excitatory and inhibitory inputs in pyramidal neurons In practical terms, inhibition does more than just subtract from excitation; it also reduces excitation’s effectiveness by opening channels that soak up current before it can reach the trigger zone.
Inhibitory neurons play an outsized role in circuit function. By precisely controlling when groups of excitatory neurons can fire, local inhibitory networks influence spike timing across populations of cells, contributing to processes from gain control to the kind of synchronized activity linked to learning.12Neuron. Neocortical Inhibitory Networks Provide a Stable Form of Timing and Synchrony in Pyramiding Cell Populations The balance between excitation and inhibition is one of the brain’s most carefully regulated variables, and disrupting it is a feature of many neurological conditions.
Electrical Synapses and Direct Coupling
Not all communication between neurons relies on chemical neurotransmitters. Electrical synapses, formed by clusters of gap junction channels that directly connect the interiors of two cells, allow ionic current to pass from one neuron to the next almost instantaneously. The channels have a large internal diameter that permits not only electrical current (carried mostly by potassium ions) but also the passage of small signaling molecules.13Neuron. Electrical synapses and gap junctions in the mammalian brain Electrical synapses are found throughout the brain and across species, and their basic biophysical behavior is relatively simple: they act as bidirectional, nearly resistive connections between cells.14PubMed Central. Synchrony and so much more: Diverse roles for electrical synapses in neural circuits
Because current flows through gap junctions with essentially no delay, electrical synapses are well suited for synchronizing the activity of groups of neurons. They are especially common in circuits that need rapid, coordinated firing, such as those controlling escape reflexes or generating rhythmic activity. They lack the fine-grained control of chemical synapses, but their speed and simplicity make them indispensable for certain functions.
The Energy Bill
Running all this ion traffic is expensive. Every action potential leaves behind a small excess of sodium inside the cell and a small deficit of potassium. The sodium-potassium pump has to burn ATP (the cell’s energy currency) to restore those gradients after each firing.15PubMed. Energy Cost of Action Potential Generation and Propagation in Thalamocortical Relay Neurons During Deep Brain Stimulation In fact, a large fraction of the brain’s total energy consumption goes toward fueling these pumps. The brain accounts for only about 2% of body weight but uses roughly 20% of the body’s resting energy, and maintaining ionic gradients is a major part of that budget.
The metabolic cost is not uniform across all neurons or all parts of a neuron. Myelinated sections of the axon, where ion exchange only happens at the nodes, are more energy-efficient per unit length than unmyelinated stretches. Neurons that fire at high rates burn through more ATP than quieter ones. And the overlap between sodium influx and potassium efflux during the action potential matters too: if both channel types are open simultaneously during the spike, some ions flow in directions that cancel each other out, wasting energy. The degree of this overlap varies among neuron types and affects how efficiently each cell uses its fuel.
How the System Gets Tuned
The picture described so far, a fixed set of channels producing stereotyped action potentials, is really a baseline. In a living brain, the electrical properties of neurons are constantly being adjusted by chemical signals called neuromodulators. Substances like dopamine, serotonin, acetylcholine, and norepinephrine do not simply make neurons more or less excitable. They reshape the entire excitability landscape by targeting the dynamics of specific ion channels and synaptic proteins.16PubMed Central. Neuromodulation of neurons and synapses A neuromodulator might speed up one type of potassium channel while slowing another, changing not just whether the neuron fires but how it fires: its rhythm, its burst patterns, its sensitivity to particular input frequencies.17PubMed Central. A unified model library maps how neuromodulation reshapes the excitability landscape of neurons across the brain
This tuning is what allows the same neural circuit to produce different outputs depending on the animal’s internal state. A circuit controlling movement, for example, can shift between different gaits or speeds partly because neuromodulators reconfigure how its component neurons respond to input. Sleep, arousal, attention, mood, and motivation all involve large-scale changes in neuromodulatory tone that alter signaling properties across wide swaths of the brain.
When Signaling Goes Wrong
Because the whole system depends on ion channels and myelin working correctly, genetic or acquired disruptions to either component can cause serious neurological problems.
Mutations in the genes encoding voltage-gated or ligand-gated channels are responsible for a family of disorders known as channelopathies. Several forms of inherited epilepsy, for instance, have been traced to mutations in sodium or potassium channel genes that alter how easily neurons fire or how quickly they recover after firing.18PubMed Central. Inherited Channelopathies Associated with Epilepsy A sodium channel that inactivates too slowly, for example, lets excessive current flow, making neurons hyperexcitable and prone to the synchronized bursts that produce seizures. The recognition that these epilepsies are channelopathies has opened the door to more targeted drug design.
Damage to myelin, as in multiple sclerosis and related conditions, degrades signal propagation in a different way. Without intact insulation, current leaks out across the exposed membrane, and the action potential may slow, become unreliable, or fail entirely. When different axons in a nerve bundle lose myelin to different degrees, their signals arrive at their targets at different times, producing desynchronized activity. Bare stretches of neighboring axons can even interfere with each other electrically, creating crosstalk that produces abnormal sensations like tingling or pain.19PubMed Central. Physiological Dynamics in Demyelinating Diseases: Unraveling Complex Relationships through Computer Modeling
Poisons and Medicines That Target the Machinery
The voltage-gated sodium channel, being the engine of the action potential, is a prime target for both natural toxins and pharmaceutical drugs. Tetrodotoxin, the infamous poison found in pufferfish, blocks sodium channels by lodging in the extracellular mouth of the pore, physically preventing sodium ions from passing through.20ChemRxiv. How Tetrodotoxin Blocks Sodium Channels: A Docking and Geometric Perspective The result is paralysis and, if the dose is high enough, death by respiratory failure, because the neurons controlling breathing can no longer fire.
Medicine has turned the same vulnerability into a benefit. Local anesthetics like lidocaine work by blocking sodium channels from the inside. Lidocaine reduces the amount of charge the channel’s voltage sensor can move and alters the voltage at which the channel activates, preventing sensory neurons in the treated area from generating action potentials.21PubMed Central. Molecular action of lidocaine on the voltage sensors of sodium channels You feel no pain because pain signals never get generated. The same basic principle underlies many anticonvulsant drugs: by modestly reducing sodium channel availability, they raise the threshold for runaway firing without shutting neurons down entirely.
Electrical Signaling Is Older Than Neurons
One of the more surprising findings in this field is that the molecular machinery for electrical signaling predates the nervous system itself. Voltage-gated sodium channels, the proteins at the heart of the action potential, evolved from calcium channels and were already present in the common ancestor of animals and their closest single-celled relatives, the choanoflagellates.22PubMed Central. Adaptive evolution of voltage-gated sodium channels: the first 800 million years Those ancestral channels were likely permeable to both sodium and calcium. Genomic analysis has found sodium-channel-like genes expressed in choanoflagellates and in placozoans, simple animals that have no nervous system at all.23PubMed Central. Evolution of sodium channels predates the origin of nervous systems in animals So the channels came first, and neurons evolved to exploit them.
Electrical signaling is not limited to animal neurons even today. Plants generate action potentials that propagate through tissue with a constant speed, using mechanisms that share broad functional similarities with animal signaling even though the molecular details differ. The Venus flytrap, for example, fires action potentials that travel through its trap lobes and trigger the rapid closure that catches prey.24PubMed Central. Plant electrophysiology with conformable organic electronics: Deciphering the propagation of Venus flytrap action potentials The signals propagate actively and at a steady rate, without strong directionality, which is unlike the one-way conduction typical of a neuron’s axon but serves the plant’s need to trigger a coordinated mechanical response across an entire tissue.
The deep evolutionary conservation of electrical signaling underscores how fundamental this strategy is to life. Long before brains existed, organisms were using voltage changes across membranes to sense their environment and coordinate responses. Neurons refined and accelerated the process, but they did not invent it.