Chapter 5: Membrane Potentials and Action Potentials

Welcome to Last Minute Lecture.

This free chapter overview is designed to help students review and understand key concepts.

These summaries supplement not replaced the original textbook and may not be redistributed or resold.

For complete coverage, always consult the official text.

You know,

usually when we think about electricity, we picture like copper wires, right?

Or batteries or a rigid circuit board.

Yeah, totally.

It feels very contained.

You flip a switch and electrons just flow cleanly from point A to point B.

Exactly.

It's predictable.

But right now, as you're listening to this, millions of tiny electrical micro explosions are happening inside your brain just so you can process these words.

Right.

And if you look closely at the nervous system, that rigid copper wire is just completely gone.

It's a totally different world.

Welcome to our deep dive, by the way.

We're so glad you're here.

Yeah, thanks for joining us.

We're looking at this messy microscopic landscape of saltwater, fatty membranes and floating proteins.

It's really the ultimate physiological paradox, I think.

Like we are electrical machines, but our electricity is driven entirely by fluid dynamics and concentration gradients.

Which is pretty mind blowing when you try to wrap your head around it.

It really is.

And that is exactly what our mission is for you today.

If you are a college seeing medical physiology for the first time, consider us your study companions.

Absolutely.

We're going to act as your guides today.

Right.

We are tackling chapter five of Geithen and Hall, which is membrane potentials and action potentials.

We're going to translate all those dense textbook mechanisms into plain logical language where anatomy creates function.

And here is the blueprint for how we're going to do that.

We're going chronologically through We start with the basic physics of how a cell builds up an electrical charge.

Then we move to the actual explosive event, the action potential.

And finally, we'll explore how that signal travels down a nerve.

Right.

Because before a nurse can fire, it has to build up potential energy.

We have to understand the resting state first.

Exactly.

You can't fire a gun if you haven't loaded the spring.

That's a good way to put it.

To give you some perspective, a standard AA battery sitting in your TV remote holds about 1500 millivolts, but a resting nerve cell is sitting at negative 90 millivolts.

Yeah.

So we are dealing with a deeply miniature, really fragile scale.

So how does a cell build up that negative 90 millivolt charge from just saltwater?

Well, it starts with understanding a diffusion potential.

So picture the membrane of a nerve fiber, right?

Inside that cell, you have a massive concentration of positively charged potassium ions.

But outside the cell, there's barely any potassium at all.

Right.

And because nature hates an imbalance, that potassium naturally wants to diffuse outward, you know, just down its concentration gradient.

It wants to escape.

Exactly.

But here's the catch.

As those positive potassium ions slip out through the membrane,

they leave behind negatively charged molecules inside the cell that physically cannot fit through the barrier.

Oh, so the inside of the cell starts losing positive charges, and as a result, the internal environment becomes increasingly negative.

You've got it.

And that growing negative charge creates an electrical pull.

It literally starts acting like a magnet, trying to pull those escaping positive potassium ions right back in.

So they want to leave because of diffusion, but they're being pulled back by electricity.

Precisely.

Eventually, the outward physical push of diffusion perfectly matches the inward pull of that negative charge.

You reach a total stalemate.

Which is where the Nernst equation comes in.

And look, you don't need to read the textbook's complex math formula to understand what it's doing here.

Right.

Definitely don't panic over the math.

Conceptually, the Nernst equation simply calculates the exact electrical voltage needed to stop a single type of ion from diffusing any further.

Right, to find that exact stalemate point.

For potassium, because its concentration gradient is so intense, that stopping point is a powerful negative 94 millivolts inside the cell.

Wow.

Negative 94.

Yeah.

Conversely, if the membrane were, let's say, only permeable to sodium, the opposite would happen.

Because sodium is highly concentrated on the outside, right?

Exactly.

So it would naturally rush in, making the cell positive.

The Nernst potential to stop sodium dead in its tracks would be positive 61 millivolts.

Okay, but biological cells don't live in a vacuum with just one ion.

I mean, it's a chaotic mix of sodium, potassium, chloride, all moving at once.

Which is exactly why we use the Goldman equation.

Right.

It takes the individual poles of all those different ions and calculates the total resting potential.

And the really crucial deciding factor in the Goldman equation is permeability.

Whichever ion can pass through the membrane most easily is the one that's going to dominate the final voltage.

So who wins in a resting nerve fiber?

Potassium.

By a landslide.

In a resting state,

the membrane happens to be about a hundred times more permeable to potassium than it is to sodium.

Wait, a hundred times?

That's a massive difference.

It is.

Potassium is just slipping through these specialized pores constantly.

Because of that huge permeability advantage,

potassium's negative 94 millivolt pole heavily outweighs sodium's positive 61 millivolt pole.

So when you run the Goldman equation with all those competing factors, the overall resting potential gets dragged way down to about negative 86 millivolts.

You know, I always think of the cell in this resting state as like a leaky boat.

Potassium is constantly leaking out through these leak channels.

Right.

Those tandem pore domains.

Yeah.

But if it just kept leaking forever, the boat would sink.

Right.

I mean, the cell would completely lose its concentration gradient.

It would just die.

So to survive, the cell employs a bouncer,

the sodium -gasium pump.

Oh, the famous pump.

How does this bouncer work?

So this pump is a massive protein complex that actively burns cellular energy ATP to bail the water out of the boat.

It works tirelessly.

It grabs three positive sodium ions from inside the cell and shoves them out.

While simultaneously grabbing two positive potassium ions from the outside and pulling them back in.

Right.

And that ratio is the absolute secret to how it works.

Because it's kicking out three positive charges but only taking two back, that means every cycle the cell loses one net positive charge.

Exactly.

It's what we call an electrogenic pump.

That unequal pumping adds an additional negative four millivolts to our Goldman calculation.

Okay.

So let me do the math.

We combine the heavy potassium leakage, dragging the voltage down to negative 86 and then the pump pushing it down another four millivolts.

And we arrive at the final resting membrane potential of a large nerve fiber, which is negative 90 millivolts.

Boom.

The battery is officially charged.

We have a loaded spring sitting at negative 90 millivolts packed with potential energy.

Right.

So let's discharge it.

Yes.

A stimulus arrives.

Now we move from rest to action.

Right.

So the voltage gets nudged up to a threshold of about negative 55 millivolts.

Once you hit that tipping point, the spring snaps.

The action potential.

I want you to picture the graph of this in the text like a roller coaster.

We start cruising flat at negative 90.

Then we get nudged up to that threshold of negative 55.

And then whoosh.

Right.

We shoot straight up past zero into positive territory.

That's the depolarization stage.

Then we plummet violently back down repolarization dip slightly below our starting point into hyper polarization and finally level out again.

It's a violent micro event.

And the mechanism behind why that graph looks the way it does relies entirely on voltage gated channels.

Okay.

So what actually happens at that negative 55 millivolt threshold?

Well, the voltage gated sodium channels experience a physical change in their shape.

They fly open because sodium is highly concentrated outside and the inside is highly negative.

Sodium just blasts into the cell, shifting the internal voltage rapidly from negative to positive.

Exactly.

That's the depolarization.

Okay.

Wait, I want to challenge this logic based on the diffusion rules we just established earlier.

Oh, go for it.

If those sodium channels fly open and all this positive sodium floods in, why does the signal ever stop?

Wouldn't it just rush in until it hits its nernst equilibrium of positive 61 millivolts and then just stay there?

You'd think so, right?

Like a permanent stalemate.

Yeah.

Why doesn't the cell just stay positive?

Why does the voltage suddenly crash back down?

That is the brilliance of the channel's architecture.

The voltage gated sodium channel is not just a single swinging door.

It's a two gate system.

Oh, really?

Two separate gates on one channel.

Yeah.

It has an activation gate on the outside and an inactivation gate on the inside.

When the cell hits that negative 55 millivolt threshold, the activation gate pops open instantly.

But that exact same voltage change also triggers the internal inactivation gate to close.

Wait, so the trigger is the exact same, but the timing of the gates is completely different.

Precisely.

The inactivation gate is structurally sluggish.

So for just a fraction of a millisecond, the corridor is completely unobstructed and sodium pours in.

Oh, I see.

But then?

Then that sluggish inactivation gate finally swings shut, completely cutting off the sodium supply.

Wow.

And right as the sodium is choked off, voltage gated potassium channels, which are also naturally slow to react,

finally swing wide open.

Right.

So the positive sodium stops coming in and an overwhelming wave of positive potassium rushes out.

And losing all that positive charge rapidly crashes the cell's voltage back down to its negative resting state.

That's our repolarization phase.

It's this perfectly timed microscopic dance.

It really is.

But it raises a huge historical question for me.

It's very easy for us to sit here today and confidently state that a submicroscopic gate opens for a fraction of a millisecond.

How on earth did scientists actually prove that?

Oh, this is one of the coolest experiments in physiology.

The definitive proof came from Alan Hoskin and Andrew Huxley.

They won a Nobel prize for this using a technique called the voltage clamp method.

Okay.

Break that down for us.

Well, human nerves are far too small to manipulate at that level.

So they use the giant squid axon.

Wait, literally a nerve from a squid?

Yeah.

It's a nerve fiber so massive, up to a full millimeter in diameter, that researchers can actually see it and manipulate it with the naked eye.

That is wild.

Okay.

So imagine taking this thick tubular squid nerve and sticking two tiny microelectrodes directly into the fluid inside.

Right.

One electrode is acting strictly as a thermometer.

It's reading the internal voltage of the cell.

The other electrode is a pump, injecting electrical current.

And the breakthrough here is the automated feedback loop connecting those two, right?

Exactly.

Suppose the researcher wants to hold the cell's internal voltage at exactly zero millivolts.

When the cell tries to fire an action potential, the sodium gates open and positive sodium tries to rush in.

And the thermometer electrode instantly detects that the voltage is trying to change.

Right.

And the machine fights back.

It instantly injects the exact opposite amount of electrical current to cancel out the incoming sodium, holding the internal voltage perfectly steady at zero.

So it literally clamps the voltage in place.

Hence the name, voltage clamp method.

You got it.

And because the voltage is locked, the researchers can look at how much current the machine had to inject to maintain it.

Oh.

And that measurement tells them precisely how many ions were attempting to flow across the membrane at any given millisecond.

Exactly.

But they needed to isolate exactly which ions were doing the work.

So they used highly specific neurotoxins as tools.

Oh, this part is fascinating.

They used tetrodotoxin, right?

Yes.

The lethal poison from pufferfish.

It physically plugs the sodium channels on the outside of the membrane.

So by applying that, the cell could only move potassium, perfectly isolating one variable.

Right.

And then they used tetraethylammonium to block the potassium channels on the inside.

By selectively shutting down one highway at a time, they mapped the exact timing and flow of both sodium and potassium.

That is just brilliant science.

But you know, we focused entirely on sodium and potassium so far.

And the text makes it very clear they don't act alone.

We have to look at the integrated system.

Oh, absolutely.

The supporting cast is vital.

For instance, we know potassium leaving makes the inside negative.

But what is physically providing that negative background charge in the first place?

The impermanent anions.

Yes.

The inside of the axon is packed with negatively charged proteins, organic phosphates, sulfates, and they are physically massive, like too large to ever fit through the membrane channels.

So when the positive potassium leaves the cell, those trapped negative anions are unmasked.

They are the physical anchor of the entire resting potential.

Which makes total sense.

And then we have the role of calcium.

Calcium is a huge player.

Most cells have voltage gated calcium channels too.

But compared to the lightning fast sodium channels, calcium channels are known as slow channels.

Right.

They take up to 10 to 20 times longer to fully open.

Yeah.

But calcium's most fascinating job actually happens outside the cell.

Calcium ions normally bind to the exterior surfaces of the sodium channel proteins.

Acting like a calming weight, right?

Exactly.

They physically stabilize the sodium gates, making it much harder for them to pop open.

So if we take that anatomical fact and apply it clinically, say, to a patient in a hospital bed, what happens if a patient has hypochalcemia?

Like they don't have enough calcium in their extracellular fluid?

The clinical consequences are really severe.

Without enough calcium acting as that stabilizing blanket, the sodium channels become incredibly twitchy.

They become hyper -excitable.

So they open way too easily.

Right.

A tiny, normally insignificant fluctuation in voltage will suddenly cause the sodium gates to fly open, triggering an unprovoked action potential.

The peripheral nerves just start firing spontaneously over and over again.

And that unprovoked firing causes muscle tetany.

The muscles just lock up and violently spasm.

If that hits the respiratory muscles, the patient can literally suffocate.

All because they are missing a microscopic calcium blanket on their sodium gates.

It's a terrifying example of how cellular anatomy completely dictates macro -level survival.

It really is.

Up to this point, we've only discussed a single spark and one tiny millimeter of a nerve.

But my brain is in my head and my toe is on the floor.

How does that single micro -explosion actually travel the distance?

The initiation relies on a positive feedback cycle.

Once a tiny bit of sodium enters at the site of stimulation, it makes the local voltage slightly more positive.

Which opens more sodium channels, bringing in even more sodium.

Exactly.

But it must hit that negative 55 millivolt threshold.

If the stimulus doesn't cross that tipping point, the feedback loop simply fizzles out.

But once you do cross the threshold, the dominoes start falling.

Because when that massive wave of positive sodium rushes in, those ions don't just stay in one spot.

They drift laterally sideways along the watery inside of the axon.

Right.

And as they drift sideways, they raise the voltage of the completely adjacent resting section of the membrane.

So once that adjacent section is nudged up to the threshold, its own sodium gates fly open.

Then the next section and the next.

The signal propagates in all directions away from the original stimulus.

We call this the all -or -nothing principle.

Once that initial threshold is crossed, the depolarization process will travel over the entire continuous membrane.

It cannot be stopped halfway.

Provided the conditions are right.

Right.

We measure this reliability using the safety factor, which is the ratio of the action potential's raw electrical strength to the threshold required to trigger it.

So as long as the ratio is greater than one, the signal propagates flawlessly down the line.

Precisely.

Which brings up a logistical issue for me.

If we are constantly firing off these action potentials, letting a flood of sodium in and a flood of potassium out, wouldn't the battery eventually die?

Do we ever run out of ions?

It's a great question.

A single impulse barely changes the concentration.

I mean, it's microscopic.

But over millions of continuous firings, the concentration gradients would absolutely begin to run down.

The cell would lose its charge.

Yeah.

This is why the sodium -potassium pump we discussed earlier has to scale up its activity.

It works overtime to recharge the battery.

And that takes energy.

It's an active metabolic process consuming massive amounts of ATP.

In fact, a rapidly firing nerve actually generates measurable physical heat just from the pumps working so hard.

It's incredible.

And speaking of stamina and pacing, different organs require vastly different rhythms.

If you look at an action potential graph for a normal nerve, it's a sharp, violent spike.

But the graph for cardiac muscle in your heart looks like a mesa.

A plateau, right.

The voltage shoots up, but then it stays highly positive for a while before dropping back down.

Yeah.

Up to 0 .3 seconds.

And that plateau is a brilliant functional adaptation.

A quick millisecond spark of electricity is completely useless for pumping blood.

The thick cardiac muscle physically needs sustained time to forcefully squeeze the blood out of the chamber.

So how is that plateau created anatomically?

It's created primarily by those slow L -type calcium channels.

While the fast sodium channels open and snap shut immediately,

these slow calcium -sodium channels stay open long after.

They constantly trickle positive charge into the cell to hold the voltage high and sustain the contraction.

But a heartbeat isn't just a single sustained event.

It's a lifelong rhythm.

How does the heart's control center actually pace itself without us consciously thinking about it?

The secret is in the resting membrane of the heart's pacemaker cells.

Unlike a normal nerve that sits firmly locked at negative 90 millivolts, the pacemaker membrane is naturally leaky to sodium and calcium ions.

Oh, so because positive charges are constantly trickling in through those leaks, the internal voltage doesn't stay flat.

It slowly drifts upward on its own.

It drifts up, finally hits the threshold, and fires.

The heart beats.

But the genius part is what happens immediately after.

During the repolarization phase, the cell experiences a massive outflow of potassium.

It actually overshoots the resting baseline, plunging into a state of extreme negativity.

Right, hyperpolarization.

It becomes so negative that it takes nearly a full second for that natural, slow inward leak of sodium and calcium to drag the voltage all the way back up to the threshold.

So that period of profound hyperpolarization provides the literal delay.

It's the physical pause between your heartbeat.

Exactly.

It creates the rhythm.

Okay, so we've solved how signals propagate and how they pace themselves.

But if we look at the raw speed of these bare fluid membranes, an unmyelinated nerve conducts a signal at roughly barrow 0 .25 meters per second.

Makes it pretty slow.

Disastrously slow.

If you step on a nail, a quarter of a meter per second is not going to cut it.

To coordinate a whole human body, we need a superhighway to increase velocity.

And evolution solved this speed problem through biological insulation.

There's a great microscopic image described in the text.

Imagine looking at a cross section of a nerve trunk.

You see these large, hollow -looking circles with thick, dark borders, right?

Surrounded by tightly -pat, tiny dots.

Yes.

The big circles are myelinated axons.

The thick border is the myelin sheath.

And the tiny dots are the slow, unmyelinated fibers.

Let's focus on that thick border.

Imagine wrapping a leaky pipe in dozens of layers of heavy electrical tape.

In the body, Schwann cells physically wrap around the large axons dozens of times.

Right.

They lay down sphingomyelin, which is a powerful lipid insulator.

But they leave tiny microscopic bare gaps every few millimeters.

The nodes of Ranvier.

Exactly.

Because ions physically cannot pass through the thick myelin, the action potential can't travel in a continuous wave along the membrane anymore.

So what happens?

The electrical current is forced to flow through the surrounding extracellular fluid and the axoplasm inside.

It literally jumps from one bare node of Ranvier to the next.

Oh, this is saltatory conduction.

And the performance upgrade is staggering.

By jumping from node to node, this increases the speed up to 100 meters per second.

That is the length of an entire football field in a single second.

Wow.

And it drastically concerns energy, too.

Huge energy savings.

Because the cell only has to pump ions back at those tiny nodes, not along the whole continuous fiber.

It is an incredibly elegant biological solution.

Now, to bring all this together for our final topic, let's look at how we can artificially manipulate this system.

Either forcing a nerve to fire or forcing it to stop.

Right.

In a lab, we can excite a nerve using a negative electrode, which lowers the positive charge on the outside of the membrane, artificially bringing the voltage closer to the threshold.

And if it doesn't quite hit the threshold, you just get an acute local potential that simply fades away.

Yeah.

But once it does fire, you run into the refractory period.

Ah, yes.

If you zap a nerve while it's already firing, nothing happens.

Why is that?

It's the absolute refractory period.

Remember those sluggish inactivation gates on the inside of the sodium channels?

Yeah, the ones that swing shut to choke off the sodium.

Exactly.

During this period, they are firmly locked shut and physically cannot reopen until the membrane returns to its resting negative voltage.

Oh, so that guarantees action potentials don't merge together into a continuous spasm.

And it prevents signals from traveling backward toward the source.

Exactly.

It's a built -in safety mechanism.

Okay.

So what about stopping a nerve from firing entirely?

Like, how do drugs like prokane and tetrakane local anesthetics stop pain at the dentist?

They act directly on those voltage gates we've been talking about all day.

These drugs are membrane stabilizers.

They physically bind to the activation gates of the sodium channels.

Making them incredibly difficult to open.

Right.

If the gates can't open, the threshold safety factor drops below 1 .0.

So the pain receptor in your tooth detects the drill, triggers an action potential, the signal races up the nerve.

But the moment it hits the anesthetized section, the domino effect just stops.

The impulse simply fails to pass along the nerve.

Your brain never gets the message.

That is amazing.

It really all comes down to those tiny gates.

Which actually brings me to a final thought I want you, the listener, to mull over today.

Let's hear it.

We started this deep dive by pointing out that the body isn't a rigid circuit board with copper wires.

Every single thought you have ever had, every movement you make, every heartbeat you have ever experienced is simply the result of tiny physical gates opening and closing to let salt ions flow back and forth across a microscopic barrier.

It really changes how you look at yourself, doesn't it?

You're an incredibly complex fluid machine.

It absolutely does.

Well, that wraps up our exploration for today.

A warm, encouraging thank you to the listener from the Last Minute Lecture Team for diving into the fascinating world of medical physiology.