Chapter 22: Signal Transduction I: Electrical & Synaptic Signaling

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.

Welcome back to the Deep Dive, where we get right down to the cellular level to understand how things work.

Exactly.

And today we are tackling the electrical and chemical logic that basically runs your entire existence,

neural communication.

It's a huge topic.

It is.

We're asking how cells and neurons in particular can generate electricity and then send that message, say, from your spinal cord all the way down to your foot, a whole meter sometimes.

Without losing any signal strength.

That's the key.

That is our central mission today.

And it really is a magnificent piece of cellular engineering.

I mean, pretty much every cell in your body has some kind of potential.

Right.

But neurons, they've taken that basic idea and just supercharged it for fast, long distance communication.

So this Deep Dive is our summary of Chapter 22 from Becker's World of the Cell.

Yep.

A step -by -step guide.

We're going to cover the whole journey of a signal.

First, how the electrical impulse gets started and moves along the neuron.

And second, how that signal then jumps from one cell to the next, which is where the chemistry comes in.

The synapse.

It's going to be a fun one.

Okay, let's unpack it.

We should probably start with the players, the actual cells involved.

Good idea.

Let's set the stage from the cellular anatomy to the physics that makes it all run.

All right.

So when we think about the nervous system, it's not just one type of cell.

It's a whole team.

A very specialized division of labor.

Absolutely.

The source material breaks them down by what they do, their function.

So first you have your detectors,

the sensory neurons.

Right.

They're the ones picking up on things like pressure or light or chemicals.

And they send that information inward toward the main hub.

The central nervous system or CNS, your brain and spinal cord.

Then you have the motor neurons.

They're the output team.

They're carrying the instructions from the CNS back out to the body.

Telling a muscle to contract or a gland to secrete something.

Exactly.

And then you have the ones in the middle, the interneurons.

And these are the processors, right?

The ones connecting everything, doing all the complex.

Billions of them, creating trillions of connections.

It's staggering.

But it's crucial to remember that neurons are actually in the minority cell count wise.

That's a great point.

They get all the glory, but they'd be useless without their support system.

The glial cells, which actually comes from the Greek word for glue.

Because they used to think they just held everything together.

Right.

But they do so much more and they can be 10 times more abundant than neurons.

And they come in a few key flavors.

You've got the microglia.

The immune system of the CNS.

They're phagocytic.

So they clean up debris, fight off infections.

Very important.

Then you have the insulators.

This is a big one.

Oligodendrocytes in the central nervous system.

And Schwann cells out in the peripheral nervous system.

Both making that fatty insulation, the myelin sheath.

Yeah.

And the location is key.

And all the dendrocyte in the CNS might wrap its arms around several different axons at once.

Whereas a Schwann cell in the periphery usually dedicates itself to just one axon.

And finally the astrocytes.

The jack of all trades.

They are these highly branched cells that are everywhere.

Surrounding blood vessels, surrounding synapses.

They're critical.

They control the chemical environment.

They regulate ions and they form the famous blood brain barrier.

Basically acting as a bouncer.

Deciding what gets from the blood into the brain's delicate tissue.

A very strict bouncer.

Okay.

So let's zoom in on the neuron structure because its shape is everything.

It's perfectly designed for sending a signal in one direction over a long distance.

It is.

You start with the central cell body or soma.

That's where you've got your nucleus, your main organelles.

And then branching off from that, you have the processes.

The first kind being the dendrites.

The receivers.

They're usually highly branched, like a tree, which lets one neuron get input from maybe thousands of other cells.

And any signal they pick up just sort of spreads passively inward toward that cell body?

Yep.

And then there's the other process, the axon.

The transmitter.

This is the one built for sending the signal outward.

And like you said at the top, they can be incredibly long.

A meter long from your spine to your foot.

It's just an immense distance for one single cell.

And the cytoplasm inside is called the axoplasm.

And at the very end of that axon's journey, you find these little swellings, the synaptic boutons or terminal bulbs.

And this is the spot.

This is where the signal has to be transmitted to the next cell across that little gap.

The synapse.

Where the electrical message gets turned into a chemical one.

Okay.

We have the anatomy.

Let's get into the physics.

The membrane potential, which the book calls Vmolars.

Right.

At its heart, Vnol is just a separation of charge across the cell membrane.

In a resting neuron, you've got a buildup of negative charge on the inside surface and positive charge on the outside.

Which gives you that negative resting potential.

The classic example from the squid giant axon is about minus 60 millivolts.

So why?

What creates that separation?

It's an interplay of a couple of crucial forces.

First, the simple concentration gradient.

Ions want to move from where they're crowded to where they're not.

And neurons work very hard to keep potassium or text plus dollar highly concentrated inside the cell.

And sodium plus reveal highly concentrated outside the cell.

And the second force.

The principle of electro neutrality.

Basically, positive and negative charges like to be balanced.

But inside the neuron, you have all these big negatively charged molecules.

Like proteins and RNA.

Exactly.

And they're trapped.

They're too big to get out.

They become what we call immobile So they're just sitting there providing this permanent negative background charge.

Precisely.

So when a positive potassium ion diffuses out of the cell, down its concentration gradient, it leaves one of those unbalanced negative charges behind.

And that's it.

It's that tiny, tiny imbalance right at the surface of the membrane that creates the entire electrical potential.

The bulk of the fluid inside and out is still neutral.

It seems like a system that would just run down pretty quickly.

So what molecular parts actually establish and maintain this?

There are two absolutely essential mechanisms.

The first one is the text plus tail lead channels.

Okay.

What are those?

They're just simple, ungated protein channels that are always open.

And the neuron membrane is packed with them.

So there's always an open door for potassium to leave.

Always.

This high permeability lets potassium continuously leak out, driven by that concentration gradient.

And since positive charge is always leaving, the inside becomes negative.

The textbook is really clear on this.

What's that?

These leak channels are the single biggest factor in setting that negative resting potential.

But wait, if that's the case, eventually all the potassium would leak out.

The gradient would disappear.

Excellent point.

Which brings us to the second incredibly energy hungry component.

The text plus text plus pump.

Ah, active transport.

This is the machine that's burning ATP to fight against the gradient.

It is working tirelessly.

It uses the energy from one ATP molecule to actively pump three sodium ions out.

And at the same time, bring two potassium ions in.

And the amount of energy this takes is just stunning.

The source estimates that this single pump consumes about 40 % of the entire ATP budget of a neuron.

40%.

Just to keep the batteries charged, essentially.

Just to maintain those gradients.

That's how important this is.

And it also contributes a little bit to the negativity itself.

Because it's pumping out three positives for every two it brings in.

Exactly.

So it's electrogenic.

It adds maybe minus five or ten millivolts directly.

But its main, most critical job is maintaining that steep potassium gradient.

So the leak channels can do their work?

So the leak channels can set the voltage.

Okay.

So we've established this is all a balancing act.

A standoff between different forces.

Which brings us to the math we can use to predict that balance point.

Right.

Starting with the idea of electrochemical equilibrium.

This is the specific voltage where the electrical force pulling an ion one way is perfectly balanced by the chemical force, the concentration gradient, pushing it the other way.

And for any single ion, we can calculate that exact point using the Nernst equation.

It gives us what's called the equilibrium potential, or x dollars.

So for potassium, texco plus dollar, because its gradient is so steep high inside, low outside, its equilibrium potential, eco, is very negative.

Around minus 75 millivolts.

So that's the voltage the cell would be at if only potassium could move.

Exactly.

And conversely, for sodium, tex plus plus dollar, the gradient is the other way high outside, low inside.

So its equilibrium potential, eta, is very positive.

About plus 55 millivolts.

So what's immediately obvious is that the actual resting potential of minus 60 is way closer to potassium's minus 75 than it is to sodium's plus 55.

And that observation is precisely why the Nernst equation isn't enough to describe a real living cell.

Because it only looks at one ion at a time.

Right.

In reality, the membrane isn't just permeable to potassium.

There's also some sodium leaking in, some chloride moving around.

So we need an equation that accounts for all of them at once.

Which is the Goldman -Hodekin -Katz equation, or more simply, the Goldman equation.

And what's the key difference here?

The real magic of the Goldman equation is that it doesn't just look at concentrations.

It factors in the relative ionic permeabilities.

So how easily each ion can actually cross the membrane.

Which is the crucial biological factor.

It's determined by how many open channels there are for each ion.

And this is where it gets really clear.

For that squared axon, if we say the permeability for potassium, p -gallallers is 1, then the permeability for sodium, p -allar, is only 0 .04.

Wow.

So the membrane at rest is 25 times more permeable to potassium than it is to sodium.

Exactly.

And that's why the resting potential is so dominated by potassium.

The voltage is tied much more closely to a -gall.

So the take -home message here is that the resting membrane potential is determined by whichever ion has the highest permeability at that moment.

Which means if you could suddenly change that, if you could suddenly make the membrane way more permeable to sodium.

Then the membrane potential would swing rapidly towards sodium's equilibrium potential, towards that plus 55.

And that's the action potential in a nutshell.

That is the action potential.

But I have a question.

If potassium's perfect equilibrium is minus 75, but the cell rests at minus 60,

doesn't that mean it's always a little bit off balance?

That's a fantastic observation.

Yes, it's resting slightly depolarized relative to potassium's ideal.

And because of that, there's always a small, steady net leak of potassium out.

Which is what the pump has to constantly work against.

It's the perfect setup.

It keeps the cell poised, ready to fire.

It only needs a little nudge to get to the firing threshold.

Let's quickly touch on the third ion in the Goldman equation.

Chloride.

Chloride is interesting.

Usually its equilibrium potential is very close to the resting potential, so not much happens at rest.

But if you suddenly open a bunch of chloride channels… The net effect is always inhibitory.

It makes the cell less likely to fire.

How?

Two ways.

First, the influx of negative chloride ions makes the inside of the cell more negative.

That's called hyperpolarization.

Which moves it further away from the firing threshold?

Exactly.

And second, even if some positive sodium comes in trying to depolarize the cell, the chloro that rushes in with it can essentially cancel it out.

So chloride channels are the molecular basis of inhibitory signals.

Okay, concept check.

Let's go back to that pump.

If we use a toxin like oobin to completely shut down the Tex -Hole plus Dala pump, what happens to the resting potential over time?

Well, the gradients would just collapse.

The constant leak of potassium out and sodium in would no longer be fixed.

This is the steep potassium gradient, the thing that sets the minus 60 millivolts.

It would slowly disappear and the membrane potential, VNL 'ers would just drift towards zero.

The cell becomes electrically dead.

It's completely inert.

It's lost its ability to separate charge so it can't fire.

Game over.

Which brings us perfectly to the main event, electrical excitability.

Right.

The big difference between a neuron and, say, a skin cell is how it reacts when you depolarize it.

If you give a small depolarizing stimulus to an excitable cell and it reaches the threshold potential, It triggers an action potential,

a huge rapid all or none reversal of that membrane potential.

To really figure out how this happens on a millisecond time scale, scientists needed to look at the individual channels themselves.

This required some truly revolutionary techniques.

The big one is patch clamping or single channel recording.

This won Nair and Sackman the Nobel Prize and it's just brilliant engineering.

It really is.

You keep this tiny glass microelectrode and form an incredibly tight seal on a tiny patch of the cell membrane.

So tight that you can isolate just one or a few ion channels in that patch.

And then you can control the voltage and literally watch the current flowing through that single channel.

And what this revealed was that channels aren't leaky pipes.

They're gates.

They snap open and closed all or nothing.

And when they're open, the number of ions flowing through is just mind -boggling.

The book gives an example.

A single sodium channel when it opens can pass a current of about one picoampere.

Which sounds tiny.

But that one picoampere is the movement of roughly six million sodium ions per second.

Through one single protein.

That's the speed we're talking about.

That's what allows for that explosive depolarization.

And the technique is so flexible, you can do a whole cell recording to see the current from the entire cell.

Or you can get really clever.

Like the inside -out configuration.

Yeah, you pull the patch of membrane off so the inside, the cytosolic part, is facing out.

Then you can just dip it into different solutions to see what internal chemicals affect the channel.

And the reverse, the outside -out configuration, lets you test things on the external face.

So you can see how neurotransmitters or drugs or toxins bind and affect the channel.

It's the foundation of modern neuropharmacology.

And the techniques just keep getting more precise.

Now we have things like optogenetics.

This is truly cutting edge.

Use genetic engineering to put light -sensitive proteins into specific neurons.

These proteins, called channel rhodopsins, are basically ion channels that open when you shine a specific color of light on them.

So instead of a clunky electrode, you can use a fiber optic light to turn specific neurons on or off with incredible precision.

It's like having a molecular light switch for brain circuits.

It's completely changed how we can study the brain.

Okay, so the ability to fire rests on these voltage -gated channels.

Unlike the leak channels,

their whole shape, their conformation,

changes dramatically depending on the membrane voltage.

Let's talk about their structure.

The potassium channels are multimeric.

Meaning four separate protein subunits come together to form the channel.

But the sodium channels are monomeric.

Right.

One single long protein that's folded up into four distinct domains that act like subunits.

But in both cases, each of these subunits or domains has six helices that cross the membrane, S1 through S6.

And the key to the whole operation is the S4 helix.

This is the voltage sensor.

Exactly.

It's studded with positively charged amino acids.

So when the membrane is negative at rest, that positive S4 helix is pulled inward, held down.

But when the membrane depolarizes, becomes less negative.

The electrical pull weakens.

And that S4 helix physically moves, it pushes outward.

So an electrical change causes a physical mechanical movement.

That's the gating mechanism.

That movement of S4 is what triggers the whole channel to open.

If you mutate those positive charges on S4, the channel loses its voltage sensitivity completely.

But just opening isn't enough.

The channel has to be incredibly selective.

This is the work that won Rod McKinnon a Nobel Prize.

The ion selectivity filter.

How does a potassium channel let all that text plus through, but block the smaller sodium ion?

It seems counterintuitive.

It's all about nanoscale precision.

In water, an ion is surrounded by a shell of water molecules.

It's hydration shell.

Okay.

To get through the channel's filter, it has to shed that water.

The filter itself is this narrow pore lined with oxygen atoms.

For a potassium ion, the spacing of those oxygen atoms is absolutely perfect.

They can substitute for the water molecules in a way that's energetically favorable.

So potassium slips right through.

But for the smaller sodium ion, the oxygen atoms in that potassium channel are too far apart to coordinate with it properly.

So it can't shed its water shell effectively.

The energetic cost is just too high.

So it's blocked.

The smaller ion is blocked because the filter is too big.

Precisely.

It's an absolutely beautiful piece of molecular engineering.

Okay.

So the channel opens,

but it also has to close.

And this is where channel inactivation comes in.

It's different from just regular closing.

It's a second locked shut state.

And it's crucial for making the signal go in one direction.

It's often caused by an inactivating particle.

Like a plug on a chain.

Exactly.

A part of the channel protein itself swings over and physically plugs the open pore.

It's like a padlock on an already closed gate.

And the crucial part is once it's inactivated, it cannot reopen even if the cell is still depolarized.

It has to wait for the membrane to get negative again to repolarize before that plug comes off and the channel resets.

And when this machinery breaks, you get diseases,

channelopathies.

Right.

Mutations in sodium channels can cause epilepsy.

Potassium channel defects can cause ataxia, which is a coordination problem.

The timing of these gates opening and inactivating is everything.

All right.

Let's put it all together.

The step -by -step action potential.

We start at rest, minus 60 millivolts.

A stimulus pushes it to the threshold potential, say minus 40.

And that's the point of no return.

Phase one, depolarization.

The voltage -gated sodium channels fly open all at once.

And because both the concentration gradient and the electrical gradient are pushing sodium in, you get this massive, rapid influx of positive charge.

Which drives the membrane potential way up, peaking around plus 40 millivolts, close to sodium's equilibrium potential.

And this is a classic positive feedback loop.

The depolarization opens sodium channels, which causes more depolarization, which opens more sodium channels.

The Hodgkin cycle.

It's what makes the AP so explosive and all or none.

But then it has to stop.

Phase two, repolarization.

Two things happen here.

First, those fast sodium channels snap shut and enter that inactivated state.

The plug goes in.

Sodium influx stops dead.

At the same time, the slower voltage -gated potassium channels finally swing open.

So now positive charge in the form of potassium starts rushing out of the cell.

And that outflow of positive charge brings the membrane potential crashing back down toward negative values.

And because those potassium channels are slow to close, it actually overshoots the resting potential.

Which is phase three.

Hyperpolarization, or the undershoot.

The potential briefly dips down towards potassium's equilibrium potential.

Maybe minus 75 millivolts.

Before those slow K -plus channels finally close and everything returns to rest.

And this whole cycle defines the refractory periods.

Right.

While the sodium channels are inactivated, you're in the absolute refractory period.

You cannot fire another action potential no matter what.

Machinery is physically locked.

Then during the hyperpolarization, you're in the relative refractory period.

The sodium channels have reset so you can fire again.

But because you're starting from a more negative place, you need a much stronger stimulus to reach threshold.

And this is what ensures the signal marches down the axon in one direction.

Exactly.

But it's important to clarify one thing.

Even though the voltage is swinging by 100 millivolts.

The actual change in the total concentration of ions inside the cell is minuscule.

Tiny.

We're talking about a very small number of ions moving right at the membrane.

The bulk concentrations are stable during a single AP.

Although with really heavy firing, potassium can build up on the outside.

And that's where the astrocytes come in, right?

To help clean that up.

Yep.

They help buffer the environment to maintain stability.

The action potential gets started at the axon hillock, where the axon meets the cell body.

Right.

Which has a very high density of these voltage -gated sodium channels.

Now how does that signal get from there all the way to the end of the axon?

We need to talk about propagation.

First, we have to distinguish between passive spread and active propagation.

The little signals on dendrites spread passively and they fizzle out pretty quickly.

Like ripples in a pond.

Exactly.

For a long -distance signal, the action potential has to be actively propagated.

It has to be regenerated over and over again.

So in a simple non -myelinated axon, how does that work?

It's like a continuous ripple.

The depolarization at one spot passively spreads to the patch of membrane right next to it.

Which brings that next patch to threshold and it fires its own action potential.

Meanwhile, the first spot is repolarizing and going into its refractory period, so the signal can only move forward.

But this continuous regeneration is pretty slow.

It is.

To get real speed, you need insulation.

You need the myelin sheath.

Formed by those glial cells, the Schwann cells, and oligodendrocytes.

It's basically layers and layers of fatty membrane wrapped around the axon.

And this insulation does something very important electrically.

It allows that passive spread of depolarization to travel much farther and much faster without leaking out.

But you still need to regenerate the signal eventually.

Which is why the insulation is interrupted every millimeter or so at the nodes of Ranvier.

These are the little unmyelinated gaps.

And these gaps are jam -packed with voltage -gated sodium channels.

So the signal, the action potential, is generated at one node.

The depolarization then travels super fast and passively under the myelin to the next node.

Where it's strong enough to bring that node to threshold, triggering a brand new action potential.

So the impulse literally jumps from node to node.

That's saltatory propagation, from the Latin word for to leap.

It's dramatically faster and also much more energy efficient.

The cell only has to run its pumps at the nodes, not along the whole axon.

It's a brilliant design.

And we see how brilliant it is when it fails.

In diseases like multiple sclerosis, MS.

Right, where the immune system attacks and destroys the myelin.

You lose that insulation.

So the signal that's trying to spread passively from one node to the next just leaks out.

It fizzles.

By the time it gets to the next node, it's too weak to hit threshold and the signal just stops.

Which leads to all the terrible symptoms of MS.

A direct consequence of failed electrical insulation at the cellular level.

It's a tragic and powerful example.

So let's use that betrachotoxin example again.

The poison that locks sodium channels open.

What's the mechanism of failure?

Well, the neuron depolarizes once.

Just fine.

But the toxin prevents the inactivation gate from plugging the pore.

So sodium just keeps flooding in.

Uncontrollably.

The cell can't repolarize.

It gets stuck in a positive depolarized state.

And if it can't repolarize, it can't reset its channels to fire again.

It's locked.

It's a one -and -done signal, which leads to paralysis.

The inactivation gate is literally what lets life go on.

Okay, the signal has made it all the way to the end of the axon.

Now it has to be passed on.

This is synaptic transmission.

And the source breaks this down into two main types of synapses.

The first and less common are the electrical synapses.

These are for circuits that need extreme speed.

They're basically direct connections formed by proteins called gap junctions.

Which form a channel, a pore, that lets ions flow directly from one cell into the next.

So there's almost no delay.

The electrical signal just continues on.

You see this in heart muscle, where you need perfect synchronization.

But most synapses, the ones doing complex processing, are chemical synapses.

Right.

Here, the cells don't touch.

There's a physical gap, the synaptic cleft.

It's tiny, but it's too big for the electricity to jump across.

So the presynaptic cell has to convert its electrical signal into a chemical one, a neurotransmitter.

It releases that chemical, which floats across the gap, binds to receptors on the postsynaptic cell.

And gets converted back into an electrical signal.

And the receptors that do that conversion come in two main types.

You have the fast ones, the inotropic receptors, which are basically just ligand -gated ion channels.

The neurotransmitter binds, the channel opens.

Simple.

And then the slower, more complex ones, the metabotropic receptors, which use second messengers.

We're going to focus on the fast ionotropic ones for now.

So the switch from electricity to chemistry is controlled by one critical ion.

Calcium, texTA2 plus tobutol.

Calcium is the trigger.

When the action potential arrives at the synaptic bouton, it depolarizes that terminal membrane.

And that depolarization opens voltage -gated calcium channels.

Now, the concentration of calcium outside the cell is about 10 ,000 times higher than it is inside.

10 ,000 times.

That's an enormous gradient.

It's huge.

So when those channels open, you get this incredibly rapid, sharp influx of calcium right at the terminal.

And that sudden surge of calcium is the direct signal to release the vesicles full of neurotransmitters.

Exactly.

The calcium causes the vesicles that are already docked at the membrane to fuse and release their contents.

This is exocytosis.

And this fusion is managed by a set of proteins called the SNARES.

Right.

You have V -SNARES on the vesicle and T -SNARES on the target membrane.

They act like a zipper, pulling the two membranes together.

But the final critical step, the one that's triggered by calcium, is controlled by another protein,

synaptotagmin.

Synaptotagmin is the calcium sensor.

Calcium rushes in, binds to synaptotagmin, which then changes shape and catalyzes the final zippering of the SNARES.

And poof, the neurotransmitter is released in milliseconds.

This is the work that won Thomas Sudhoff the Nobel Prize.

And because this machinery is so precise, it's a huge target for toxins.

Like tetanus and botulinum toxin, or botox.

Both of them are proteases.

They're enzymes that literally cut up the SNARES proteins.

Tetanus blocks release from inhibitory neurons, which causes all the muscles to contract uncontrollably.

While botulinum toxin blocks release at the neuromuscular junction, so it paralyzes the muscle.

It prevents contraction.

All from just cleaving one tiny protein strand.

It's incredible.

So if these vesicles are constantly fusing, wouldn't the terminal just get bigger and bigger?

It would, but the cell recycles the membrane immediately through endocytosis.

For really fast -firing neurons, they even use a method called kiss and run.

Kiss and run.

The vesicle just briefly fuses, opens a tiny pore to release its contents, and then quickly detaches without fully merging.

It's much faster.

Okay, the neurotransmitter is out.

To be officially called a neurotransmitter has to do a few things.

Right, it has to be found in the neuron, be released on stimulation, and then cause a specific response.

And that response is either excitatory and EPSP or inhibitory and IPSP.

Let's start with a key excitatory example.

Acetylcholine, or AA.

It's the neurotransmitter at the neuromuscular junction.

Its receptor, the nicotinic acetylcholine receptor, is a ligand -gated sodium channel.

Two ATG molecules bind,

the channel opens, sodium flows in, and you get a rapid depolarization of the muscle cell.

And things can go wrong here.

A poison -like curare is an antagonist.

It blocks the receptor.

Causing paralysis.

While nicotin is an agonist, it mimics A .C., but it lingers and overstimulates the system.

And in the disease Myasthenia gravis, the body's own immune system attacks and destroys these very receptors.

Leading to profound muscle weakness.

Now, in the brain, the main excitatory player is glutamate.

And one of its receptors, the NMDA receptor, is really special.

It lets in both sodium and calcium.

And it's a coincidence detector, right?

Exactly.

To open, two things have to happen.

Glutamate has to be present, and the postsynaptic cell has to already be depolarized.

Which is a fundamental mechanism for learning and memory, for strengthening connections.

Okay, now for the breaks.

The main inhibitory neurotransmitter in the brain is GABA.

And its receptor is a ligand -gated chloride channel.

So when GABA binds, the channel opens and negative chloride ions rush into the cell.

Making the inside more negative hyperpolarization.

Which makes it harder to fire.

And this is the target for drugs like Valium and other benzodiazepines.

They don't open the channel themselves, they just make it much more sensitive to the GABA that's already there.

So they boost the brain's natural inhibitory system.

Precisely.

And we should quickly mention there are many others.

The catecholamines, like dopamine, serotonin, and even small proteins called neuropeptides, like endorphins.

And the weird ones, the endocannabinoids.

They're fascinating.

They're made in the postsynaptic cell and travel backward across the synapse to inhibit the presynaptic cell.

A retrograde signal?

A local volume control, telling the presynaptic neuron to calm down a bit.

Okay, once the neurotransmitter has done its job, it has to be cleared out of the synapse.

Immediately.

If it hangs around, the signal becomes a mess.

So you have two main ways to terminate the signal.

First is degradation.

An enzyme just chews it up.

The classic example is acetylcholine, which is destroyed almost instantly by an enzyme called acetylcholinesterase.

And if you block that enzyme with something like the nerve gas serine, the cell builds up, causing continuous uncontrolled stimulation and eventually paralysis.

The second method is reuptake.

This is where transport proteins on the presynaptic cell literally pump the neurotransmitter back inside to be recycled.

And this is where a lot of modern drugs work, like Prozac.

Prozac is a selective serotonin reuptake inhibitor, or SSRI.

It blocks the pump that removes serotonin.

So more serotonin stays in the synapse for longer, boosting its signal.

Now, a single action potential usually isn't enough to make the next cell fire.

It just causes a tiny voltage change, a PSP.

An EPSP or an IPSP.

So the postsynaptic neuron has to add up all these little inputs it's getting.

This is signal integration, or summation.

And the decision is made at the axon hillock.

There are two types.

Temporal summation is about timing.

Right.

If you get several EPSPs from one neuron in rapid succession, they can add up over time to reach threshold.

And spatial summation is about location.

This is where you're adding up all the EPSPs and IPSPs arriving at the same time from many different neurons all over the cell.

The cell is like a tiny analog computer, adding the positives and subtracting the negatives.

And only if that grand total, the net sum, is enough to hit threshold at the axon hillock will a new action potential be fired.

This is the cellular basis of all complex thought.

So if we just recap, the whole amazing system that allows us to think and move is built on three molecular stages.

It all starts with setting up that negative resting potential.

Right.

Which relies on the huge energy cost of the sodium potassium pump and all those potassium leak channels.

That sets the stage for stage two, firing the action potential.

An all or none event driven entirely by the very different split second timing of the voltage gated sodium and potassium channels.

With that inactivation gate being the crucial brake on the system.

And then finally stage three is synaptic transmission.

The electrical signal becomes a chemical one, released with insane precision thanks to calcium and the snares.

Allowing the signal to jump that gap and be integrated by the next cell.

It's just.

From start to finish, the entire complexity of our minds relies on this molecular machinery just working perfectly.

It's truly startling to think that a signal that can travel a meter down an axon depends on processes happening in a 50 nanometer gap.

I know the density and speed are just hard to comprehend.

And the precision.

Think about that potassium selectivity filter, telling ions apart based on how they feel about shedding their water molecules.

Or that a tiny puff of calcium in a terminal is the final decision point for every single thought or movement you make.

That connection from the microscopic biology to our macro experience of being alive, that's what it's all about.

It is.

So what single molecular event are you relying on right this second that's determining your complex behavior?

The answer is billions of them all at once.

A profound thought to end on.

Thank you for joining us for this deep dive into the electrical like of the neuron.

We hope this helped you conquer chapter 22.

We'll see you next time.