Ion Channels and Electrolytes

The key electrolytes

An electrolyte is simply a salt that, dissolved in water, splits into charged particles, ions. In the body these ions carry charge, and it is the movement of that charge across membranes that constitutes an electrical signal. Four ions do nearly all the work of the nervous system, and each has a distinct job.

The crucial fact is that these ions are not spread evenly. Sodium and calcium are far more concentrated outside the neuron than in; potassium is far more concentrated inside. The cell spends continuous effort keeping it that way, and that carefully maintained imbalance is the wellspring of every signal the brain sends.

It is worth pausing on how large these differences are. Sodium sits roughly ten times more concentrated outside the cell than inside, and potassium roughly thirty times more concentrated inside than out. Calcium is the most extreme: the concentration outside the neuron can be tens of thousands of times higher than the vanishingly small amount held inside. These are not incidental facts of chemistry but deliberately maintained conditions, and each one is exploited for a different kind of signal. A neuron is, in a sense, a cell that has turned the careful separation of a few common salts into a language.

Gradients as stored energy

An uneven distribution of ions across a membrane is a store of potential energy, in exactly the way a raised weight or a charged battery stores energy. Two forces act on each ion. One is the concentration gradient: ions tend to drift from where they are crowded to where they are sparse. The other is the electrical gradient: ions are pulled toward opposite charge. Together these define an electrochemical gradient, the net push on each ion. Everything that follows on this page is a matter of working out which of the two forces wins, and where.

A related point, because readers routinely get it wrong. A single action potential moves only a vanishingly small fraction of the ions available. The membrane needs to move very little charge to swing its voltage by a hundred millivolts, because it is only a few nanometres thick and therefore holds very little charge in the first place. A neuron can fire thousands of times before the internal concentrations have shifted measurably, and it does not need to wait for the pump between spikes. The neuron never "runs out of sodium". What the pump does is prevent a slow, cumulative drift over minutes and hours, not refill a tank between impulses.

This is why the resting neuron is not idle. Maintaining the gradient is active, effortful work, and the readiness it buys is what lets a neuron fire in a fraction of a millisecond when the moment comes. The energy of thought is, at bottom, the controlled discharge of these ionic batteries.

Every ion has a voltage it is content at

The two forces above, the chemical push of the concentration gradient and the electrical pull of charge, are usually described and then abandoned. But the moment you let them act on the same ion at the same time, something falls out that is arguably the single most useful idea in the whole of neurophysiology, and one that most introductions never state. Follow it slowly, with potassium, one step at a time.

1. Start with the gradient

   Potassium is roughly thirty times more concentrated inside the neuron than outside. Now open a channel that only potassium can pass, and nothing else.

2. Potassium leaves

   Crowded inside, sparse outside, so potassium drifts outward down its concentration gradient. So far this is ordinary diffusion.

3. But it carries its charge with it

   Every potassium ion that leaves takes a positive charge out of the cell and leaves an unbalanced negative charge behind. The inside of the cell grows steadily more negative.

4. The negativity pulls potassium back

   Potassium is positive and the interior is now negative, so an electrical force now draws potassium back in. This force did not exist a moment ago. Potassium's own escape created it.

5. The outward flow slows and stops

   The more potassium leaves, the more negative the inside becomes, and the harder it becomes for the next potassium ion to leave. At some particular voltage the inward electrical pull exactly balances the outward chemical push. Ions still cross in both directions, but no longer on balance. Net movement is zero.

That voltage is potassium's equilibrium potential, and for a thirty-fold gradient it works out at roughly minus 90 millivolts. It is not a property of the neuron or of the channel. It is a property of the gradient alone: tell me how unequally an ion is distributed across a membrane, and I can tell you the voltage at which it will sit still. Every ion therefore has one.

Now the payoff, and it is a large one. Because these values are voltages, and because a channel that is open lets its ion move whenever the membrane is not sitting at that ion's equilibrium potential, one sentence follows.

Almost everything else on this site is a consequence of that one line. Consider what it explains, without a single further assumption.

Chloride and inhibition

Chloride is the odd one out among the four key ions and it is routinely under-explained, usually with the bare assertion that chloride flows in and inhibits the cell. The bare assertion is nearly the wrong picture, and the rule above shows why.

Chloride's equilibrium potential in a mature neuron is about minus 70 millivolts, which is roughly where the resting membrane already sits. Apply the rule: an open chloride channel drags the membrane towards minus 70. But the membrane is already at about minus 70. So very little happens. Open every chloride channel on a resting neuron and its voltage barely moves. If inhibition worked by pushing the voltage down, chloride would be a poor tool for it, and yet chloride carries most of the brain's fast inhibition. The resolution is that inhibition does not have to push.

Put the two mechanisms side by side, because inhibition uses both and they are not the same thing.

Two consequences are worth drawing out. The first is anatomical: shunting works best where the excitatory current has to pass, which is why inhibitory synapses are so often placed on the cell body and the axon hillock, close to the point of decision, rather than out on the dendrites. An inhibitory synapse sitting on the hillock can bleed away the summed excitation of an entire dendritic tree.

The second is developmental, and it is a striking demonstration that the rule really is doing the work. In immature neurons, chloride is not kept at the same level: the young cell accumulates chloride inside itself, so chloride's equilibrium potential is less negative than the resting voltage. Apply the rule again, and it predicts that opening a chloride channel in an immature neuron should drag the membrane upward, and therefore that GABA, the brain's great inhibitory transmitter, should be excitatory early in development. It is. That reversal is real, well documented, and it happens because a chloride transporter changes over during maturation and shifts the gradient. Nothing about the receptor changes; only the gradient does. The effect of a channel is not a property of the channel. It is a property of the gradient the channel is connected to.

Ion channels

The membrane itself, an oily double layer, will not let charged ions pass. Ions cross only through dedicated proteins that span the membrane and form a water-filled pore: ion channels. These are not simple holes. Each channel is exquisitely selective, shaped to admit one kind of ion and turn others away, so that a potassium channel passes potassium but blocks the smaller sodium ion. And most channels are gated: they open and close, so the cell can control exactly when ions flow.

Because channels open and close on command, the neuron can steer the flow of charge with precision, opening sodium channels for a fraction of a millisecond to fire an impulse, then closing them and opening potassium channels to reset. The action potential is, from this angle, a carefully timed sequence of channels opening and shutting.

Selectivity deserves emphasis, because it is a remarkable feat of chemistry. A sodium ion is smaller than a potassium ion, so it might seem that any pore wide enough for potassium would let sodium slip through easily. Yet potassium channels admit potassium and reject the smaller sodium. They manage this by lining the pore with just the right pattern of atoms to replace the shell of water molecules that surrounds a potassium ion, a fit that sodium cannot match. This is why the same membrane can carry two opposite signals on two different ions without confusion: each channel reads its ion by shape and chemistry, not merely by size.

Kinds of channel

Channels are grouped by what makes them open. Three kinds account for most of the electrical life of a neuron, and each is suited to a different job.

Ion pumps

Channels let ions flow downhill, along their gradients. Something has to carry them back uphill, or the gradients would soon run flat and signalling would stop. That job belongs to ion pumps, proteins that move ions against their gradient by spending energy. Two pumps matter most.

Pumps and channels work as opposites in balance. Channels discharge the gradients to make signals; pumps recharge them in the background. The neuron is never truly at rest: even when silent, it is spending energy to stay poised for the next impulse.

A third kind of transport bridges the two. Some proteins do not spend ATP directly but instead let one ion flow downhill to drag another uphill, borrowing the energy already stored in the sodium gradient. Transporters of this sort clear excess calcium and recover neurotransmitters from the synapse. They are the reason the sodium gradient is so precious: it is not spent only on impulses but tapped as a general power source, a common currency the cell draws on for many secondary tasks.

How the pump works

The sodium-potassium pump is worth following step by step, because it shows how a protein turns chemical energy into an ion gradient. Each cycle moves five ions and consumes one ATP.

1. Sodium binds

   Three sodium ions from inside the cell bind to the pump, which is open to the interior.

2. ATP is spent

   A molecule of ATP is split, and a phosphate group attaches to the pump. This chemical energy changes the pump's shape.

3. Sodium is released outside

   The new shape opens the pump to the outside and lowers its grip on sodium, so the three sodium ions are released into the extracellular fluid.

4. Potassium binds

   Now two potassium ions from outside bind to the pump, which prompts the phosphate group to detach.

5. Potassium is released inside

   Losing the phosphate returns the pump to its first shape, opening it to the interior and releasing the two potassium ions inside. The cycle is ready to repeat.

Because three positive ions leave for every two that enter, each cycle carries a net positive charge out of the cell, so the pump makes the inside slightly more negative than it would otherwise be. A transporter that moves unequal charge in each direction, and therefore generates a current of its own, is called electrogenic.

Why balance matters

Because signalling depends on precise ion concentrations, the brain is acutely sensitive to electrolyte balance. Clinical accounts usually list the symptoms of each disturbance and stop there, which leaves the reader memorising associations. There is no need. With the equilibrium potential in hand, each clinical fact can be derived, because an equilibrium potential is set by a ratio of concentrations, and a doctor changing the concentration in the blood is changing one side of that ratio.

Too much potassium in the blood

Trace the chain. Raise the potassium concentration outside the cell and the inside-to-outside ratio shrinks. A smaller ratio means a less negative equilibrium potential, so potassium's target voltage moves upward from minus 90 towards, say, minus 80. The resting membrane is dragged mainly towards potassium's target, so it follows: the cell depolarises, sitting at perhaps minus 60 instead of minus 70. It is now closer to threshold, and a smaller input will fire it. This is why hyperkalaemia is initially excitatory: nerve and cardiac tissue become irritable and fire too easily.

Push it further and the effect reverses, which looks paradoxical until the two-gate structure of the sodium channel is recalled. The inactivation gate closes when the membrane is depolarised and reopens only when it repolarises. A membrane held chronically depolarised never repolarises, so its sodium channels inactivate and stay inactivated. With no available sodium channels there is no positive feedback loop and no spike at any stimulus strength. The tissue goes from over-excitable to entirely unexcitable, and the cause of both is the same depolarisation. This is depolarisation block, and in the heart it is what makes severe hyperkalaemia lethal.

Too little sodium in the blood

Now the other direction. Lower the sodium concentration outside the cell and the sodium gradient shrinks, so sodium's equilibrium potential falls from about plus 60 towards, say, plus 40. The upstroke of the action potential is the membrane being dragged towards that value, so the ceiling has come down: the spike still fires, but it is smaller. Amplitude, not threshold, is what suffers. A weaker spike delivers less current to the membrane ahead of it, so conduction slows and becomes less reliable. Meanwhile a fall in blood sodium also draws water osmotically into brain tissue, which swells inside a rigid skull, and it is largely this swelling, rather than the altered spike, that produces the confusion, headache, and seizures of severe hyponatraemia.

Calcium is the instructive exception, and it is worth noting because it does not follow the same route. Low blood calcium makes nerves and muscles hyper-excitable, producing the spasms of tetany, but not by shifting a gradient the cell signals with. Extracellular calcium ions screen the negative charges sitting on the outer face of the membrane, and in doing so they alter the electric field that the sodium channel's voltage sensor actually reads. Remove some of that calcium and the sensor reads a field that looks more depolarised than it is, so the channels open more readily and threshold effectively falls. Even the exception, then, is a story about what a channel senses, not about a symptom to be memorised.

All of this is why electrolyte disturbances, common in dehydration, kidney disease, and some medications, so often show up first as neurological or cardiac symptoms. The tissues that suffer first are the excitable ones, precisely because they are the ones that had turned a concentration gradient into a signal. The chemistry of salt is, quite literally, the chemistry of thought.

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