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耶鲁大学公开课:生物医学工程探索:第七讲 细胞通讯和免疫学
2011年10月23日 讲座课堂 暂无评论 ⁄ 被围观 6,006+


Lecture 7 - Cell Communication and Immunology

课程摘要

Professor Saltzman talks about cell communication, specifically ligand-receptor interactions that are important in maintaining homeostasis in the body. Different types of receptors and ligands, the nature of their interactions and ways to apply this into developing drugs are discussed (eg. Aldopa, Taximofen, beta-blockers). Next, Professor Saltzman talks about kinases, phosphatases, cyclic AMP and the mechanism of switching protein states. Three categories of cell communication signals are introduced: autocrine, paracrine, and endocrine. Finally, an example of cell communication using regulation/response to blood sugar level is presented.

辅助阅读

Biomedical Engineering: Bridging Medicine and Technology, in preparation by Mark Saltzman (forthcoming by Cambridge University Press); chapter 6

Summary and Key Concepts: Chapter 6 [PDF]

课程内容

Chapter 1. Overview of Cell Communication [00:00:00]

Professor Mark Saltzman: Good morning. So, this is kind of a transition week. We've been talking about more basic, more biological subjects. Starting this week we're going to sort of mix physiology and Biomedical Engineering, and that's going to start sort of this week and next. The topic for this week is self communication: how mechanisms that cells within a complex organism use to communicate with each other at short distances or long distances. Then we're going to talk about two physiological systems just briefly, where cell communication sort of dominates the behavior of the organ. That's in the immune system and in the nervous system.
This will lead us into a discussion of sort of bioengineering of the immune system, in particular, and we're going to talk next week about vaccines. This will be the first real example where we've talked about the physiology of an organ system together with engineering approaches to modulate that organ, and that will continue throughout the semester. You'll notice that the chapters because of this go out of sequence, so we're reading Chapter 6 this week and next week we'll read parts of Chapters 14 and 15, that's because the book has a different kind of organization. It talks about the basics, then it talks about physiology in the second part, and then it talks about Biomedical Engineering separately. But we're going to in class treat the physiology and the Biomedical Engineering together. Any questions about that, or that makes some sense?
Cell communication and immunology is what we're going to - is the topic for this week. I don't need to say too much probably about why cells need to communicate with each other but this is a schematic version. One way to draw sort of a schematic diagram of the operation of the human body where it shows separated organ systems and tries to show them in context. The respiratory system, for example, the renal system, the digestive system, these are examples - three examples of organ systems that contact the external environment. We've talked about the interesting way in which the digestive system contacts the external environment. Depending on what you call external and internal environment, this path that I'm tracing here, deep within your digestive system, is really directly connected to the outside world through both ends.
Of course when molecules get absorbed through the intestinal tract they become part of your internal environment. We've talked about one the main concepts in physiology being homeostasis, that is 'how do you maintain a constant internal environment? '. We need to have conditions internally that are relatively constant in terms of temperature, and pH, and chemical composition in order for us to thrive. In order for life to proceed, you need to maintain a constant internal environment. That's achieved - in fact that's the main goal of many of these organ systems, right?
The main goal of the respiratory system is to bring fresh in so that you can extract oxygen from it, and blow used air out so that you can rid of carbon dioxide which is the end product of carbon metabolism inside our bodies. The respiratory system plays an important role in maintaining our internal environment at the proper level of oxygen, by bringing the right amount in. You regulate your breathing rate in order to accomplish that and we'll talk about this in a couple of weeks.
The renal system has an equally important function in that way, in maintaining your water balance. The amount of water that you need to have the optimal sort of concentrations of things is determined by how much urine your kidneys produce and how much they excrete each day. In addition, the kidney controls the composition of your body of many important ions, sodium bicarbonate which is important in pH balance, potassium. By determining how many of those molecules to hold onto, how many to keep in the body, how many to release determines the internal composition with regard to that ion.
The digestive system, of course, is responsible for bringing in sort of fresh nutrients, fresh substrates for cellular metabolism, fresh quantities of amino acids, and nucleotides, and the things that we can't generate internally. So, these are all involved with our ability to maintain homeostasis by exchanging materials with the external environment.
There are some organ systems that are totally internal. The circulatory system which we'll talk about in a couple of weeks, the heart, the blood vessels, and the blood work together to form a totally internal function. There's no point where the circulatory system crosses the boundary between being inside you and outside of you, it's totally internal. Its role is to move molecules around in the body so that they're available to cells everywhere within your body regardless of how close they are to your skin, and we'll talk about that.
The nervous system, the endocrine system which we'll start talking about a little bit today is the system that's responsible for sending signals back and forth between tissues of your body. The nervous system does the same thing in a different way. These two systems which are shown in the core of this diagram really are responsible for regulating and exchanging information between the other organ systems. How do your lungs know what your heart is doing? How do your kidneys know what the status is of inside your blood, for example? They know that because they receive signals from the endocrine system and the nervous system. These are primarily communication systems which act to allow your other organ systems to work in concert.
We're going to talk about the mechanisms by which these work as well. Now there's something very wrong about this diagram, in that it's showing these functions as sort of centralized in the core, and of course that's not how your body is organized. It's not that all these layers are wrapped around the nervous system and the endocrine system. These systems are dispersed throughout your body and their dispersal is important, and so we'll talk about that as well.

Chapter 2. Mechanisms of Cell Communication [00:07:41]

Take a step way back and think about what's the basic mechanism by which cells receive signals. It turns out that cells receive signals or information from the rest of the body in a variety of ways, but there's one way in particular that's a very useful way for thinking about how cells receive most information. It's shown schematically on this diagram here. On the side over here shows a cell membrane and so this is outside the cell above it, and this is inside the cell below, and this is the lipid bilayer that separates the outside of the cell from the inside of the cell. I've already mentioned many times that the lipid bilayer, the cell membrane, isn't just a lipid bilayer. That there are other molecules in the lipid bilayer and they're important for cells getting information or getting molecules from outside.
We've talked about one class of molecules, they're transporters that move molecules from inside to outside, or outside to in, that wouldn't ordinarily be transported through a cell membrane. Glucose is a great example of that and we're going to come back to that a little bit later in the lecture. If a cell membrane was indeed just a lipid bilayer, then glucose could never enter the cell because it can't permeate through cell membranes. Glucose has to get into cells, that's the main source of energy source that cells use, metabolism of glucose. It does so because there are some molecules in the surface of the membrane that allow glucose to move in and out. Those are called glucose transporters.
There's another whole family of molecules that sit in the surface. They're not responsible necessarily for moving molecules inside and out, but they sit at the outside of the cell and they wait for signals. When they receive the signal they make - they change in a very specific way and the cell can recognize this change that's occurred at the cell surface. That general class of molecules is called receptors and its shown here just as a block of material living in the cell membrane. We're going to talk about different classes of receptors in just a minute. For now, just picture it in this simple way as a molecule, usually a protein, that's embedded in the cell membrane and many receptors have a part of them that is extracellular. They go across the membrane - this is the trans-membrane part of the receptor that's going across the membrane. Then there's a part that's inside the cell sticking down into the cell cytoplasm. So, this is called the extracellular region or domain, this is the trans-membrane region or domain, and this is the cytoplasmic region.
Because these molecules can span across the membrane from outside to inside, they're in just the right position to take messages that they receive from outside the cell and transmit them through the membrane into the cells internal apparatus, and that's what they do. The signal comes in the form of molecules which we're going to call throughout the lecture here 'ligands'. This terminology 'ligand' and 'receptor' you've probably heard before. It refers to usually 'receptors' that are fixed in a cell, on a cell membrane, and 'ligands' which are dispersed throughout the body and free to diffuse around, and occasionally will find the cell. When they do find the cell they're capable of interacting with the receptor forming some kind of chemical interaction with the receptor.
Now, usually this is a non-covalent interaction. There's not actually chemical covalent bonds that are formed but it's a non-covalent interaction, usually dominated by hydrogen bonding. We're going to talk about this kind of non-covalent interaction more when we talk about the immune system, because one example of ligand and receptors that's important in the immune system are antigens - foreign molecules, and antibodies - molecules that we produce.
Today let's think about it more generally as ligands and receptors. The ligands are bringing some message, they transmit the message by binding to the receptor. When they bind, they produce some change in the receptor molecule which is experienced inside the cell. The way that the cell experience it is through some sort of biochemical changes. Those changes usually involve enzymes. They often involve the generation of what are called 'second messenger' molecules which carry the signal further into the cell. They often involve networks of reactions, not just one enzyme but a series of enzymes that serve to amplify each other. A reaction performed by one enzyme creates a product that stimulates another enzyme that creates a product, and stimulates another enzyme, and through this cascade of reactions you amplify and carry the signal forward.
That's what's illustrated here with the end result being that there's some change in the life of the cell. What would that change be? Well, it might be that this signal is a signal to divide. 'It's time for you to reproduce', and so the cellular response would be mitosis. It could be that that signal is 'you need more glucose', and so the cellular response is to create more glucose transporters to bring more glucose into the cell. It could be the response is 'there's something dangerous in the environment, we got to move away', and so the response is for the cell to crawl in the opposite direction. There's a diverse range of responses that might occur, but that response is initiated by this simple chemical process of a ligand binding to a receptor.
Now, the other thing to keep in mind is that for any cell there's not just one receptor on the cell, there are thousands, or hundreds of thousands of receptors. All of them could potentially be receiving signals from a ligand or a chemical. So, this pathway might not be the only one that's being activated inside the cell at any given time. It might be getting a signal from this receptor and a signal from this receptor, and a signal from this receptor. What the cell needs to be able to do is to integrate that information into a response. You need to be able to integrate that information into a response, and that happens through these biochemical reactions.
I hope that makes sense as background, and I'm just going to basically illustrate that basic concept with a few examples throughout the rest of the lecture. The other thing that's on this slide here is sort of a simple analogy that I've already described. If you think about receptor ligand system as an input into the cell. If it was sound that was being received that might be beating of a drum, for example, that sound gets transduced. We're used to thinking about sound being tranduced; for example, being converted by acoustic waves into electrical signals that can be recognized by your iPods. This same thing happens here, there's a transduction, one kind of a signal gets converted to another kind of a signal. In the case of a ligand-receptor, a chemical signal in the form of a concentration of ligand gets converted into a biochemical signal. That signal is carried here, for example, by the concentration of second messengers - the concentration of something else. Often that signal gets amplified so it can be used, same thing happens inside cells and there's some output that's generated.

Chapter 3. Agonists and Antagonists [00:16:28]

What are - one of the - this understanding of receptor-ligand interactions has been really the biological basis of much of the pharmaceutical industry. Much of the work that pharmaceutical companies do in terms of searching for drugs is searching for new ligands that activate receptors and create biological responses inside cells. There are two classes, two broad classes of drug sort of type ligands that are defined, agonists and antagonists. An agonist is a substance that mimics the action of a natural ligand, and I show you a couple of examples of agonists here. Now, sometimes the agonist is the natural ligand itself and that's - an example of that is when you use insulin as a drug. Insulin is a naturally occurring hormone, it's a protein hormone that circulates in all of our bodies and regulates glucose metabolism. When you don't produce enough insulin yourself, as diabetics do not, then you can use insulin as a drug. What insulin is doing inside your body is acting as a ligand for insulin receptors which stimulate certain kinds of cellular responses. I'll talk about that more in a minute.
Another example is in the nervous system, patients that have Parkinson's disease have too little of a natural ligand called dopamine. That can be supplied by an antagonist called Aldopa - which is not exactly the same as dopamine, it's slightly different. It turns out when you give Aldopa to people, it gets converted biochemically into natural dopamine which then serves as its own agonist. Sometimes you can design drugs that act like a natural ligand without being the natural ligand. We've identified many drugs that stimulate insulin receptors, for example, but they're not exactly insulin, and those can potentially be used as agonist type drugs.
An alternate is to design an antagonist. This would an example of a substance that inhibits the action of a natural ligand and they can inhibit in a variety of ways. Sometimes they inhibit by just preventing the ligand from interacting with its receptor. They prevent the ligand from reaching its natural receptor, and so that antagonizes or inhibits the function of the natural ligand. Sometimes they act by actually binding to the receptor. They bind sometimes better than the natural ligand does, but they don't create the right biological reaction. So, they bind to the receptor - they occupy the receptor so now the natural ligand can't enter it but they don't create the same sequence of biochemical events. An example of a drug that works like that is the anti-cancer drug Tamoxifen which binds to estrogen receptors and blocks estrogen signaling. Many types of cancers, particularly breast cancers, many breast cancers but not all, are sensitive to estrogen. Estrogen is a natural signal for cells to grow. It's a natural signal for cells to grow. and if you design a drug that blocks estrogen interaction you stop growth. Stopping growth in tumors can be a very beneficial thing.
There's a whole class of antagonistic drugs that have been designed to influence your cardiovascular system. One class of them is beta-blockers, they bind to beta-adrenergic receptors, which are receptors that exchange information between your nervous system and the contractile system that beats your heart and that causes the heartbeat. They can antagonize that reaction, and a result they affect blood rate. More importantly, they can affect blood pressure as well, the strength of your heartbeat and the pressure that your heart generates. These are just some examples. I mentioned earlier, we thought about receptors as being these blocks and membranes but there are different families of receptors. One useful thing about separating receptors into types or families is that we found that many different receptors work by the same basic underlying mechanism. They might have different ligands which stimulate them, but once they're stimulated they work the same way. Understanding this has really led to lots of advances in biology. We'll talk about that as we come to it.

Chapter 4. Receptors [00:21:31]

What I want to do in here is just introduce some of the basic kinds of receptors. The one that's on the top here is called ligand-gated ion channel and an ion channel is a protein that sits in the surface of a cell. It can exist in - a gated ion channel - can exist in one or two states. A state where it's closed, so imagine a channel with a lid on top of it; when it's closed nothing can go through the channel, when it's open then things can go through. Now, these are special channels in that they only allow certain molecules to pass through. The ones that are most important in physiology are ones that only allow ions to go through: sodium, potassium, chloride, calcium, bicarbonate. We'll see just briefly in this course if you go onto study physiology you learn much more, about how these channels cause changes in the electrical potential of cells which lead to events like conduction of a nerve, or contraction of a muscle, or beating of the heart. We'll talk a little bit about that but not much.
For these purposes think about a channel, it only allows sodium to go through for example. It has a gate on it and that gate is in open or close state depending on whether a ligand is present or not. If a ligand comes and interacts with a receptor, it opens up; if the ligand goes away, it closes. In the presence of this ligand, this molecule, it's open, it allows transport of this ion, when the ligand is gone it doesn't. That changes a cell and here's some examples of it. Many neurotransmitters that carry signals between neurons in your brain work this way. The cells that take an electrical signal, which is coming down your nerve and convert it into a muscle contraction work this way, so 'neuro' nerve, muscle junctions act based on ligand-gated ion channels.
Another family is called the G-protein coupled receptor. It's called the G-protein coupled receptor because it's a receptor, like the one shown here, that's coupled to a special molecule called a G-protein. When the ligand is present it binds to the receptor outside the cell and it activates this G-protein. The G-protein then goes on to create some other biochemical changes inside the cell. We're not going to talk about this in any detail, there's a little bit more detail described in your book. These are fascinating molecules that turn out to be ubiquitous. They're everywhere in cells throughout your body and they are responsible for lots of the biochemistry of cell/cell interaction and signaling.
Another family is receptor tyrosine kinases, I'll show another picture in a moment that tells you more about what a kinase is, but a kinase is basically an enzyme that can add a phosphorous to another molecule. It can 'phosphorylate' or add a phosphorous to another protein. This is a signal - this passing of phosphorous - is a signal that's used very frequently in intracellular communication. I'll talk a little bit more about that in a minute. In this case, a receptor tyrosine kinase is a receptor molecule that binds a ligand at its surface outside the cell and initiates this enzyme activity - this kinase activity - and causes phosphorylation of another molecule. This is - there are also other receptors that are linked to other enzymes besides kinases. I've included that as a general family here. So, these are receptors, for example, that bind the ligand and then liberate an enzyme which promotes some sort of reaction inside the cell, often it's kinases but doesn't have to be.
One of the enzymes that often gets activated is an enzyme which converts ATP, a small molecule that is inside all of our cells. ATP is famous for its ability to store energy but it's also a messenger molecule. When a certain enzyme is activated inside cells, ATP gets converted into a molecule called cyclic AMP, and cyclic AMP is an example of one of these molecules called second messengers. It gets produced in response to a signal so there's a binding of a ligand to a receptor, the enzyme that does this conversion is activated and more cycle AMP is released. As cyclic AMP levels rise inside the cell, something about cell behavior changes.
Now, one of the advantages of having second messengers is this is one way that you can integrate between different receptor systems that are acting inside a cell. If you have two different ligands stimulating two different receptors, and one causes activation of this enzyme and generation of cyclic AMP, cyclic AMP levels will start to rise. If another receptor operating from a different ligand does the same thing, generates an enzyme which causes cyclic AMP to increase, the rate of cyclic AMP increase is going to go up faster than if only one of these was activated. The cell is going to experience something different inside because both receptors were activated instead of just one. Sometimes second messengers collect signals from a variety of different receptor systems, translate them into one kind of internal change, and the cell then just has to know about that one thing changing. Does that make sense? This is another example of a second messenger, the inositol lipid pathway. These are molecules that exist naturally in cell membranes and are activated by certain enzymes and kinases generated by receptors. More is said about this in the book I just include it here as an example, but it's sort of beyond the scope of what I wanted to talk about today.

Chapter 5. Protein Signal Transduction [00:28:02]

I did want to say a little bit more about kinases because they're so important in intracellular communication and kinases take advantage of the fact that proteins can often exist in more than one state, and that's what makes them useful molecules inside cells. That's what makes proteins useful in transmitting or responding to signals. Often the state of a protein depends on whether it's phosphorylated or not. Now, being phosphorylated means that a phosphate group has been added to the protein, and phosphate groups can only be added to certain amino acids along a protein. Proteins are only susceptible to phosphorylation if they have certain kinds of amino acid sequences. One of the amino acids that can be phosphorylated is tyrosine, for example. So, a protein that has tyrosine and it has tyrosine in a position such that it's on the outside of the protein and accessible to chemical reaction can be phosphorylated. What a kinase enzyme does is that it recognizes this protein, and for example, the tyrosine that's on the protein. It performs a chemical reaction on the protein, taking a phosphorous from ATP and moving that phosphorous onto the protein.
Now, you know already, or you could review in Chapter 4 that I provided to you, something about how proteins work. You know that the function of a protein is intimately related to its structure. Proteins have three dimensional structures in solution and their structure determines what they do. Sometimes subtle changes in the structure of a protein can convert it from an active state into an inactive state. That's one of the beauties of proteins as working molecules is that their structure can be changed by subtle means. Sometimes that subtle change can lead to a big change in the function of the protein. Well, imagine if that change in structure could be switched on and off by addition of a phosphorous; and in fact it can in many proteins. Some proteins can be switched from an 'off' position where they don't do anything to an 'on' position where they now do something by only a chemical reaction like this where a phosphorous is added.
Kinases can, in many cases, serve as a mechanism for switching a protein on or switching a protein off. If that protein is an enzyme then you've - and you've switched it from an 'off' position where it's not catalyzing a reaction to an 'on' position where it is, you've changed the biochemical state of the cell, you've changed the chemical reactions that can occur within the cell, and you've changed its behavior. That's a very simplified version of why kinases are important.
Well, if this kinase happens to turn this protein on then you would like to have a mechanism to turn it off as well. The other beauty about - beautiful thing about proteins is that if you make subtle conformational changes, often those changes are reversible. Now, you all know that we can make irreversible changes in proteins, you can denature them completely, that's what happens when you cook an egg for example. You've taken all the proteins inside the white of the egg, for example, you raise the temperature. Tou make not small changes in their chemistry but big changes in their chemistry. Tou denature them, you can watch them denature because the egg white turns from clear to white and it doesn't go back. You've irreversibly changed that substance because you've changed the structure of all the proteins inside.
That - irreversible changes happen all the time too but here I'm talking about very subtle small changes where you're changing the structure of the protein but only a little bit such that it can go back. One way that you could switch this on and off inside the cell is by taking off this phosphorous, proteins enzymes that do this opposite reaction, the opposite to kinases are called phosphokinases. You could imagine a protein that's existing inside a cell at some level of abundance. There are 100 of these molecules, when a receptor gets activated a kinase activity gets activated, the kinase acts on the protein, the protein gets switched on, something new starts to happen inside the cell. Another receptor eventually activates a phosphatase, that phosphatase now turns the protein off. It's a switch that from outside can be used to change the life of a cell.
That was some, not too complicated, but hopefully understandable description of a whole area of biology called signal transduction. If you hear about signal transduction in biology, people that study signal transduction are studying just these things we talked about, how biochemical messages get transferred into cells and through cells. I want to look at a slightly higher level of magnification now and think about different kinds of cellular communication. One kind of cellular communication occurs by similar mechanisms to what we were talking about. Here, there are receptors on one cell and the ligand that they experience is not a dissolved molecule, but actually a molecule that's attached to another cell. Sometimes signals are transmitted between cells by cell/cell contact. By cell/cell contact, I mean that there's a receptor in one cell that makes some kind of a chemical interaction with a receptor in another cell. Depending on which cell you are you would call one the 'receptor' and the other the 'ligand'. This is a mode of communication that's used very frequently in the immune system as we'll see later. It's the way, for example, that foreign molecules or antigens get presented to cells of your immune system in order to start the process of making an immune response, so sometimes a cell/cell interaction.

Chapter 6. Autocrines, Paracrines, Endocrines [00:34:54]

The rest of these examples refer to receptors as I've been describing them and ligands that are soluble and can move around the body. It's useful to separate these kinds of signals into three categories. One is shown at the top here, its call autocrine. This is, maybe, the strangest because the ligand that stimulates the receptor is produced by the cell itself; so sometimes cells make signals that they receive. This is commonly used in the immune system as well, but it's a way of amplifying a signal. For example, what if I activated this cell by encouraging it to produce this particular ligand? That ligand was one for which the cell had a receptor that further encouraged it to produce more of the ligand. Well, then you could imagine a cycle here where activation of the receptor is leading to production of more ligand, is leading to activation of the receptor and production of a ligand. That's an example of a process called positive feedback. The more the receptor gets activated the more feedback it gets to activate. That can be a very strong amplifying response, and that happens in the immune system in many cases. An example is production of certain molecules called cytokines by T-cells that activate themselves.
Another example is called paracrine. Here, what's different between autocrine and paracrine is that there's some distance between the cell that produces the signal and the cell that receives the signal, but it's not too great a distance because the blood system doesn't have to be involved. Molecules are produced here and they flow directly over, usually by diffusion, to the neighboring molecule. 'Para' means near, 'paracrine' means 'a signal from nearby'.
Endocrine are signals that get carried through the blood system. The cell that's producing the signal produces enough of the molecule so that it enters the bloodstream, it circulates throughout your body, eventually it reaches a cell at a great distance, which has a receptor for that ligand and the signal gets received. An example of that is, of course, insulin which is produced by cells of the pancreas and acts on cells all over the body. Adrenaline is another one, produced by cells in your adrenal gland but used by cells all over your body.
Well, the endocrine system is a body organ system that is specialized in producing these kinds of signals that are used - that accumulate in the blood and are used by cells all over the body. There are two general classes of molecules that are produced by the endocrine system. All of the molecules are called hormones, so a hormone is another name for a ligand that operates in this endocrine fashion. A hormone is just a ligand that operates in this endocrine fashion. Hormones can be proteins, endocrine hormones can be proteins, meaning they're large molecules that are usually fairly water soluble, or they can be steroids. Steroids are small molecules - much smaller than proteins - smaller molecules that tend to be hydrophobic or lipid soluble. Example, protein hormones are insulin which we've talked about before and glucagon, and growth hormone which we haven't talked about but that's very important during periods of life like adolescence, for example, when rapid growth of your bones is occurring.
Well, insulin is a protein, it's produced by cells in the pancreas, it circulates in your blood. It can't enter cells because it's too big and it's too water soluble so it can't go through cell membranes. So, it interacts with receptors called insulin receptors that are on cells that are sensitive to insulin. Steroid hormones, on the other hand, molecules like testosterone and estrogen, progesterone, the sex steroids that determine sexual characteristics and are important for reproductive function are molecules that are all derived from a similar source. Many of them are derived from cholesterol and they're hydrophobic, which means they can penetrate through cell membranes. So, it doesn't need to bind to a receptor on the surface of the cell in order to work because the molecule can actually enter the cell directly. Many steroid hormones act because they bind to cellulars - to receptors that are deep within the cell, often inside the nucleus. I'll show how that works in just a moment, but estrogen for example, is one of those. When estrogen is present it can enter cells in the vicinity and it can bind to receptors that are deep inside cells. This is a new concept, receptors don't have to be these molecules on cell surface, there can be receptors that exist in other places within the cell, for example.
Go a little bit further with this schematic and talking about what insulin does. You know about this but maybe you haven't thought about it at this level of detail, but you know that when you - after you eat, you eat lunch for example. After class you're going to go to lunch, you're going to eat whatever you eat. Hopefully it's not a Snickers bar but let's assume it is a Snicker's bar and your blood glucose is going to rise because you're taking a lot of sugar in. When it does your pancreas receives a signal that your blood glucose has started to go up, and it will secrete insulin. So, there are cells in your pancreas which recognize glucose levels and they secrete insulin in response. When they do that, this insulin then starts to circulate throughout the blood.
If you measured, if somebody measured levels of insulin in your blood after lunch, if they took it ten minutes, 30 minutes, an hour, you would see that it's going slowly up. As it's going up, it's circulating around your body. Most cells in your body have insulin receptors so insulin is starting to bind to insulin receptors on those cells. When it does it makes biochemical changes inside the cells and one of the things it does is increase glucose uptake into certain kinds of cells, particularly fat cells and muscle cells. Well, why does it increase uptake of glucose into muscle cells? Because muscle can use and frequently is using glucose as a source of energy. So, when there is extra glucose you want to put it into the cells that can use it immediately.
Why does it go into fat cells? Because maybe you ate more glucose than you needed immediately and so it goes into cells that can store glucose. That's what fat cells do, they convert glucose into a form for storage. Well, how does glucose uptake get enhanced in those cells? It gets enhanced because when insulin binds to the insulin receptor, it activates the receptor. How does it activate it? It generates a kinase activity which leads to phosphorylation of the protein. Insulin binding leads to phosphorylation, leads to other biochemical changes. Eventually what happens is that glucose transport molecules which are expressed and stored inside the cell get shuttled up to the surface, so the cells permeability to glucose goes up and more glucose can come in. This is a highly simplified version, but sort of closes the loop on what we've been talking about. Insulin, the ligand binds to its receptor, creates a change through a kinase activity that's exposed, which leads to other biochemical changes, which leads to a change in cell behavior - in this case the cell behavior is that more glucose transporters are brought to the membrane and more glucose can enter the cell. Does this make sense?
Sometime after you've eaten, say you had this Snickers bar at lunchtime and you don't have time to get anything else to eat during the day, your blood glucose level will go down. Why does it go down? Well, one because you're not taking anymore glucose in, but the other because when you did eat glucose you got more insulin and the glucose got shuttled into cells where it's either used or stored. So, that brings your glucose level down. Another hormone gets produced by the pancreas in response to low glucose levels, it's called glucagon. It has many of the opposite effects that insulin has, so not only does insulin go down and stop these behaviors but a new hormone called glucagon gets produced which reinforces that change. These - you're going between these states throughout the day. Where your cells experience those states is through these extra cellular ligands called insulin and glucagon.
Steroid hormones can operate in a different way because of their structure. They're small molecules, they're lipid soluble, they can go from extracellular to intracellular. Let's take an example of estrogen, for example. A small molecule gets produced by cells in one part of the body, circulates in the blood, estrogen enters cells, and sometimes that estrogen is able to penetrate deep within the cell, even into the nucleus. The receptor for estrogen is a special molecule called a DNA binding factor. Estrogen can combine with this receptor to form a new sort of unit which interacts with DNA. When this bound receptor interacts with DNA it could, for example, turn on expression of a target gene. One of the things that estrogen does when cells are exposed to estrogen is that certain genes get turned on that weren't turned on in the estrogen-free state. It leads to expression of new genes, production of new proteins, and a change in a behavior of the cell.
Sometimes receptors, when they interact with ligands, create changes in what proteins are actually being produced by the cell. This is one very direct way for that to happen. These kinds of molecules which activate genes, they're activating the process of transcription. They're sometimes called transcription factors and this is an example of a transcription factor that is itself activated or turned on by the presence of a steroid. That's the end of what I wanted to say today. What we're going to talk about next time, and I encourage to read ahead because you'll see that there's a lot more detail in Chapter 6 than what we're talking about here, I've emphasized the main points, the ones that I think are important, that are clearly important for your understanding. We're going to take these general topics and talk about how they work in the nervous system and the immune system next time.

第7讲 细胞通讯和免疫学



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