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0:00
[class murmuring] Kevin Ahern: Welcome back!
0:03
Did everybody miss having this class on Friday?
0:07
Who said yeah? "A" for the day. [Kevin laughs]
0:15
I hope you guys did fun stuff on Friday. Did anybody do anything fun on Friday? Float the river? [class laughing] You can float the river. It might not be too much fun if you were having to go home or something.
0:28
Okay, so we are behind but fortunately this term I built in some flexibility. If you look on the schedule page you'll see I have an entire lecture before the exam that's listed as review. We'll probably gobble that time up now.
0:44
But that's fine. People have asked me where the exam will go to. I haven't decided. I will follow, find a logical place for us to stop, and that will likely be sometime Friday but I can't tell you until I see how far I get going with my lectures. So I will definitely let you know. The exam is a week from Wednesday.
1:03
Yay!
1:07
Yes, and we'll talk about that more at that time. So last time I was talking I was finishing talking about different transporters and I got up to these two terms right here that I didn't get a chance to cover. Some of you have noted that I did mention them in my highlights and so now I want to make sure that you know what those terms refer to. When we look at the categories of transporting things across membranes we put the proteins really into two main categories. Your book lists three here
1:39
but we won't talk about the uniporters on the end.
1:43
We're more interested in the first two, the antiporter and the symporter. And they're very simple. These are membrane transport proteins that do movement of molecules across membranes. They just do them in different ways. So an antiporter, as you're seeing on the screen, is moving two molecules in opposite directions.
2:06
One in, one out. There might be two or three. We're not counting numbers here,
2:10
but moving molecules in opposite directions. The symporters move molecules in the same direction. That can be either both in, it can be both out. So it really varies on what's being moved. And you'll also see as I noted in the highlight that sometimes people spell this S-Y-N-porter, and I will take either of those as acceptable. So S-Y-M or S-Y-N, okay?
2:36
Another term that we frequently associate with these that we don't see on the screen but I'll tell you is a transporter that is electrogenic.
2:47
An electrogenic transporter is a transporter
2:52
whose action causes charge to change as a result of what they're moving. So last time when I was talking about the sodium-potassium ATPase I said it was kicking three sodium ions out and it was kicking two potassium ions in. That means every time it does a cycle of transport one net positive charge is going outside. That's electrogenic meaning that the charge is changing as a result of the action of the transporter.
3:24
If we look at the glucose transporter that I talked about, lets say a GLUT protein. A GLUT protein, for example, which allows glucose to come into the cell is electroneutral because there's no charge associated with glucose, and that would simply indicate that. You had a question? Student: Would that also be an antiporter or is electro-, electrogenic... Kevin Ahern: Electrogenic and electroneutral have nothing to do with whether they're antiporters or symporters.
3:50
It's just as a result of their actions does the charge change.
3:55
So electrogenic involves a net change of charge as a result of their action. Okay, let's see. The last transporter I want to talk about is an interesting one. I mentioned it to you briefly because it's an example of a transport system that uses the energy from an electrochemical gradient to move things.
4:22
Now this is where students sometimes get confused. Let's remember that cells can pump things outside of cells. We saw the example of the sodium transporter kicking things out and I talked about how that sodium gradient could be moved, could be used to kick calcium out, right? Remember that? So we saw that there's a concentration gradient and there's an energy associated with the concentration gradient. We can use that energy to do active transports.
4:53
So in active transport we're moving something against the concentration gradient. In this case, the thing that's being moved against a concentration gradient is the sugar lactose.
5:05
So in this example cells have more lactose inside of them than they do outside.
5:12
But they want more! And the reason they want more is this is probably a little bacterial cell that's floating around that whenever it's got lactose it wants to grab it as quick as it can because it never knows when it's going to have another meal.
5:26
So it has to move lactose against the concentration gradient. It has to move it into the cell and so it uses a proton gradient to do that. In this case the protons are in higher concentration outside the cell than inside, so the protons want to come in.
5:44
They have an energy associated with them because of the different concentrations on the outside versus the inside. That concentration is used to bring lactose in, and that's what you see happening here. So we see first of all a proton binding to the transporter,
5:59
lactose binding next, and the binding of the lactose causes a shape change. We see the shape change go as we see here. Lactose gets dumped in. The proton gets dumped in and we get back to where we started.
6:12
You'll notice this is an active transport system. No ATP.
6:18
So ATP can be an energy source for a transport system but it doesn't have to be. It depends on the system. This system doesn't require ATP. It's using a concentration gradient to move something against a concentration gradient. That's kind of a cool thing.
6:34
Yes sir? Student: Is this an example of a symporter? Kevin Ahern: Is this an example of a symporter? Well you tell me, what's happening here? Student: Well you have a proton and lactose both going into the cell. Kevin Ahern: So they're both going in the same direction so this would be an example of a symporter, yes. What else could we say about this transporter?
6:53
It's electrogenic because we're seeing positive charge, or charge change as a result of action of this guy. So it's both electrogenic and it's a symporter.
7:06
So those are the transport proteins I wanted to talk about. I want to spend a little bit of time talking about a subject that students find fairly interesting, as do I, and I will tell you I'm not an expert at it but it's nonetheless a fascinating topic, and that's the topic of nerve transmission.
7:22
Nerve transmission is really remarkable in how well it works, how fast it works, and how efficiently it works.
7:33
Without our nerves firing we're in pretty deep doodoo. We stick our hand in a fire and it takes an instant and we feel. We know that we've done something wrong. Our nerve system tells us we've done something wrong when we do that. So what I want to do is spend a little bit of time telling you how, at least at a simple level, how that nervous system works, and then we'll move on. We can't teach you an entire topic of neuroscience but we can at least see how nerve cells work.
8:03
So how do nerve cells work? I've got this finger and I'm sticking it in the fire.
8:08
Not a smart guy, but you guys already know that. And all of a sudden my nerve cell that responds to pain out there says, "Hey Ahern, you did something dumb here. "Let's try to get that finger out of that fire as quickly as we can." How does it tell me that? Well it does that by communicating information and that information it's communicating is happening as a result of chemical gradients. Chemical gradients.
8:40
Here's this nerve cell. This nerve cell's been sitting in here literally as a loaded gun waiting to fire.
8:48
Your nerve cells are that, they're loaded guns waiting to fire. And the reason I like to think of them as loaded guns is because they're just like a regular cell in one sense in that what have they been doing? They've been pumping out sodium and they've been pumping in potassium.
9:06
They have, as a result of that action,
9:10
more sodium outside of them than inside, and they have more potassium inside than outside. There's a gradient. Sodium wants in, potassium wants out.
9:25
This nerve cell, when I stick the finger in the fire,
9:29
fires the gun first by doing the following thing. It opens up a specific gated channel
9:39
that is specific for sodium.
9:43
It allows sodium to freely move.
9:48
Well what's going to happen if sodium concentration is higher outside than inside? What's going to happen is sodium is going to come rushing in through that open gate. And only sodium. We'll see in a bit how that works. Only sodium comes rushing in.
10:04
When sodium comes rushing in
10:07
we see the concentration of sodium rising inside.
10:11
So the chemical gradient is changing.
10:16
We also see the charge changing because now we've got a whole bunch of positive charges rushing in.
10:23
The voltage is changing.
10:26
So the potential is changed as a result of that very first thing that happens. And because we've got a nice gradient set up those sodium ions are racing through there. They're racing through there.
10:40
We want our nerves to work fast and chemical gradient, when we poke a hole in the dam we want that water coming out as quickly as possible. In this case the water is the sodium rushing into this nerve cell. We've started the process of transmitting that information to the brain.
10:59
Sodium comes rushing in.
11:04
We see sodium rushing in. We're depolarizing the membrane.
11:10
It's polar when there's a charge distribution. However, the cell has to act as quickly as possible. We want that nerve cell to be ready to fire again as quickly as it can.
11:27
So the nerve cell says, "Whoa, look at this voltage change going on there! "We've got to do something about this charge difference," and so the nerve cell, after the sodium gates have opened opens the potassium gates.
11:41
Why does it open the potassium gates? Well potassium is higher concentration inside. What happens if we have a charge rushing in that's positive and we have a highly positive potassium ion? What's it going to do? It's going to go rushing out.
11:57
So the cell opens the potassium gates to let potassium escape and try to balance that charge difference.
12:09
So sodium in, potassium out. Well what's happening in that nerve cell? Well now at the very point of where I stuck my finger in that nerve cell has all of a sudden a high concentration of sodium and it's losing potassium.
12:25
What do you suppose happens along the length of the nerve cell?
12:29
Well that gradient information is transmitted along the entire nerve cell.
12:36
And that first process you saw at the very end of the cell happens repeatedly at various junctures along the way because any perturbation in that voltage change that happens as a result of the movement of those ions causes more gates to open, open, open, open, all the way along the nerve cell.
12:56
Now what's remarkable is how fast that happens. In milliseconds you've got a signal back that you've got your finger in a place that it shouldn't be. "Get it out of there."
13:06
That's pretty darn cool.
13:10
How does the nerve cell recover?
13:12
Well I've told you how the nerve cell basically depolarizes. How does it repolarize?
13:21
The first thing that happens is the gates close. Duh. If we want to hold water behind the dam we darn sure better close the gates so water doesn't come rushing through. In this case the sodium and potassium ions aren't rushing through and so those gates close.
13:37
Closing of the gates allows the normal sodium/potassium ATPase to start pumping sodium out and start pumping potassium in. That is getting back to the original state.
13:51
During that phase there's a recovery.
13:56
And after those gradients are reestablished that nerve cell is ready to fire again. A pretty remarkable process.
14:07
Questions about that?
14:09
Student: How long does it take to get back to the normal? Kevin Ahern: How long does it take to get back to normal? It depends a bit on the cell, and on the order of seconds it's not very long.
14:18
Not very long.
14:21
Yes sir? Student: So is that massive ATP expenditure from those pumps the reason that our CNS even being sedentary takes up so much of our daily caloric intake? Kevin Ahern: Is the reason that these pumps take ATP
14:33
an explanation for why your central nervous system takes up a decent amount of our ATP? And the answer is yes, it is.
14:43
Your brain and your eyes which are really enormous signalers or responding to signalers are consuming disproportionate amounts of ATP in your body.
14:56
Disproportionate amounts of ATP in your body. It's something like a quarter of all your ATP, I think, is going through your brain.
15:04
Yes? Student: So I know if, like, you get burned for too long your signaling goes dead? Is that your ions just kind of... Kevin Ahern: So if you're burnt too bad your signaling goes dead. If you burned yourself too bad you've probably have destroyed some nerve cells.
15:21
That'll definitely do it. Yes Jen? Student: [Inaudible] Kevin Ahern: Chronic pain, yeah. Chronic pain's a common question I get with that and chronic pain can arise from a variety of things. Chronic irritation. You know, an irritant that doesn't go away.
15:37
And chronic pain is difficult to manage and predict because what happens is your brain also has to some extent an ability to filter
15:47
so if you have things that are constantly firing, firing, firing, eventually your brain will, in some cases, ignore that. In some chronic pains that doesn't happen. But things like, you have probably noticed if you've ever been around something that really stinks,
16:00
you're around it for a period of time and you don't notice it, and it's because the brain is saying, "Okay, you're distracting me too much with this. "I'm going to ignore that now."
16:09
If you've ever worked in a lab with mercaptoethanol, really foul stuff. And if somebody spills it, man I'll tell you a good way not to be popular in a lab is to spill mercaptoethanol. It's a really foul odor. And when you first walk in you guy, "Oh my God." I mean it's just too much and the very tiniest amount will really give you this foul odor. And after you're in it for an hour or so you won't even notice it. Your brain just says forget it.
16:35
There are ways of dealing with chronic pain that some strategies involve using, and I'll talk about this at the end of the term, the compound known as capsaicin. Capsaicin is the active ingredient in hot peppers
16:49
and so one thought about the way that capsaicin does, capsaicin works to relieve chronic pain is it's activating another set of receptors and getting the brain to just quit paying attention to the one so much and reduces the problem as a result of that. Yes sir? Student: [Inaudible]? Kevin Ahern: Being numb, I know a lot of people numb in the brain, so... [students laughing] You let me walk into that one, didn't you? So being numb is a brain thing? I don't think I would agree with that, no.
17:22
I think, and again I'm not an expert in this, but you get your arm numb because you've been leaning over the wrong way, you're probably interfering with that ability of those nerve cells to signal. So I would say no. Yes sir? Student: So local anesthesia. Is that, um... Kevin Ahern: Local anesthesia. What's local anesthesia doing? So what typical various types of anesthesia are doing is they are permeabilizing these membranes. So they're basically inhibiting their ability to signal.
17:51
They're inhibiting their ability to signal and so they're confusing them. They're not signaling. The brain is going, "What the hell is this all about?" and as a consequence you don't feel anything or in some cases you get, you become unconscious.
18:02
Boy there's a lot of questions out there. Couple quick ones, yeah? Student: Do nerve cells have a higher density of the sodium/potassium ATPase? Kevin Ahern: Do nerve cells have a higher density of the sodium/potassium ATPase? That's a good question and I believe they do, yes.
18:14
Student: [Inaudible.]
18:20
Kevin Ahern: Say it again? Student: [Inaudible.] Kevin Ahern: What causes different degrees of pain? One of the things that would cause a different degree of pain would be the number of nerve cells that are firing. So if I stick myself with a pin it's going to be a little bit different than if I smash my whole finger with a hammer, right? So, I've got an awful lot more nerve cells that are firing in that case.
18:40
Yes, one last question. Student: How do you explain phantom pain? Kevin Ahern: Explain what? Student: Phantom pain. Kevin Ahern: Phantom pain? Well there's where your brain comes into it.
18:49
People who have amputations will frequently describe feeling that missing foot or missing arm or whatever and it's because the brain still expects it to be there. I can't tell you in every case that's the case but in many, many cases the brain is still associating that thing with being there and it's confusing it.
19:11
This is usually the one I get the most questions about. I said one last one, this will be the last one. Lawrence? Student: You said that potassium goes out right after sodium starts coming in. Doesn't that reduce the charge or reduce the action potential? If I misunderstood... Kevin Ahern: It does change the charge in the action potential. So sodium goes in first, and then potassium goes out. So that changes that. And so if you look at this thing,
19:33
what's happening you see depolarization happening. You see the repolarization starting to happen when the sodium gate's open.
19:41
Okay? You had a whole bunch of positive charges come in. Now you've got positive charges going out. This is before the pumps are even kicking in. Student: Okay. Kevin Ahern: It's only after the pumps have gotten back down into here that they're able to restore what was the original conditions. But the first response is to restore that voltage difference. That's why the cells are actually opening those potassium gates. Student: So the potassium gates are opening more slowly than the sodium gates?
20:05
Kevin Ahern: They open after the sodium, the question is do they open more slowly. The answer is the potassium gates open after the sodium gates do. So the sodium gates always are the first signal.
20:16
Cool stuff. Very cool stuff.
20:21
Nasty compounds.
20:23
Tetrodotoxin.
20:26
Anybody like pufferfish?
20:30
The toxic compound in pufferfish, pufferfish being a great delicacy in Japan, the toxic compound in pufferfish, you hear about people, a few people a year who die from pufferfish because the organs of the fish haven't been properly removed contain this toxic right here. This toxin blocks sodium gates.
20:49
Blocks them. And blocking all your sodium gates, a neurotoxin will kill you.
20:58
There's a depiction of what the potassium channel looks like.
21:02
And I show you that, obviously just to first of all show you the kind of cool complexity that proteins can have, but also to get you thinking a little bit about how is it possible that cells can have a protein
21:18
that is specific for a specific ion? Let's think about this. Sodium ions and potassium ions. They're both charged, positive 1, so they're not doing it on the basis of their charge.
21:32
It has to be doing something with the size of the individual atoms, the electron clouds around them.
21:41
Potassium is larger than sodium is.
21:46
Potassium is larger than sodium is. So that means that potassium has got to have a wider opening into which it comes. Right? So if I have a potassium gate and it's only letting potassium through it, how in the world is that larger opening stopping something smaller like a sodium from coming through it? That's a pretty remarkable thing.
22:16
The answer to the question, first of all, is that it's not done on the basis of size, at least for potassium gates. They're not excluding solely on the basis of size.
22:32
There are energy considerations for how a potassium is excluding a sodium.
22:43
Let's think about this. So I've got two different gates. I've got a sodium gate that lets only sodium ions pass. I've got a potassium gate that let's pretty much only potassium pass. There's a little bit of leakage but not much.
22:58
The sodium atom is smaller than the potassium atom.
23:04
So if the potassium atom tries to go through a sodium gate, what's going to happen? Well what's going to happen is that smaller sodium gate, it's going to be size-excluded. Potassium won't fit into the sodium gate.
23:18
On the other hand, sodium is smaller than potassium. Sodium atom will physically fit into the potassium gate. And as I've told you there has to be some other exclusion besides size because a potassium gate cannot exclude a sodium on the basis of size because the sodium is too small.
23:38
This figure shows us how it is, and it's confusing so I'm going to take you through it, how a potassium gate excludes a sodium ion that is smaller than a potassium ion.
23:54
You want molecular magic, you're seeing it on the screen right here. This is pretty cool stuff. A Nobel Prize was actually won for understanding how this works. We actually had the Nobel Laureate who won for this thing that you see on this screen here at OSU three or four years ago and he talked to students. And he was a wonderful man.
24:16
And you know what he told students? He came here and he sat and he met and he specifically said, "I want to meet with students "and I want to meet with pre-med students."
24:27
I thought that was pretty cool. I'm a pre-med advisor, you know, and I work with some very talented pre-med students. And he told them something I absolutely loved. He said, "You've gotta get out of that box that you're in. "You've got to think about problems more broadly "and you've got to think about your career more broadly. "And if you're a pre-med student the number one thing "you should be doing is looking to see every other possible "thing you should do besides medicine."
24:53
Why did he say that? The reason he said that was because he was a pre-med.
25:01
He went all of the way through medical school.
25:06
He got out, he was a practicing physician and he says, "I hate what I'm doing, but I didn't question it any "along the way because when I was ten years old "I thought I wanted to be a doctor."
25:21
And he used that advice as a ten-year-old to go be a doctor. And by the time he was a 25-year-old he realized that 10-year-old thinking didn't work very well for him.
25:31
Now I know nobody in here would have that happen but just on the remote chance that it does. So he got through medical school and he goes to his wife and they've paid a half million dollars to get him through medical school and he says, "Honey, I'm ready for a career change."
25:48
Now the remarkable thing is his wife says, "What do you want to do?" He says, "I want to do research." And you know what she said? She said, "Okay."
25:58
And he did! I'm not kidding, I'm not making this story up.
26:02
And he went off and he did research and he won the Nobel Prize and he said, "You know, there's an awful lot of people "that get in that category and they get out "and they get in careers and they discover, "'Ooh, I didn't investigate enough other things "before I wanted to go there.'"
26:19
I'm getting off subject, aren't I?
26:23
So I want all you pre-meds in here to think about that. And you pre-vets. And you pre-pharmacy. And your pre-dentists.
26:31
Because everybody has to do that. It's very, very important to think outside that little box you want to put your head in.
26:38
Let's get back to this little box. This little box involves a channel, and it involves a channel that's too big to physically exclude sodium. How does it exclude sodium? It turns out that size really does matter. [scattered laughing] Why are you laughing at that? Size really does matter.
27:02
The potassium channel is set up with its dimensions in such a cool way that it interacts with potassium ions very nicely and it doesn't interact with those sodium ions so nicely.
27:20
It's cold outside. You go out, you buy a pair of gloves. And you get a pair of gloves that fit nicely and they feel good. And you can do things with your hands and they work well, right? And you go out and you buy a pair of gloves that's six sizes too big and you try to work with those gloves. Are you going to get anything done? No, size matters.
27:42
The potassium channel is set up so that potassium comes along and by the way, when we have an ion in the cell we never have just a free ion. We have an ion surrounded by hydrogen bonds to water molecules because this is an aqueous environment.
27:58
So in addition to having the size of the atom we have this shell of water around it.
28:05
These channels are set up so that that shell of water basically has to get stripped off in order for it to make it through.
28:14
The shell of water has to get stripped off.
28:17
As potassium enters the channel its dimensions are perfect for the channel. The removal of those water molecules from the potassium takes a certain amount of energy. That's the amount of energy that's invested as it starts.
28:33
As it gets going further along and when it starts exiting the channel it starts acquiring those waters again,
28:41
it regains that energy. And it regains them so nicely that there's a net energy gain
28:50
in the potassium going through there. I shouldn't say there's an energy gain. Energy's released as a result of that potassium going through that channel. It's energetically favorable overall for potassium to move through that channel.
29:06
Sodium comes through and like that little tiny hand inside that great big glove it's wiggling around.
29:14
It does not have its waters removed very effectively because its dimensions aren't right.
29:22
As a consequence, the energy that's realized in regaining those waters as it comes through is much lower than it is in the case of potassium.
29:33
As a consequence, sodium is energetically disfavored from moving through the potassium gate. That's a remarkable thing. Yes sir? Student: Does that mean the potassium has to enter the channel in a certain orientation? Kevin Ahern: Does that mean the potassium has to enter the channel in a certain orientation? The answer is no because potassium is basically a circular molecule, or a circular atom. No.
29:56
Yes sir? Student: So it's this resolvation within the calcium, or within the potassium channel site, but if it's within it wouldn't it be a type of chelation and then resolvates on the other side? Kevin Ahern: It is chelating as its going through and so we can see interactions of the potassium moving along the spread of that channel, yes, that's correct.
30:16
But those chelations, those interactions that potassium is making with that protein are perfectly set up. It works really well. It doesn't work if the atom is the wrong size.
30:30
Pretty cool stuff. Other questions? Back there? Jerry? Student: Is there research on mutations of these proteins and how effective they are? Kevin Ahern: Is there research on mutations in these proteins and how effective they are? I'm sure there is. I'm sure there is. And you could imagine that very tiny changes in dimension might have some very drastic effects on the exclusion abilities of these. I'm not familiar with that area but I would be amazed if that had not been done, yeah.
31:03
Pretty cool.
31:06
Let's see here.
31:08
This sort of depicts what's happening. We see that the entry, we see the stripping, we see the things making their way through and the movement of one starts allowing others to go through and they go all the way through. Finally, as they get through they regain their waters as we see over here. There's the resolvation happening, and the potassium ion has made its way in.
31:29
Okay, that's pretty cool. These electric rays use chemical gradients to create enormous electrical potentials. That's how an electric ray kills its prey is with an electrical charge because of chemical, electrochemical gradients that are just created from pumping.
31:50
The last thing I want to talk about with respect to nerve cells is how one's nerve cell talks to another.
31:57
How do nerve cells communicate with each other?
32:01
What we see on the screen are two nerve cells. One that might have been out here that had my finger being burned and now going to communicate with another one up here, let's say.
32:12
Here's the second nerve cell, here's the first nerve cell. How do materials or how does that signal get from one nerve cell to the other?
32:21
Well first of all that process occurs at what's called a synaptic cleft or a synaptic junction right here. The boundary between the two nerve cells, right in here. These two guys are placed right neatly next to each other so that when one does something it disturbs the other one.
32:43
And the thing that the one does is as a nerve signal is coming down the first nerve cell has within it what are called synaptic vesicles. These synaptic vesicles are little circular blobs that contain chemicals in them, and that chemical has a name. That chemical's known as a neurotransmitter. These synaptic vesicles are full of neurotransmitters.
33:09
So when the signal comes along the synaptic vesicle fuses with the membrane. We see a fusion that's happening here and we see it dumping its chemical into that synaptic cleft.
33:22
What does that chemical do? That chemical interacts with next nerve cell
33:27
and starts the whole process over again. So when this neurotransmitter hits this guy, what happens? Sodium gates open, sodium rushes in.
33:38
Potassium gates open, potassium rushes out. And now the same thing is happening in this nerve cell that was happening previously in this nerve cell.
33:48
Pretty cool stuff.
33:52
There are a variety of different neurotransmitters. It depends on the nerve cell.
33:56
Acetylcholine is a very common one. There are many others.
34:02
And it's at this point that I usually take a minute and talk about drug addiction because drug addiction, some types of drug addiction, actually play into this right here.
34:11
They actually play into this right here.
34:13
Let's imagine that these nerve cells are involved in getting a pleasurable feeling to you.
34:24
We all have pleasurable feelings. We might get it from eating, we might get it from drinking, we might get it from our, whatever. [class giggling] You guys are laughing at everything today! I just said "whatever." Dirty minds.
34:39
Or maybe you have clean minds and I have the dirty mind. I don't know, maybe that's what it is. Alright, but you feel good. You feel good about this. So cocaine is a compound that elicits a high, it's a very pleasurable feeling that happens. And cocaine is very addictive. And one of the reasons that cocaine is addictive is it does the following. Here is a pair of nerve endings that when they fire will give a pleasurable response.
35:14
Well I've told you how a nerve cell will depolarize and then repolarize and basically go back into its original state. If this first nerve cell has fired into the second one, normally what happens is we've got this neurotransmitter our here and this neurotransmitter has to be removed because if it's not removed it's going to continue to cause this guy down here to fire.
35:41
So normally what happens in this pleasurable junction right here is these neurotransmitters are released but then they get recycled back into the original nerve cell.
35:55
That causes their concentration out here to decrease. That causes the firing of this nerve cell to stop.
36:03
What cocaine does is for some types of neurotransmitters it interferes with the recycling of them. That is it interferes with the ability of the first nerve cell to retake up the neurotransmitter.
36:20
What does that mean? That means then that the neurotransmitter is going to stay in high concentration out here. This nerve cell is going to continue to fire and you're going to get that pleasurable feeling for a longer period of time, and it might be very intense because "Oh wow! "I'm still getting it, I'm still getting it, I'm still getting it." Well of course that's an addictive thing after a point of time and that's one of the reasons that cocaine
36:43
is addictive as well as obviously problematic. Yes sir? Student: Does that also lead to desensitization over time which requires the increased... Kevin Ahern: It does. His question is does that lead to desensitization over time and it absolutely does which is why it takes a bigger and bigger dose to get the same high over time. Yes absolutely.
37:02
Yes? Student: Does the cell, the nerve cell have a fixed member of the synaptic vesicles or can it increase or decrease in the cell? Kevin Ahern: Well the body has a fixed number of synaptic vesicles of course because we are a finite organism, so yes.
37:20
As we lose nerve cell function we will have fewer of those, yeah.
37:29
How are we doing on time? We can get started on oxidative, I'm sorry, mitochondrion oxidation. So we're getting caught up.
37:43
So why did I spend all that time going through and telling you guys about transport across membranes and now we're going to go and talk about mitochondria. Well it turns out that understanding membrane transport is really essentially for understanding how mitochondria do what they do. Mitochondria combine really interesting features of membrane transport with chemical processes that involve oxidation, reduction, and synthesis of ATP. All of that is happening inside of your mitochondria.
38:20
So there are two major processes that occur in mitochondria that we're going to talk about, and don't confuse them. They do relate to each other but they are completely separate processes. The first of those is known as electron transport
38:36
and it's in this process that we're finally going to see how those electrons in NADH and FADH2 get used.
38:48
We're going to see how those electrons in NADH and FADH2 get used.
38:56
To understand this we first of all have to look at mitochondria. Okay we've looked at mitochondria.
39:04
Here's a better view of mitochondria. This is a schematic representation of what a mitochondrion looks like.
39:11
As you can see it's kind of a cool structure. And I like to think of it as kind of like a little capsule. And this shows the major features very nicely. The mitochondria has an outer membrane shown in yellow, and to be honest it doesn't do very much. A lot of things move through it. It's not a very protective membrane.
39:35
It provides a little bit of a barier but not a lot.
39:39
The inner mitochondrial membrane, which is this convoluted thing that you see here in blue, is very impermeable to things.
39:47
Most importantly for our purposes it's very impermeable to protons.
39:55
Protons can move somewhat through the outer membrane but they cannot move very well at all through the inner membrane. In fact they can't move at all for all intents and purposes.
40:07
We see that these inner foldings of the blue have a name. They're called cristae. So you see this fold, fold, fold, fold, fold. Why do we have all those foldings? Well the more folds, the more surface area there is.
40:20
And as we're going to see, all of the action
40:24
in the mitochondrion occurs in the inner membrane. All of the action of electron transport and oxidative phosphorylation occurs in the cristae,
40:35
that is these inner foldings, of the inner membrane.
40:40
We also see that there's a section called the intermembrane space. That's just a gap between the inner membrane and the outer membrane. For our purposes it doesn't do very much.
40:49
And last we see this section called the matrix. The matrix is where the liquid of the mitochondrion is located. We can think of it as sort of the equivalent of the cytoplasm inside of the mitochondria. And it's in here that the enzymes of the citric acid cycle
41:08
and fatty acid oxidation are dissolved.
41:13
The enzymes of the citric acid cycle and the fatty acid oxidation are dissolved in the matrix, and the one exception to that is the succinate dehydrogenase, as we will see, that's found in the membrane.
41:24
Other than that, everybody else is pretty much dissolved in the matrix.
41:33
Now the inner membrane is very important in protecting against protons. Protons can't move across it except for in places where cells let them in.
41:44
This schematic is very simple but it depicts for us the processes of electron transport and oxidative phosphorylation in the most simple of terms. Electron transport is shown over here in yellow. Oxidative phosphorylation is shown in red. And you see that both of them are occurring in the inner mitochondrial membrane. That's the grey thing here. That's the inner membrane. That's a folding of the inner membrane.
42:12
In electron transport what's happening is electrons are being dumped into proteins that we will see later.
42:21
The electrons move from one protein to another protein to another protein.
42:26
As a result of the movement of the electrons, protons get kicked out of the matrix and into the intermembrane space.
42:35
That's where the proton concentration starts to grow.
42:42
As you put electrons into one end what happens to electrons as they're going through? Electrons have to have a final destination and the final destination of electrons in the electron transport system is oxygen to make water.
42:58
The reason that we're breathing and the reason we breathe heavily when we're exercising is we need oxygen to absorb those electrons that we're generating from oxidative processes.
43:11
If we run out of oxygen we can't absorb any more electrons.
43:18
So oxygen is what we call the terminal electron acceptor.
43:28
Well the result of action of the electron transport system is to kick protons out of the matrix into the intermembrane space. That corrects an electrochemical gradient. You've seen this before. [crowd murmuring outside classroom]
43:45
Should I close that door?
43:48
I guess I will.
43:55
That means we have a higher concentration of protons outside than we do inside. Protons want in.
44:01
There's energy in electrochemical gradient and that electrochemical gradient is like, what I like to think of as a battery that's just been charged. The charge is there.
44:11
The energy of the protons coming back in is used to make ATP and that's the oxidative phosphorylation part of the cycle.
44:22
Electron transport over here, oxidative phosphorylation over here. They are independent. If I don't have a proton gradient I can't possibly have oxidative phosphorylation.
44:36
And conversely, as we're going to see, if I stop oxidative phosphorylation the proton gradient starts getting bigger, bigger, bigger. Last time I talked about the difficulty of pumping water up into the balcony, and the more I pumped, the harder it got to pump.
44:56
As that gradient gets larger and larger and larger, it becomes harder and harder and harder for this system to pump protons. Finally it throws up its hands and says, "I can't pump anymore."
45:08
That means that electron transport requires oxidative phosphorylation going on.
45:17
There's one exception to that I'll tell you about next time and, I won't tell you about it here, actually maybe I will tell you about it here. It's kinda cool.
45:26
Since we're talking about it in simple terms. I'm not going to dive into the details of stuff today.
45:31
I'm going to tell you about, I've got five minutes and this is about the right amount of time. I'm going to tell you about a miracle diet drug.
45:38
Everybody likes diet drugs, right? Diet drugs are perfect things, right? You take a pill, you go to bed, you sleep, and you burn off all that excess fat. [class laughing] I mean you guys read the internet. You know it's true, right?
45:52
You burn off all that excess fat, right? In your sleep! And you know what? There actually is a diet pill that will do that.
46:01
There is!
46:04
There's a perfect diet pill that would do that, and it would do it-in fact it's been known for over a hundred years.
46:11
When they discovered this miracle diet pill they found that you took this before you went to bed and you woke up in the morning and you were a little bit warmer but you actually burned fat in your sleep. How did it work? Well, how did it work? It did a really cool thing.
46:30
This material's called dinitrophenol, DNP. It's specifically called 2, 4-dinitrophenol, 2, 4-DNP.
46:39
And when I say it's a perfect diet drug I'm exaggerating a bit but it's great at losing weight because what it does is it causes the mitochondrial membrane to become permeable to protons.
46:55
Now when this guy pumps them out protons come back in. What's happening to the synthesis of ATP?
47:02
You're not making any ATP.
47:06
Your body needs ATP. What's it going to do? Well it's going to try to keep pumping more protons and more protons and where is it getting the electrons to pump those protons from?
47:15
Oxidation right? We're burning things in our sleep.
47:21
The perfect diet drug. Well perfect except for the fact that 10% of the people who took it died. [class laughing] I am not exaggerating. This is before there was a Food and Drug Administration.
47:33
It was really good. If you were in that 90%,
47:38
"Wow, man, you're looking thin." "Oh yeah well I take some DNP," right?
47:44
Now as we will see later, the reason I said you wake up warm,
47:49
well actually you guys can probably figure that out. Why would you wake up warm? Student: It's an exergonic process. Kevin Ahern: Yeah. You're burning things that are exergonic, that are releasing energy like we saw in glycolysis. We saw the big bang reaction. Citric acid cycle releases energy. The more of it we do the more heat is generated. The warmer we get the less ATP we make.
48:10
No you can't take just a little bit.
48:13
Do you want to take a little bit of arsenic? [laughter] Just a little bit?
48:18
It'll kill some cells. Maybe I'll kill some fat cells, right? No, you can't do that. Well we'll talk about that next time. How's that? [classroom murmur]
49:21
[END]
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