The Science of Everything Podcast - Episode 118: Cell Signalling

Episode Date: May 31, 2021

A discussion of cell communication and signalling, including an overview of the purpose of cell signalling, the main types of signals, and applications such as hormones, neurotransmitters, and cytokines. The difference between G protein-coupled receptors, enzyme-linked receptors, and intracellular receptors is also considered, concluding with a summary of the process of signal transduction and the role of second messengers. Recommended pre-listening is Episode 116: The Cell Membrane. If you enjoyed the podcast please consider supporting the show by making a PayPal donation or becoming a Patreon supporter. https://www.patreon.com/jamesfodor https://www.paypal.me/ScienceofEverything

you're listening to The Science of Everything podcast, episode 118, cell signaling. I'm your host of James Fodor. So in this episode, we are going to talk about how cells communicate with each other in multicellular organisms, which is cell signaling. In particular, I'm going to talk about the different types of signaling molecules and the receptors that detect them on the surface of the cells, mostly. And we're going to look at the difference between intra and extracellular receptors, and some of the main types of receptors, including G-protein, couple of receptors and enzyme-linked receptors,

and also the signal transduction process that occurs after the initial signal has been received on the outside of the cell, as well as talking about the purpose and overall structure and function of cell signaling and the relevant pathways. So, recommended pre-listing for this is episode 116, the cell membrane, because we'll be building on some concepts relating to that. Without further ado then, let's make a start and begin by talking about what cell signaling is and why it matters. So this topic is one that is, I think, relatively neglected in cell biology or biochemistry education. I mean, you know, it's there, but it's not something that gets brought up as often, certainly in the public consciousness or even in, I think, intro courses compared to, say,

looking at the structure of DNA and protein synthesis and genetics and stuff like that. the whole deal of how cells communicate with each other is often sort of not mentioned or brushed over fairly quickly. So this topic doesn't get as much attention, but it actually is extremely important because it comes up again and again in studying lots of different systems. I'll go through some of those in a moment, but before I start talking about some of the applications or like instances of where cell signal is important, let's talk a bit about what it is more fundamentally. So cell signaling is also called cell-to-cell communication. is the process by which cells communicate with each other and coordinate their activities in multicellular organisms, particularly when there's specialization of different cellular function or tissue function.

So throughout here I'm going to be talking mostly about mammals and humans specifically, but similar mechanisms exist in other types of animals as well. So whenever you have an organism that has many, many different cells and multiple different tissue types and specialization of cells for particular functions, there needs to be some way of coordinating their activities, metabolic functions and so forth so that they contribute to the overall health and functioning of the organism. And that's what cell signaling is for. At a fundamental level, a cell's activities are regulated internally through the existence of various signaling molecules and proteins and so forth within the cytoplasm,

which then can move organelles around or move vesicles which contain various signaling molecules or proteins to this part of the cell or that part of the cell and send a signal in to the nucleus, or from the nucleus and to the mitochondria and so forth. So the cytoplasm axis is sort of a space through which things can move as well as the endomebrane system that we talked about in the previous couple of episodes. But all of that is bounded by the cell membrane. And the cell doesn't have direct access to anything outside of the cell membrane. It can only communicate to the outside or receive information from the outside via receptors, which are mostly proteins, that exist on the surface of the cell membrane. And because that's true for all cells effectively, that means that

there has to be some mechanism for translating, basically, communicating a change in the cytoplasm of one cell into a change in the cytoplasm or organelles of another cell. And that has to be converted then into some sort of signaling molecule that exists in the extracellular space that's dumped into the extracellular space, generally by exocytosis, or a similar mechanism, that then is transported through the extracellular space

and then is detected by the receptors on the target cell. and then it's converted back into some signal or process within the cytoplasm of the target cell. So it's key to understanding the purpose and overall function of cell signaling, that there's this need to translate signals or mechanisms or just happenings that occur in one cell into a new sort of medium for the signal to be transported across the extracellular space because there's no direct way for a cell to know what's happening outside of itself. So that's the overall objective of cell signaling. it's to be able to receive those signals coming from the outside and translate them into the relevant

changes that it needs to make in response to that signal. The signaling agents that I've been mentioning, I mentioned that they're often molecules, although they don't have to be, so they can be really any physical or chemical event or agent. So this includes things like mechanical pressure, changes in voltage, change in temperature or light. So different receptors in the nervous system are responsive to all of these different physical agents, such as the cells in our retina, which are responsive to light, or we have temperature receptors in our skin and mechanosensors that detect pressure or vibrations of a particular frequency and so forth. There are also many chemical agents that can be signaling agents, so this includes peptides,

the building blocks of proteins, steroids, which are type of lipid molecule or gases like oxygen or carbon dioxide. There's really no limit to what can potentially be a signaling molecule. it can be really any physical or chemical agent. But often in this episode, when I talk about a signaling molecule, we're generally talking about some small chemical like a peptide or something similar or maybe a modified organic molecule of some other form. So although it doesn't have to be that, in general, that's often what is meant when a signaling molecule is referred to.

Now, what is the ultimate purpose of extracellular signaling? Well, as I've said, it's to elicit some sort of change in the target cell in its metabolism or function, because it's not like the cell just needs to know random information that happens in the environment. It's not like it's curious or anything or needs a news bulletin. All it needs to do is keep track of things that require it to take some action, that is, change its gene expression or modify proteins in some way or divide or kill itself or whatever. Some change that it needs to undergo. So that's ultimately what the purpose of extracellular signaling is, or cell signaling, to elicit the relevant change in the target cell.

So the signaling process is not only involves how the signaling molecules are initially detected by receptor molecules on the membrane, but also how that signal is then transduced, is the term this used, into a relevant response within the target cell. So the overall process consists of four steps. First, there's the synthesis and release of the signaling molecule by the signaling cell, so that's like the source. It has to synthesize and release the signaling molecule. Often that's going to be through exocytosis, so dumping out the relevant molecule into the extracellular space by fusing vesicles with the extracellular membrane.

We talked a bit about that in the previous episode. The next step is transport of that signal to the target cell. There's different ways this can occur. I'll talk through those in a moment. The third step is binding of the signaling molecule by a specific receptor, usually on the cell membrane of the target cell, although sometimes certain signal of molecules can actually pass through the membrane directly. but usually the receptor will be on the surface of the target cell membrane. And then the fourth step is the initiation of the signal transduction pathways, which I just mentioned. Those are the pathways that basically convert the initial detection of a signal into the relevant metabolic changes in the target cell.

So basically it's sending out the signal, transporting the signal to the target, receiving the target signal, and then converting that signal into the relevant metabolic change. Now in this episode, I'm not going to talk so much about the first step, the synthesis and release of the signaling molecule, because that's kind of covered in the previous episode that we did talking about intracellular protein sorting. That's basically the process by which many of these signals, at least the chemical ones, are produced and released through exocytosis. So have a look back at that if you're interested in that side of it. In this episode, we're mostly going to focus on the binding of the signal by the receptor and the initiation of signal transduction pathways.

Now, before we talk about some of the different types of signals and how they're transported to their target, I want to just make a couple of other sort of observations at this point. First is that cells in multicellular organisms are constantly receiving hundreds or even thousands of different signals. So it's not like this happens. Sometimes it's happening constantly. And so it's not usually the case that one signal causes one specific effect, although that can happen.

But it's more often that it's the combination of signals in their intensity over time that elicits particular responses. So the cell is constantly basically acting as an information processing device with respect to all of the signals that it's detecting. And based on the combination and intensity of these, it would sort of decide what to do. And that decision obviously occurs through mostly protein modifications or changes in gene expressions and so forth, although there are other mechanisms as well, which we'll talk about. So it's not really just a, often we talk about one particular signal at a time, but it's more of an integrated process with many, many signals being

combined together over time. The second sort of general point that I wanted to make is that the time that it takes for a signal to have its effect depends on how long the signaling molecules, as well as the sort of second messenger relaying molecules, but here we'll just focus on the signal molecules, how long it takes these molecules to be degraded, which is their half-life, so how long they last, essentially, in the extracellular environment. So if the molecule is turned over quite rapidly, so it's rapidly degraded or is unstable and falls apart quickly or something like that, that means that the signal won't last very long, which means that signals change very quickly. Whereas if it has a very long half-life, then it takes a long time for the amount of

that signal to change. I mean, suppose you'd completely turn off the production of new signaling molecules. Well, there's still a bunch that were already there, right? And it would take a long time for their existing quantity to be decreased due to, you know, they're being metabolized or whatever. Whereas if they're metabolized very quickly, then if the source is turned off, then almost immediately that will be felt at the target. So the point here is that the stability of the singling molecule has a direct effect, or basically directly determines how rapid the response will be felt. And so that can be tailored to the specific situation. So some signals you want to be very quick acting. If that's the case, then the signaling molecules need to be very quickly metabolized. So certain aspects of the immune

response, for example, like swelling or blood clotting, you want that to happen quickly. Whereas other It doesn't matter if they take longer. So developmental processes, for example, that elicit specialization of different types of cells. I mean, those take, you know, days, weeks, and months. They don't need to happen within a matter of seconds or minutes. So for those you might expect longer-lasting signaling molecules. But the point here is that there's a tailoring of how long the molecules last to how rapidly the signal needs to take effect. And so that will vary between different systems.

Now, the final general point that I wanted to make is that just as the single, can take effect rapidly or slowly depending on the molecule, the signaling process itself, so too can the consequence or the effect of the signal be relatively long-lasting or be quite temporary. So there are some cells that, or some types of responses, I should say, that are permanent or persist for a very long time in response to the receipt of the relevant signal. So, I mean, apoptosis would be one example where their cell kills or stuff. I mean, that's a permanent change, right? But others as well that can elicit fairly permanent or very long-lasting changes in, say, gene expression or in the number of receptors that are expressed or something

like that, that persists for a very long time. On the other hand, in other cases, the opposite can occur. Cells can become desensitized to the signals that they're receiving so that even though they keep receiving the same signal, the effect of that signal diminishes. So this is basically the mechanism here behind tolerance to many different types of drugs. It's because the target cells become desensitized due to slow-acting negative feedback mechanism. So basically it might be, I continually receiving this signal, what I'm going to do in response is reduce the number of receptors I have to that signaling molecule so that the same number of signaling molecules only list it to smaller effect. And therefore, to get the same effect as you did before, you need to

increase the amount of signaling molecule that you put in. So this is how you can get tolerance and increasing need for a larger dosage of certain types of drugs, such as caffeine or illicit drugs. But this doesn't happen for all types of drugs. So it depends on the system in question. All right. So that's some of the basics of cell signaling, kind of what we're doing here. Now, let's talk a bit about how the different signals get to the target cells. So remember, the first step is synthesizing and release the signaling molecule, generally by exocytosis, or if it's a physical process, like light or temperature. Obviously, that doesn't happen. But then the next step is, transporting that signal to the target cell. So again, the focus here will be on chemical signals.

So how does the chemical signal get from the source to the target? Well, there's many different mechanisms by which that can occur. And it can be described as the different crimes. So intracrine, autocrine, juxtacrine, paracrine. You probably heard some of these terms before. So let's go through them and explain how they're relevant to this process of transporting the signal. So probably the most well-known of the words here is endocrine, because we've got the endocrine system. So that's responsible for a lot of hormones, which basically are just molecules that signal to other cells. But we'll get to that in a moment. But the endocrine system is a signal that targets distant cells.

So endocrine cells produce hormones, so these small organic molecules, basically. I mean, they don't have to necessarily be organic, but again, most of them will be. so let's just simplify it by that. Endocrine cells produce these hormones that then are released into the blood vessels, so into the bloodstream, and that then travel then reach ultimately all parts of the body. Obviously, it would take a little bit of time for them to be transported throughout the body, so it's not very fast acting. It can be relatively fast, but it's not like immediate,

but it has the advantage of that it can reach distant cells all over the body. So that's how endocrine signals work, that the signaling molecules enter the blood stream, which then carries them to the, you know, through capillaries and so forth to basically all cells in the body, which will eventually receive them. Of course, not all cells will have the relevant receptors, so not every cell will respond to the signal, but it will at least reach all signals in the body. Next on the list, we'll talk about intracrine signals. Intracrine signals are kind of the complete opposite of endocrine,

whereas endocrine is produced by a source and is related to the bloodstream that ends up targeting every cell. Intracrine signals are actually intracellular signals, so they're produced by a target cell and stay within the target cell. So these aren't technically an example of cell to cell signaling because they're entirely intracellular. But it's important to understand that these processes do occur within cells as well. It's just obviously they're sort of simpler when you don't have to have receptors on the cell membrane and so forth. Now, there are also paracrine signals. So paracrine signals target cells that are nearby the emitting cell. So endocrine, that's distant signals because it travels through the bloodstream.

But paracrine, the signaling molecules do not travel through the bloodstream. They just travel through the extracellular space. And therefore, they will only target nearby molecules. The reason is because the extracellular matrix or the extracellular fluid that surrounds pretty much all the cells in the body, really the only way you can be transported through that is by diffusion. And that's going to take a long time, and you're not going to be able to get to all parts of the body through that, because there are cavities that are closed off from each other and so forth. And eventually those molecules are going to be metabolized.

They'll be eaten up by something or be unstable. And so when you release a signaling molecule into the extracellular fluid, it will only be able to reach nearby cells in the same sort of tissue cluster or in that part of the organ or whatever. It's not going to get across the whole body. So paracrine signals are good for controlling local responses. Or, for example, during development, when paracrine signals can reinforce the developmental pathway of a particular type of tissue region that's specializing for a particular purpose. So that's paracrine signals. autocrine signals are produced by the target cell secreted into the extracellular fluid,

but then come back and affect the target cell itself. So this is a form of cell signaling, but not purely internal, which is intracrine. It goes into the extracellular space, but then affects back on the very cell that emitted it. Sometimes autocrine cells can target other cells that are different but very close by if they are the same as the emitting cells. So immune cells would be an example of this, where they send out signals that they themselves respond to, but also other nearby immune cells. will respond to. So that's kind of similar to paracrine, except it's sort of even more localized

generally. Then there's juxtacrine signals. So these target touching cells, not nearby, but they have to be physically in contact with each other. So these signals signaling molecules are transported along the surface of the membrane by special proteins or lipid components that are embedded in the membrane, and they will therefore only be able to affect other cells that are physically connected to that cell. You can see why that would be advantageous if you, you, you'll be a advantageous if you need to have, for example, epithelial tissue that sort of closes up and forms a membrane around something, juxtricyne signaling would be useful for forming that. There are also something called gap junctions. Now, these are not one of the cry signals, so they're a little bit different,

but they are specialized intercellular connections, which exist in various types of animal cells, including neurons. And the difference between a gap junction and these other types of signaling is that when gap junction is actually a series of physical connections between the cytoplasm of adjacent cells. So it's a physical connection so that cells have to be touching each other. But unlike juxtocrine, the cells are actually connected to each other. There are special channels called connectsons, which connect the cells together, the cytoplasms together, and signaling molecules or other proteins. I don't know exactly how big they are, but things can move across these connectons from the cytoplasm of one cell directly to a

another. Now, these are mostly useful to ensure that you have coordination or rhythmic timing of electrical impulses between nearby cells. So these are used in the heart muscle, for example, where you need to have coordinated rhythmic firing of all of the cells at a very similar time. It doesn't. If you have uncoordinated firing, then you get arrhythmia and, you know, that's very dangerous. So that's one example of where this is used in a muscle cell like the heart, for instance. So gap junctions are another form of intercellular. cellular communication, although they're quite different in that it's sort of a direct highway between the cells rather than a way of sending signals between them. So I just thought I'd mention those here.

But to recap, the two main ones that I think it's important to remember are endocrine, which is the signal goes into the blood system and travels a great distance across the body, and paracrine, which is nearby, but not necessarily touching cells. Then there's also juxtacrine, which it has to be touching, and then autocrine and intracrine, which are two different forms of self-signaling, but probably less important when we're talking about cell-to-cell signaling. So these are the different ways by which the signal goes from the source to the target cell. Now, let's talk about a few specific applications of cell-to-cellingling in different body systems, which I mentioned a bit earlier.

So hormones, I've already mentioned, so these are the major signaling molecules of the endocrine system. And they are responsible for a very wide range of functions, particularly mediating homeostasis. So, you know, you've probably heard of the flight and fight response or fight, flight, rest, and digest being the two sort of aspects of that. This is also related to the peripheral nervous system. So there's the sympathetic and the parasympathetic nervous system, which I've talked about in a previous episode. I forget exactly which one it was. But anyway, hormones play an important role in all of those processes as well. So people often talk about hormones in popular culture in a very, I think, confusing way.

Probably you'll do an episode on this in more detail at some point. But the important point is that hormones are released into the bloodstream and have relatively quick, but not immediate. So you're talking on the order of minutes, not seconds, but also not generally hours. I mean, it can take longer, but hormones have an effect on tissues throughout the body and are involved in regulating things like heart rate and blood pressure and breathing and sleep, wake cycle, hunger, and all sorts of things like that. So they are one very important application of cell to cell signaling, because basically these are signaling molecules that are dealing molecules that are delivering. down to the blood travel around the body and then are detected by receptors on the target cells. Another example are neurotransmitters. So I've talked about this in some of the episodes I've done in the nervous system.

I want to do a further episode just talking about neurotransmitters specifically because these are also widely misunderstood in the popular culture. People often talk about, what is the one? They often talk about like a dopamine hit, for example, which I think is misunderstood. But these are signaling molecules in the nervous system and they are released at the synaptic cleft, so the gap between the cells of pre and the post-synaptic neurons. So you've got the axon that sends out the electrical signal that then terminates generally the dendrites, although it can be the cell body of the post-synaptic cell,

and then there has to be a mechanism for transmitting a signal between those cells that don't directly touch each other, and that's the neurotransmitters. So the electrical signal gives rise to fusing of vesicles, which contain the neurotransmitter to the cell membrane, which then dump out the neurotransmitter into the synaptic clefts, the gap between the cells, and then those neurotransmitters bind to receptors on the target cell. So that's another example of cell to cell signaling. This would be a paracrine signal, because the signaling molecules are not being released into the bloodstream, but instead they're being released into the extracellular matrix and diffused to nearby cells. I suppose sometimes it could be juxtacrine

if the cells are directly in contact, but generally for synapses, that's not going to be the case there's going to be a gap between them. A third type of specific example of cell cell signaling are cytokines. Now these are the signaling molecules of the immune system. And these usually have, these usually operate in either parochryne, so nearby tissues or juxtacrine so when they touch each other. Although, as mentioned before, you also find autocrine examples in the immune system because they can affect themselves in very nearby cells of the same type. And so cytokines are basically responsible for initiating various types of immune responses. So activate, immune cells that then need to go on and produce antibodies or produce T cells or

whatever it is depending on the relevant responses required. And I've talked more about that in the episodes I did on the immune system. So check that out if you're interested. So these are just some sort of examples of where cell signaling crops up. It crops up in a massive way in the endocrine system, through hormones, in the nervous system through neurotransmitters, and in the immune system through synachines. And they're all, I mean, they're all chemically specific to the particular functions that they have, but they're all variations on a theme. They're signaling molecules that are produced by a cell, released either into the bloodstream or the extracellular matrix, and then transmitted to their target cell, which then bind to receptor and have the relevant

effect on their target cell. So that's sort of an overview of what cell signaling is, where it occurs and why it matters, and also a bit of a discussion about how signals are transported to their target cell. But what happens when the signal gets to its target cell? That's the the third stage we talked about. Remember, there's synthesis, transport, binding, and then response, essentially. And now we're at the third stage, which is binding of the signal by the relevant receptor and activating that receptor. Now, this leads us to talking about some of the different types of receptors. There are many, many different types of receptors. And we could, well, I could spend weeks just talking about this because there are just, well, there are probably

thousands of, I don't know exactly how many. There's definitely hundreds. And then there's different subtypes and so forth. So we're not going to do that. I'm just going to talk about, some of the main types and some of the major differentiating factors between them. I'm not really going to give too much in the way of specifics about particular systems because I think that that's not as useful and is very hard to do without being able to show you a specific diagram. So apologies if I missed your favorite example of an extracellular signal receptor, but that's just the way of it.

So what is a receptor? Well, a receptor is a thing that exists generally, not always, but generally, on the surface, on the external surface of the cell membrane, which will bind to and respond to the signaling molecule that has been produced by some other cell. So, receptors are, I think, always proteins, although they may be like lipoproteins or have carbohydrates connected to them and so forth,

but I'm pretty sure they always at least involve some proteins. I don't know of any exceptions to that. Maybe there are some, but you can think of them as proteins complexes, which have a special shape. And you've probably heard about the lock and key idea that applies to enzymes generally. So think of receptors as basically doors with a lock on them. And the signaling molecule is the key. The key will be specifically shaped to that particular lock.

And there are many different types of keys, many different types of doors with different locks on them, depending on the type of cell and so forth. When the right key comes into contact with the lock, that is when the signaling molecule comes into contact with the receptor, It will bind in the relevant site. So there will be a physical match between the shape of the key and the shape of the lock. And it will therefore open the door by the way it interacts with the lock. So effectively, what happens is that the signaling molecule binds to the receptor,

eliciting a conformational change. So a physical change in the shape of the protein complex, the receptor, which then elicits further responses. And we'll talk about what those are. It depends a bit on the case. But that's the basic mechanism. And effectively, this is how most things work in sort of biochemistry. It's you'll have one thing by and a other thing changes the shape of the other thing, which then

has further effects. Now, bear in mind, there are other types of signals as well, not just chemical signals. So we talked about mechanical pressure, temperature, light and so forth. These can also change the shape of receptors. For example, I've talked in the past about how vision works by the photons being detected by further adoption at the back of the retina, which changes its shape and then elicits further further responses. But again, here I'm just going to focus on chemical signaling molecules just to keep things simpler. As I've said, there are many, many different types of receptors. Some of the main types

that are important include voltage-gated ion channels. Now, I've talked about those in the past episodes which we've done on the nervous system. And so these are ion channels that allow ions to, or specific types of answers to enter and or exit the cell, and they're responsive to changes in voltage. That's what they're called voltage-gated. When the voltage changes, they'll open or close. because I've already talked about that, I'm not going to talk about them further, but they are an example of, you know, cell signaling cell receptors. So they fit in this category, but I'm not going to talk about them more here because they generally discussed under the nervous system, which I've already talked about. There are also ligand-gated ion channels, and these are, I've also discussed those in the past in the nervous system podcast episodes, but these are the type of iron channels that, again, open and close to allow ions to enter or exit the cell, but they are responsive to neurotransmit. So the difference there is whether they're responsive to voltage changes or neurotransmitters.

They are also an example of this, but again, I've already talked about, so I won't cover them here. Two other big types of receptors that I will discuss are G-protein-coupled receptors and enzyme-linked receptors. They're both receptors that protein complexes that sit on the membrane surface of the cell that change confirmation in response to detecting the S-signals. So, I mean, that applies for pretty much all of these, but there are differences in how that works, which I'll get to in a moment. But before we go through the details, I'm just going to talk about some more general characteristics of receptors. The purpose of a receptor is to effectively convert the signal, which exists currently, say, as a molecule or a series of molecules in the extracellular space, into a signal cascade process which occurs inside the cell. So their primary function is to go from a signal outside to a signal inside. And that's why they have to sit on the, again, usually, we'll get to the exception in a moment, but usually they sit on the external membrane surface of the cell.

cell and they are membrane-bound proteins so that there's a part of them that effectively hangs over or exists in the extracellular space, but then they'll have a transmembrane domains, which allow them to be studded inside the membrane, and then there'll be parts of them that exist in the intracellular space, usually. So they can basically interact on both sides. They can interact outside and inside, and that's necessary because the whole point of them is to convert the signal from a signal outside the cell to a signal inside the cell. So obviously they have to sort of straddle both sides of the membrane there. And these sorts of proteins are produced by, produced through the end of membrane system, through the endoplasmic reticulum moving through the gold gap bradus and so forth. And that I

discussed in the immediately prior episode, intracellular protein sorting. So have a look at that if you're interested a bit more about how these things end up there. But this is why that end of membrane system is so important. It's one of the reasons it's so important is because there needs to be away for all of these critical receptor proteins to get there. And well, that's how they get there. So that's their basic function. And so what we're going to do in a little bit is talk about how that signal transduction process is initiated. So again, the third step in the chain of extracellular signaling is the binding of the

signal to the receptor, which activates it by changing its shape and then eliciting further changes. And then the final step is initiation of the signal transduction pathway, which is stuff that happens intracellulially that elicits the relevant response. The receptor not only has to respond to the signal, but has to be the first step in the chain, like the first domino, if you like. of that single transduction pathway. So we'll talk a little bit later about how that happens.

But for the moment, let's talk a bit more about the two main types of receptors that I've identified, the G-protein-coubled receptors and the enzyme-linked receptors. So G-protein-coubled receptors, they're sort of the big boys. There are many other types of receptors, but these are some of the most important ones. They're a huge family, so there's over 800 members, apparently, according to one source at least. And you're pretty much guaranteed to study them if you do a course on, well, like in neuroscience, at least maybe like a second year, a high-level course on neuroscience, or they sell biology, or the immune system, like that, they're just everywhere. So these are very important

family of receptors. Why are they called G-protein coupled receptors? Well, because they involve this protein called a G-protein. Don't ask me why it's called a G-protein. I've forgotten. I don't remember. It doesn't matter. Like a lot of things in biology, the name doesn't tell you what it is. Sometimes it does, but often it doesn't, unfortunately. So that's just, when I say G-prote, I mean the letter a G. It's just a G, capital G, and then a protein coupled receptors. So the receptor is coupled to the G protein. I'll tell you what the G protein does in a minute, but first I want to describe the shape of the receptor itself, because the G protein is not actually the receptor. It's connected to it, but it's a separate protein. The receptor itself contains a series of seven

transmembrane domains. So these are helices that extend across the membrane. So remember I said that pretty much every receptor will have these. One distinguishing characteristic of the G-protein coupled receptors or GPCRs is that they always contain seven of these domains. Now again, there's many, many different types of these receptors, so they're not all identical, but they do always have these seven domains here. And they're always linked to a trimeric G-protein. So we'll talk about that in a moment. Trimeric means it has three bits to it.

So how does this work? Well, by the way, I should mention if you ever look up diagrams of G-protein-compet receptors, I find them quite confusing, or at least I did for a long time, because what you'll see when they depicted is you'll see these seven trans membrane helix domains. And there are other parts too as well, but that's an important part. There's an extracellular part, an intercellular part. The thing is that they're generally shown as like existing in a line. So it's like, you know, one, two, three, and up to seven in a line across the membrane. Now, that's just shown that way for clarity. They don't actually exist that way. They're actually sort of bundled up. It's like a bundle of

sticks that shove through the membrane, well, seven sticks exactly, with their, you know, ends poking out on either side. That's kind of how it looks like structurally, except they're not sticks there. for helices, but you get the idea. However, for diagrammatic simplicity, they're shown as a line, but they don't exist that way. They're bundled up together. I just thought it emphasized that because for a long time, I was confused about how this exactly looked, and why would they just be in a long line in the membrane, and that didn't seem to make sense. But yeah, that's not what their actual structure is, it's just how they're often depicted. So we know that these receptors will bind to a relevant signal molecule. So for basically every type of receptor, there'll be one or maybe a small number,

but generally one specific signal molecule that they respond to. So that's why they need to be a huge range of them because there's lots of different types of signals that need to be detected. But for a given receptor, it'll have its given signal molecule, which will bind to a specific region in the extracellular matrix, which will be specialized to bind to only that particular signal molecule. Now, this will elicit a conformational change, so the protein will rearrange slightly, and this will have an effect on the G protein. So once we start talking about the G protein, we're sort of moving away from the receptor part directly and moving into the single transduction part. But, you know, they're directly connected to each other. Obviously, they have to be

for it to work, but just bear that in mind that we're sort of, as soon as the receptor has detected the signal molecule and changed in confirmation in some way, in a sense, its job is done, right? That's the point of the receptor. The next steps in the process will be part of the signal transduction pathway, which happens intracellularly. But the G protein, or the G protein here, plays a very important and very sort of characteristic role. So I'm going to explain a little bit more about how that works. And we'll come back to the rest of the signal transduction pathway a bit later. So first, the G-protein starts off being inactive, coupled to the receptor. Think of it this way.

The receptor is a bunch of these helices stuck through the membrane. On the intracellular side, connected to the receptor, but distinct from it, sits the G-protein. And it's just kind of chilling there. It's not directly in contact with the membrane, usually, although I think maybe it can be, but it's mostly just attached to the receptor itself. And it's kind of just not doing there. It's just not doing much, it's just sort of chilling, sitting there, waiting for something to happen. The G-protein, remember, is trimeric, so there are three units.

There's the alpha, the beta and the gamma unit. If you don't like the Greek alphabet, you can just think of it as the A and B and C subunits. So at least there it kind of makes sense. Now, that's important that there are three subunits, and I'll get to that in a moment. But at the moment, we've just got the whole G subunit, the whole G protein, all three subunits. They're connected to the intracellular part of the G protein-coupled receptor and not doing very much. Then a signaling molecule is detected or is bound by the receptor. The receptor changes its confirmation.

that changes the G-protein. Well, how does it change the G-protein? Well, it causes it to activate the G-prote. And specifically what happens is that the alpha subunit of the G-protein binds the molecule of GTP. So that's an energy-rich molecule, kind of like ATP, you've probably heard for adenosate but it's the guanine instead of the adenosine version.

So it's a high-energy molecule. The alpha subunit of the G-protein binds a G-tube, which activates it, because now it's got energy. and in the process it disassociates from the beta and the gamma subunits. So basically the beta and the gamma, they're just there to drag it down, right? They're just killjoys, right? They prevent, or at least maintain the G-protein in a state of being attached to their receptor and not really doing anything.

That's the off-state. But when there's a conformational change in the receptor, that triggers a process by which the alpha subunit disassociates from the killjoy beta and the, gamma subunits and also is energized by the binding of a GTP molecule. The whole result is it energizes and excites and sort of activates the alpha subunit of the G protein. Well, what's the point of that? Well, that is basically then the first step in the signal transduction pathway. So the activated G protein subunits detach from the receptor. So now that they're activated, they dissociate from the receptor so they can move around now and initiate signaling in various ways. So we'll talk about what

that looks like in a moment. I don't want to get too far ahead of the game. Here, here I'm mostly describing the receptor itself. One of the very interesting features of the G protein coupled receptor is the fact that it's got the G protein alpha unit and then the beta and gamma subunits, which dissociate from each other. And that's important because they can both go and activate further signal transaction pathways, but they can do that separately. So the beta and the gamma unit can be doing one thing, like modulating ion channels, because they tend to stay more associated with the membrane, whereas the alpha subunit, that's the part that binds to the GTP, that can sort of float off and then activate a whole range of different signal transduction

pathways in the interior, in the cytoplasma of the cell. And again, I'll get to in a moment bit more what those look like. But the point is that the G protein coupled receptors always have this G protein, trimeric subunit, and that is then activated when the receptor receives its signal. And the beta gamma and the alpha subunits can then kind of go and do their own. thing. Once they've done that and eventually their sort of activation will be spent and they'll re-associate with each other and then reattach to the receptor. So it's a process there. They're activated. They separate. The GTP is energizes the G protein. Then they do their thing and then eventually their energy sort of is depleted. They re-associate and then attach back to the receptor and

then wait for another signal. So that's sort of the whole process. The reason I went through that in a bit more detail is because G-protein coupled receptors are so important and they're so characteristic in their sort of key features. So just as a refresher, the key features of the G protein couple receptors are first that there's just so many of them, like 800 different types of them. Second, that they have seven transmembrane helices. And third, they are associated with the G protein, which has its sort of three subunits, the alpha and then the beta and gamma, which are activated in response to the receptor

detecting the relevant cinglin molecule. Now, the next type of receptor that I'm going to talk about, a bit more briefly, are enzyme-linked receptors. Now, I can't help but think that this is not a very good name because, I mean, most of the proteins that we're talking about here are enzymes in some form or other, but, well, that's just what it's called, so whatever. An enzyme-linked receptor, also called a catalytic receptor,

is a trans-membrane receptor where the binding of the signal, or the ligand, it's sometimes called, causes enzymatic activity on the intracellular side. So basically, it activates an enzyme. The way you'll often see this depicted, because this is a particularly important example, is there is there is a transmembrane protein that has sort of two subunits to it they start off kind of separated or at least deactivated but what happens when a single when the relevant signaling molecule or the ligand associates on the extracellular side is that it brings the two subunits together or activates them in some other way which then activates the enzyme so here i guess the difference is that the receptor itself is an enzyme or directly attached to an enzyme and so when it receives the signal it activates the enzyme that's not true true in the case of the G protein coupled receptors, because the receptor itself doesn't really do anything.

It just activates the G protein, which then goes on and does stuff. So that's why it's called an enzyme-linked receptor, because the enzyme is directly linked to the receptor. So in terms of what sort of catalytic functions the enzyme carries out, well, I mean, it can be lots of things, but a very common example would be a kinase. So a kinase is an enzyme that phosphorylates protein. So phosphorylate means add one of those high-energy phosphate groups. So GTP, which you talked about four, has three of those. but even one of them is fairly high energy.

And so a kinase adds those to a target protein, which basically energizes, it gives it energy that it can use to do stuff. Kinase is a particularly common type of protein that will activate things, and that could be an example of a protein that's activated by, or that is linked to an enzyme-linked receptor. I mean, it could be many others as well, but that's just one example. Okay, so we've talked about G-protein-coupled receptors. We've talked about enzyme-linked receptors.

There's one more type of receptors, or like broad category, I guess, than I'm going to talk about. There are others as well. just going to go through a few of them, but the other one that I'm going to talk about are intracellular receptors. So I've mentioned a few times that most of these receptors are on the surface of the cell membrane, but there are some that exist actually inside the cell. And you might ask, well, what's the point of that? I mean, the signal is outside of the cell, right? So, I mean, how is the receptor going to detect the signal if the receptor itself is inside the cell?

Well, the answer to that is that there are some signaling molecules that can pass directly through the plasma membrane and therefore act. on the receptor directly inside the cell. You know, peptides are not going to be able to do this, for example, but there are some types of signaling molecules that can do this. Mostly these are either going to be small gases, such as nitric oxide, that can just diffuse straight through the membrane because it's small and uncharged. Oxygen also can, although I don't think it's used as a signaling molecule. Or various types of steroid hormones. So, yeah, hormones such as steroid hormones or retinoids or similar molecules that are basically a hydrophobic, and so they can pass through the plasma

a membrane. There are only certain types of signal molecules that can do this, but there are some that can, especially steroid hormones are probably going to be the big example there. And for these, there's no point for the receptor being on the surface of the membrane because the signal is just going to come right through. So it exists somewhere in the cytoplasm. What usually happens is that because the whole process of receiving the signal and then eliciting a transduction pathway is a lot simpler when you don't have to sit on the cell membrane, the process can be sort of shortcutted. So often the receptor, when it detects, say, the steroid hormone, will then itself move into the nucleus and bind directly to the DNA.

Not all intracellular receptors do this, but many of them do. So they're kind of doubling up as a receptor and an effector, basically, like they do something directly, not just transduce the signal. So these are called nuclear receptors, which exist in the cytoplasm, but then move into the nucleus when they are activated. These then bind to the DNA at specific sites, which are called hormone response elements or HRE sequences, which are generally located in the promoter region of the gene. So the promoter region is, or in the area of the promoter. That is, if you recall, where the DNA or RNA preliminaries binds in preparation to then either duplicate or transcribe the gene and produce an MRI. So if you've got HRE sequences that are nearby to that, basically these are going to have gene regulatory effect.

So this modifies gene expression. talk too much about control of gene expression. I will do an episode on that relatively soon. It's a topic that I'll be meaning to cover. So I'll talk more about this sort of thing then. But basically the point is that these nuclear receptors can directly affect gene expression, which is one of the purposes of cell signaling, so change gene expression, by itself binding to the relevant part of the DNA. So this is pretty cool. It's sort of a simple shortcutted system. And the reason that, again, this is able to happen this way is because you don't have to have a protein that sits on the extracellular side of the membrane and then

then has an effect on something that exists in the cytoplasm, you can shortcut that process because some types of hormones like steroid hormones can transport themselves across the membrane without having to go through a receptor. So that's the particular sort of unique characteristics of these intracellular receptors, especially the nuclear receptors. All right, so we've talked about some of the main different types of receptors, G-protein-coupled, Ensem-linked, and intracellular. So that covers the third stage of the signaling process, which again is the synthesis and release of the signals, transport of the signal to its target, binding of the signal to the relevant receptor and activation of that. The last step, which we're going to now talk about, is the

initiation of the signal transduction pathways. And this is sort of the overall purpose or the goal of cell signaling is to elicit one of these signal transduction pathways, which will end up in some sort of metabolic or other change in the target cell. So how do these signal transaction pathways work. But basically what we're talking about here is a process by which a chemical or physical, again, I'm going to focus on chemical, signal is transmitted through the cell as a series of molecular events. So a molecular event can be one protein binding to another protein or a protein phosphorylating or being even digested by a different protein or being modified in some other way. So these are all different types of molecular events. It's just molecules interacting in

some way. Often proteins bind into each other or affecting each other in different ways. So that's the process by which their signals are transmitted. But it's not usually just a single step. There's usually a Molesly step process. And in fact, they can be quite complicated. Well, they are quite complicated. So that's why it's called signal transduction, because there's sort of many parts to it. It's not a one, it's not a one step thing. It's a little bit like passing on a message from one person to the next who then, you know, walks to a different room and then passes it to another person who then, you know, takes the elevator to another level and then pass it to another person who then, you know, goes to the office and then passes it to the secretary who then walks into the

room and hands out to the boss, something like that, right? It's a series of processes where the message is passed from one to the other to the other. Although that analogy is not perfect because there, at least the message is on a piece of paper that stays the same, but here the form of the message changes. So it might be a bit more analogous to, you know, someone says an email who then prints it out and then hands it to someone who then faxes it to another person who then, I don't know, takes a photo of it, an email back to someone else. I don't know why it would be done that way, but you get the idea that the message is not just transferred, but it also changes form. And so that's what happens in these signal transaction pathways.

The message is transformed as it's transducted or transduced through the different events that happen. So let's explain how that works in a bit more detail. So again, the target of this, the end response is usually some sort of translational or transcriptional change, so effects on the gene expression, or some sort of post-translational modification or conformational changes in proteins or movement of proteins around the cell, something like that. Right, so that's the end target to change stuff like that at the metabolic level. So how do you get there? Well, let's think about it this way. Suppose that I want the cell to produce more of the particular gene.

How does that happen? Well, the DNA polymer, RNA polymerase in this case, has to bind to the promoter for that particular gene and has to bind more than it used to. Well, maybe it didn't bind at all, or maybe it was only producing a little bit, so it's got to produce more. How does that happen? What you're going to need to do is produce more of the relevant sort of enhances and other transcription factors that are relevant to facilitating transcription of that particular gene. Don't worry if you don't know what those are. They're just proteins that help that gene be transcribed effectively. So, okay, then we need more of those proteins. How do we get more of those proteins?

Well, we might need to transcribe a different gene. How do we do that? Well, there's probably a particular protein that will need to bind to that gene to then produce more of that transcription factor that then, you know, binds to the actual gene that I want to produce more of. Well, how do I do that? Well, then I need to get some sort of signal to the protein that needs to bind to the promoter of a gene that I need to produce more of, that I need to then bind to the

that I need to be a transcription factor for the gene that I ultimately want to produce more of. So you sort of see how it goes. You can imagine working backwards from the goal to sort of further and further away to eventually you have to work back to whatever the receptor does. So there has to be a chain of biochemical events that starts with the receptor, changing confirmation, and ends with, let's say, the desired target. So increase in gene expression of a particular protein or something like that. So there's going to be a series of events that happens.

And the different, I guess, elements of this pathway have different names. Many of them are proteins, although not all of them. So I'm going to talk a bit about some of the different sort of elements of this pathway. But first, I need to introduce a couple of terms. You will hear a term called second messenger. To understand what a second messenger is, I need to tell you what the first messenger is. The first messenger is the signaling molecule itself. So like the hormone, the neurotransmitter, the paracrys signal, whatever it is.

These are the things that the chemicals that are detected by the, the receptor in the extracellular space, usually, although, you know, some of them can enter the cell, but mostly they're outside the cell, and that they're detected by the receptor. So that's the first messenger. The second messenger is a substance that is in the cytoplasm and acts within the cell to trigger a response. So generally the idea is the first messenger, which is the signaling molecule, buys the receptor, which then changes confirmation, which then has a further effect on other proteins, which at some point then will produce a second messenger or activate a second messenger that will then carry that signal and often amplify the signal within the cell.

So first messenger outside the cell, second messenger, inside the cell and has intracellular effects. That's a general way to think about it. There are many, many different second messenger molecules, but some of the main ones include cyclic AMP, cyclic GMP, IP3, and calcium ions. These are just different types of molecules except for calcium, which is a single, well, it's an ion. Calcium is very important because many intracellular, well, many signals have an effect on cytosolic calcium levels. Normally the calcium concentration within a cell is kept very low by the calcium pump

that pumps out these aisles, but there are special channels that in certain circumstances allow the calcums to rapidly enter the cell. An example of something that might happen is you've got your receptor, which changes to confirmation. That causes a particular protein to then open up the calcium channels, which increases the amount of calcium in the cell. The calcium then acts as a second messenger, which now there's a lot more of it, binds to various proteins, which has an effect on their metabolism.

metabolism or causes them to change confirmation, which has an effect on their activity, which then has a further effect and so on, and you end up at some sort of change in the gene expression. So calcium is not the only second messenger, but it's a particularly important and common one. Scyclica and P is also another very important one, which is why I mentioned it, but there are many others as well. So I'm not going to focus too much on the specifics of those. I just wanted you to understand what the second messenger is and give a few examples. But now let's talk about some of the other proteins that involved in the pathway. So there's a bunch of names that I'm going to walk through here to give you an idea of how this works. So there are relay proteins. These proteins just pass the

scene along to the next member of the chain. So a protein will bind to another protein, which is the relay protein, it will change confirmation, which then allows it to buy to another protein, whose confirmation it will in turn change, and then the signal is carried on. So that's a very, you know, it's just carrying the bat on, right? It doesn't really do very much by itself. There are messenger proteins, which are basically relay proteins, except they'll be transported across the other parts of the cell. So you might need to transport a signal from the cytosol to the nucleus or from the nucleus to the mitochondria or wherever else. So that's what a messenger protein. And it may be transported in vesicles, for example, using the cytoskeleton

or other mechanisms to ensure that it ends up where it needs to. There are amplifier proteins. So this is very important because the initial signal will often need to be amplified, because maybe you've only got a few signaling molecules that are actually detected, but you want a very large response. So you need to modulate and amplify that signal up by producing a cascade. So basically this is the idea that one produces two, which produces four, which produces eight, something like that. So you get an amplification of the initial signal. So this is what amplifier proteins do. So that will often generate large numbers of the secondary messenger molecules. So there may be enzymes like adenyl cyclase, which synthesizes cyclic amp. And I mentioned before,

that's a secondary messenger. An amplifier protein could be an enzyme that produces more second messenger and therefore amplifying the initial signal. There are transducer proteins. So these change the signal into a different form. So an example of that would be a voltage-gated ion channel, which transduced the initial signal from a change in voltage to a increased concentration of whatever the second messenger is by allowing those ions into the cell. But these don't have to be on the surface of the cell.

They can be within the cell as well, they're transducing it into a different form. There are bifurcation proteins. So these branched signal into different pathways, because you might want multiple things to happen. If I detect a signal, I might want to do more than one thing. So there's going to need to be a way that that single branches into different pathways which have separate effects. So bifurcation proteins can do that.

Often they'll have to bind to two different types of proteins which have different effects, for example. There are integrator proteins, which is the opposite of a bifocation pathway. This is when the cell needs to process information. Remember I talked about that before? Maybe you only want to do something if I get signal A and signal B. So an integrator protein can do that by only activating when two different things bind to it at the same time, for example. that integrates multiple signals into a single pathway. Or, I mean, you could have integrators proteins that are basically or,

so it will activate if A or B, but it doesn't need both. So this is sort of the way in which cells process this information by the way in which their protein networks interact with each other. So they can process signals and they can amplify signals, they can bifurcate signals, they can transuse them in different forms. Anchoring proteins tether particular components of the signaling pathway to specific locations in the cell, such as the plasma membrane or the nucleus or cytoplasma or whatever it needs to be.

So that ensures that you get the signal in the right place where you need it. Adaptor proteins are quite common. They basically just sort of link things together. They don't really do anything directly themselves. They kind of like relay proteins, except I think the main difference would be that adapter proteins are just physically in contact with the things that they're adapting for. So that's why it's called an adapter, right? It's like you plug something into your adapter so you can plug it into something else.

It just helps things fit together. A relay protein actually will move itself. So these are some of the main types of proteins that are involved. in these signal transduction pathways. So hopefully that gives you an idea of the complexity that happens here. There'll be scaffolding proteins, keeping things on the right position, relaying proteins, moving signals from one place to another, generally fairly close, adapter proteins connecting everything together, bifocation or integrating pathways, processing the signal and ensuring that it operates on the right pathway. There'll be

amplifier and transducer proteins which produce second messenger molecules for amplifying effects. These second messengers will then have further effects on other proteins, ultimately triggering often a messenger protein which will then carry the signal to the nucleus or the mitochondrial, wherever it's needed to have the relevant metabolic effect. So it's all a very complicated process here. And very quickly you get very complicated webs of interactions where this protein binds to this, but also binds to this other thing, and then there's this other thing that also binds to it, and there's this other thing that also binds to it, and there's binds to other. And you see these very complicated diagrams about all of the effects that this have. And this is how the cells act as a

very complex information processing device to integrate these signals. and have the produced the requisite response. All right, well, that's basically all I wanted to talk about. Maybe I'll just conclude by going briefly through the four main steps of extracellular signaling that we've talked about. So the first step is the synthesis and release of the signaling molecule. Again, only relevant for chemical signals, but that's a large number of them. Common sources of these signaling molecules would include cells in the endocrine system, neurons producing neurotransmitters, and various immune cells producing cytokines.

These signaling molecules then need to be transported to the target cell. So this can occur in different ways. In the endocrine system, they're released into the bloodstream. In the immune system and also generally for neurotransmitters, they will only diffuse to nearby cells, so that's paracrine interaction. There are some cases where they'll only affect cells that are in direct contact with each other, which is juxtocrine. And then there are other cases like autocrine and intracrine where the cell has an effect on

itself. The third step is the binding of the signal molecule to a specific receptor leading to its activation. We've talked about the different types of receptors, which are usually protein complexes on the membrane of the target cell, although there are some types of intracellular receptors that exist in the cytoplasm itself, and they can have a direct binding effect on DNA in the nucleus, and this is possible because their particular signal molecules are able to pass through the membranes, such as steroid hormones or nitric oxide gas, which is quite small. But the other main types of receptors will be the G-protein-coupled receptors, which consist of the seven trans-membrane

helices and also the trimeric G protein, which, remember, dissociates into alpha and the beta and gamma subunits when it's activated, and then that goes on to have effects on various transducer or amplifier molecules and second messages, and you get that signal and cascade and so forth. And then there are also enzyme linked to receptors, which is basically an enzyme directly linked to or associated with a receptor, but only activated when the receptor is activated by the external signal. And then the final step of the process was the initiation of the signal Transduction Pathway, which involves a complex integration of and amplification of different signals, involving many different types of proteins, such as scaffold, relay, adapter, bifurcation,

integration, messenger, anchoring, and other types of proteins, as well as the second messengers, which helped to transport the signal and often amplify it within the cell, some of the main second messages being cyclic AMP, IP3, and calcium ions. So, hopefully you found that interesting and added to your sort of knowledge of how cells work. In the future, as I said, I do want to do a podcast covering gene control of gene expression, which I haven't covered yet, but that is an important topic. Otherwise, in terms of what's coming up, the next episode I'm planning to do will be one on computational chemistry, which I've teased for quite a while now, but finally getting around to. So we'll talk about some

of the methods they're used to basically apply quantum mechanics to more real-world atoms and molecules as opposed to very simple systems that we've talked about in the past, and that are often covered in physics. So that'll be an interesting one. And then going forward, I think we need to cover earthquakes and volcanoes, which is kind of where we've left off in the earth science area. So that's another thing that is on my radar to cover. And just as a tantalizer, I've been doing some thinking and reading on the interpretations of quantum mechanics recently. So maybe in a few months time, I'll look into doing an episode on that. So that's a more advanced sort of physics topics for those of you who are interested. If you'd like to support the show and sort of help this content

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