All right, so we're talking about the functions of the autonomic nervous system, and then eventually we're going to talk about why things happen the way they do with certain neurotransmitters and chemicals, and the role of the receptor, and specifically how the receptor triggers the change in the cellular behavior, which then does and makes the change that we want to do to maintain homeostasis. All right. So when we talk about sympathetic function, you probably know that this is our fight or flight System it's if you look at the evolution of the brain. It's one of the oldest parts of the brain or that nuclei which are controlling these are one of the oldest part of the brain and It's about you either stick around to preserve your life as an organism because the ultimate goal of an organism is to reproduce and pass on its genes, you stick around and fight for your life or you run away to protect it. Essentially what it is.
And so sympathetic, we will see that being activated in, I guess we could say, stressful situations. And this is controlled in two ways. So you have the nervous system, meaning neurons, specifically the sympathetic.
So we have neurons, and these neurons are going to release norepinephrine on the receptors. So when you think sympathetic, you need to think norepinephrine being released from those neurons. But the endocrine system is also involved in this, specifically the adrenal medulla, and that's going to release epinephrine, which is very similar in structure to norepinephrine.
It's a monoamine. It binds to a lot of the same receptors. Not all the same, but a lot of the same. So about 75% of the secretions from the adrenal medulla.
into the blood are epinephrine. About 25% are norepinephrine. So the fight or flight is going to be activated by both.
Because what we have, and you should have reviewed this or should have seen it when you reviewed 9-2, is that there are neurons that are part of the sympathetic that connect to the adrenal medulla. Now remember in the autonomic pathway there's two neurons. There's the pre-ganglionic and there's the post-ganglionic neuron.
Always two neurons in an autonomic pathway. When I say autonomic you need to automatically think motor. Involuntary motor.
I don't care if we're talking sympathetic or parasympathetic there's always two neurons in that pathway. And those neurons will synapse, if we just look at a single pathway, those neurons will synapse at an autonomic ganglion. Now remember, a ganglion is a collection of nerve cell bodies in the peripheral nervous system. A nucleus is a collection of nerve cell bodies in the central nervous system. Now if we look at this sympathetic, Now all these effectors are going to be cardiac muscle, smooth muscle, or glands.
So digestive glands, other endocrine glands, and so on. If we look at the pathway to the adrenal medulla, we have a neuron, and these come from the spinal cord. We have a preganglionic neuron that synapses with all the individual cells in the adrenal medulla. So here's your adrenal gland sits on the superior poles of the kidneys.
There's two parts. There's the inner part and outer part. Each of these cells in the adrenal medulla is a postganglionic cell. In a sense, these cells in the adrenal medulla are neurons that do not have axons.
And so when this acetylcholine is released from this neuron onto these cells, they're going to secrete epinephrine and norepinephrine into the blood. So when you have an activated fight or flight, you will have all of these activated. And that's what's, I guess, unique about the sympathetic is it's very broad, widespread acting. Is that when it's activated, it...
activates everything that could possibly have sympathetic innervation. Whereas the parasympathetic is very localized, and you can have very specific and fine control of your parasympathetic, things that are under parasympathetic control. And this has to do with the divergence of these postganglionic cells. So there could be many, many postganglionic cells that synapse with a single preganglion. I want to talk briefly about something called autonomic tone.
This simply refers to the continuous firing of neurons in the background, that these neurons are always sending signals to their effector. So the continuous firing of autonomic neurons, which then in turn, I don't want to say affect the effector, but that's what they're doing is they're causing the effector to do something. And we can have both sympathetic and parasympathetic tone. I'll talk about parasympathetic tone in a minute.
Let's look at sympathetic tone. So what this means is that there's a constant firing and sending of sympathetic stimuli down these sympathetic pathways, which tells these effectors, skeletal muscle, cardiac muscle, fluid muscle, or glands, to keep doing something. Which means that if we, and let me look, let me draw you this here. So if this represents, if this represents the number of signals in a specific unit of time, we're going to get effect, we'll just say 1x. Bear with me.
If we increase the sympathetic stimulation, the constant background firing, and we have more signals in a specific unit of time, that means we're going to, in a way, see more activation of that effector. It's going to do more. If we slow down that sympathetic firing, and we have less action potentials in a unit of time, then that will slow down whatever that cell does. And a really good example of this is what happens in your blood vessels of your arteries, arterioles. Is that in order to maintain a certain diameter, is that we are constantly sending parasympathetic signals to the smooth muscles in those arterioles.
And when those smooth muscles are stimulated, they will contract. And in order to maintain a certain level of contraction, which keeps your blood vessels at a certain diameter, we have to send a certain amount of stimuli. So if the diameter of the blood vessel at a stimulation of 1x is this, and we increase the number of signals going to those smooth muscle cells, that is going to cause those smooth muscle cells to contract and the diameter of that vessel is going to shrink. At the same time, if we send less signals to the smooth muscle in those vessels, then that vessel will dilate because those cells are relaxing and they're not contracting as often.
And so the diameter of your blood vessel will be bigger. This is important because sometimes certain tissues and cells are only innervated by one of these branches. So like the blood vessels are only innervated by the sympathetic nervous system.
So the only way we can get those smooth muscles to relax and cause vasodilation is to decrease the amount of stimuli going to those smooth muscle cells. That's what autonomic tone is. We have it in parasympathetic as well, and that's to keep your heart rate less than 100 beats a minute at rest. Let me call your attention to, where is it? So in your packet, find page 216. And I will give you all these tables.
So I'm going to give you what's on page 213 on the test. I'm going to go over that today. I give you page 214 on the test and I give you page 216 on the test.
You don't have to memorize it. You got to understand what it's telling you. So page 216 is telling you where we have this tone, this autonomic tone and background firing.
So you can see the second one down, arterioles. Predominant tone is sympathetic, meaning that we are constantly sending sympathetic signals to those smooth muscle cells of the arterioles. And if we lose that tone, if for some reason the sympathetic stops firing, that means those smooth muscle cells are going to relax.
And when your blood vessels dilate and you get a lot bigger in diameter, your blood pressure drops. Hence, what's the effect of the loss of that sympathetic tone? Hypotension, low blood pressure.
Now we're going to come back and talk about this in Unit 4. I am going to talk today about these Alpha-1 adrenergic receptors to hopefully help you understand why, what happens when we stimulate those, why we see smooth muscle contraction happening. and causing that vasodilation. You can also see that there's parasympathetic tone, that the heart is constantly receiving stimulation from the vagus nerve at rest, which keeps your heart rate low, below 100 beats a minute.
And if something were to happen, and you were to lose that vagal tone, it's called, your heart rate would go up. So the vagus nerve acts as a brake on the heart to keep the heart rate lower. Again, something we address in more detail.
in unit four and we'll look at the physiology of the SA node and why the parasympathetic causes the heart rate to decrease. Anyway, you'll probably see a question or two about tone on the exam and you may have to refer to this chart. Okay, I will give you page 216, 214, and 213. You don't have to memorize those. You have to understand how to read them, but I will give you those. What's on 215 is basically the same as what's on 214, just broken down a little differently.
So you can ignore 215 if you want. It's pretty much the same. I think 214 is a little bit more concise.
And you don't even really need to memorize what the sympathetic and parasympathetic do, because it's on the chart. And if you know how to read the chart, you can probably guess or determine the sympathetic or parasympathetic effects. Okay.
All right. So we'll come back to page 213 shortly. All right. Let's quickly look at the parasympathetic. This is what we call our resting.
and digesting. This is predominantly active while at rest, not in a fight-or-flight situation. Parasympathetic, again, two neurons in the pathway. Synapse in the ganglion. What neurotransmitters are always released from the first neuron in an autonomic pathway?
Acetylcholine. I think I addressed this last time. And what type of receptor is found on the dendrites and cell body of that postganglionic cell, the second cell in an autonomic pathway? It's the receptor that binds to acetylcholine that ensures an action potential will happen in that cell.
Well, the receptor is a nicotinic receptor, and I'm going to come back and review these. It's a nicotinic receptor, but nicotinic receptors are always ligand-gated, meaning that when acetylcholine binds to them, it actually opens a channel, lets sodium in, potassium out, and that's what triggers that postsynaptic potential that's going to put that second neuron over threshold. So regardless if it's sympathetic or parasympathetic, that first neuron will always release acetylcholine and it will always bind to nicotinic receptors on that second cell. You have to make sure you understand that. Where some of the differences come in is what's released from that second cell.
We said sympathetic, it's going to release norepinephrine. Now there's a couple of exceptions which I will just not get into. your sweat, I'll mention it, your sweat glands actually are only innervated by the sympathetic. But those neurons actually release acetylcholine, even though it's sympathetic. For whatever reason, those release acetylcholine.
It will not be on the test. Okay, don't worry about it. If we're talking parasympathetic then, and let's say this is the heart, okay, these are going to be, this also releases acetylcholine. So parasympathetic always releases acetylcholine from the second neuron. And the receptors are what we call muscarinic.
I'll talk about those today. We're going to look at M2 and M3. What were the types of receptors that the found associated with sympathetic? Everybody remember that?
I think I addressed that when we were talking about Section 7.5 last time. Alpha and beta. Okay, we're going to go over this again.
The alpha and beta receptors are what we find on the effectors over here if this is a sympathetic pathway. So this releases norepinephrine, and these receptors are either going to be alpha or beta. And we're going to look at that. We're going to look at what happens when an alpha receptor is stimulated.
What happens inside the cell, and why do we get smooth muscle contraction of the blood vessels? And that's the kind of stuff that's related to section around page 213. I'll go over that chart with you too. Okay. You don't really need to know this.
Again, this is kind of a duplicate of those tables on page 214 and 215, but it tells you the different receptor types. And I can't read this because I'm going to bring my glasses again today. It breaks it down by sympathetic and parasympathetic. All right, so let's, I guess I kind of talked about some of this already.
So let's talk about acetylcholine real quick. So cholinergic is going to refer to acetylcholine. So we already mentioned the nicotinic receptors. I guess I forgot this slide was here. We'll just write it again.
So the nicotinic receptors, remember these are ligand-gated. They're going to allow sodium in, potassium out, and this is what produces that postsynaptic potential. which then leads to the action potential in the postganglionic cell.
So there's our first neuron in the autonomic pathway. This is always acetylcholine. And these receptors on the second neuron In any autonomic pathway, as I said, these are always nicotinic receptors.
They're excitatory. They create excitatory postsynaptic potentials, increasing the likelihood of an action potential in that second cell, which is what we want. And if an action potential happens in cell two, that means that this second cell is going to be able to release its epinephrine or norepinephrine or acetylcholine, depending if it's sympathetic or parasympathetic.
Now the other place, or the other types of receptors as I mentioned, are the muscarinic receptors. These are only associated, with one exception, with the parasympathetic effectors. So any of the cardiac muscles, smooth muscle, or glands that are activated when we want the parasympathetic to do its job, those are always going to be muscarinic receptors.
We have M2 and M3 as I just previously mentioned. And what we'll find is that some of these, the M2s, are actually what we call inhibitory. They actually inhibit the effector or change the behavior of the effector to kind of slow something down. Whereas the M3 are going to be what we call excitatory.
And they actually increase the behavior or excitability or, you know, cause something more to happen. Yeah. So when we look at the fact that sympathetic always releases norepinephrine, there is an exception to that.
And the neurons that innervate your sweat glands. which are only sympathetic, they actually release acetylcholine, which means that the receptors on those are going to be muscarinic. I'm not going to ask you that. We're just going to go with sympathetic norepinephrine, parasympathetic acetylcholine.
Okay. Maybe later on, you'll have to learn something about that. But right now we're just going to try and eliminate one of those, except this, except that.
All right. So let's look at adrenergic then. So when I say adrenergic, I'm talking about norepinephrine, epinephrine as the chemical that's going to bind to the effector.
So you can always think sympathetic when you hear the term adrenergic. So sympathetic effects. And we know that norepinephrine and epinephrine bind to the Alpha and beta receptors. We're going to only look at alpha 1, but there's beta 1, beta 2, beta 3. We're going to look at just beta 1 and beta 2, because they do different things in different situations. So if we can draw our pathway.
This first neuron, even though it's sympathetic, is still going to release acetylcholine. And these receptors are still going to be nicotinic. Excitatory, creates excitatory postsynaptic potentials. They're ligand-gated. But down here, this neurotransmitter is norepinephrine.
And these receptors on, let's say, the heart or smooth muscles of the bronchioles or... blood vessels those are either going to be alpha 1 or beta receptors depending on and you may have both as well sometimes you will have both i'll explain that when we get there I talked about the neurotransmitters, the autonomic nervous system. Not sure I need to go over this. I do want to point out, however, that in both sympathetic and parasympathetic, there are different ganglia. And in the sympathetic, anybody remember what we call those ganglia in the sympathetic?
Where the two neurons meet? Where the two neurons synapse? Nope, not the inner neurons. So this is peripheral nervous system.
So if you recall from biology 152, if you were to look at the spinal cord, running on the lateral sides of the vertebral column, we have these little ganglion. Okay, those are the sympathetic chain ganglia. That's one of the ganglia. We're also called paravertebral. And then we have what are called the collateral ganglion, and these actually innervate your abdominal and pelvic viscera.
And then with the parasympathetic, those ganglia are either really, really close to that effector or actually embedded in it. And we have what are called terminal ganglia, which are really, really close, or we have the intramural. which are actually embedded within the tissue.
If I ask you anything about that, that's from 9.2, and that would be on the take-home part of the exam. If I ask you about the ganglia, it would be on the take-home part. So section 9.2 is only going to be on the take-home.
Yeah, you're probably going to have to understand some of the basics to understand 9.3, but... Now when we look at smooth muscle, smooth muscle cells don't necessarily have the axon terminals directly on each cell. What we actually find is that the motor neuron, that would be the postganglionic cell, has these swellings in it. called varicosities.
Now smooth muscle comes in sheets essentially and what we have is this neuron as you can see in the picture here kind of goes in between those cells within those smooth muscle sheets and as the action potential travels down it stimulates the release of neurotransmitters from these varicosities. So it does the same thing as far as changing the behavior of the cell. It's just that the neurotransmitter isn't released at the very end, the terminal portion of the axon.
It's that these little bulbous parts of the axon contain neurotransmitter vesicles, and they actually release their neurotransmitters kind of out to the side of the axon to the tissues that surround it. That's kind of a key characteristic for smooth muscle. Any questions?
That's just kind of an intro. Now we're going to get into looking specifically at the different receptor types associated with the different sympathetic and parasympathetic. All right, take a minute, look that through.
Yeah, this is on page 213. So if you can find 213 and have that ready. So I'm going to explain this chart and how to read it. Again, I will give you this chart on the test.
You just need to know how to read it. So let's take a, if there's no questions, let's take a look at this. So if you look at the chart, it's kind of divided into three areas. So right in the middle.
We have the receptors. So we have in green the muscarinic receptors, and they're showing us three subtypes. There's actually five subtypes.
We're only going to focus on M2 and M3. And then we have the nicotinic receptors. We have the nicotinic receptors associated with those ganglia in the autonomic pathway.
But we also have the nicotinic receptors associated with skeletal muscles. That's something we look at in Unit 3. And over here then, these are the receptors, the alpha and beta. So if I said alpha and beta receptors, what should immediately come to mind? Sympathetic or parasympathetic?
sympathetic So if you see a question and I say something about alpha beta you immediately need to think okay He's gonna ask something most likely about the sympathetic nervous system Because alpha beta are only associated with effectors connected to the sympathetic nervous system or Sympathetic effectors and carrying out those sympathetic responses if I said muscarinic you should automatically think what? Parasympathetic. Now if I said nicotinic, this is going to refer to obviously what happens at the ganglion between the pre-ganglionic and post-ganglionic cell.
You're going to need to know what I mean when I say pre-ganglionic and post-ganglionic. Two neurons in the pathway, an autonomic pathway. First one is pre-ganglionic, second is post-ganglionic. The ganglion is where neurotransmitter 1 is released and it's the NN subtype.
So that's kind of the only thing if I say parasympathetic you can probably a good chance that you can ignore this part of that table. Because we're going to be mainly looking at why does the parasympathetic cause the heart rate to go down when it binds to an M1 receptor? Or why does the heart rate go up when a certain chemical binds to the M2 receptors? And I'll walk you through this. Okay.
All right. That's one part of these tables. Now up here, we see something that says agonist. And then you have all these names. Now first off, don't memorize the table.
And you don't need to know what these chemicals do. Now maybe you already do. If you work in healthcare, you may already know what some of these chemicals do.
Fine, great. You don't need to know that because I give you a description, typically. So an agonist is a chemical that has the same effect, in this case on this table, that has the same effect as acetylcholine.
It's going to bind to the same receptors as acetylcholine and trigger the same response that acetylcholine would. If we look over here on the sympathetic portion, a sympathetic agonist is a chemical that's going to bind to an alpha or beta receptor that's going to have the same response as epinephrine or norepinephrine. So what do you think an antagonist is?
It's opposite. It's something that will bind. So all these chemicals down here under agonists, these are chemicals that will bind to the receptors. But they don't actually cause the same effect as the regular chemical would.
They actually block the receptor site and prevent, in this case here, prevent acetylcholine from binding and therefore preventing acetylcholine from changing the cell's behavior. Same over here is that these antagonists over here on the sympathetic They will block the alpha or beta receptors and prevent either norepinephrine or epinephrine from binding to those receptors. And if epinephrine is supposed to, you know, relax the smooth muscle like in the bronchioles, norepinephrine or epinephrine, I should say, will bind to receptors on the smooth muscles in your bronchioles and cause the smooth muscles to relax, causing bronchodilation.
Opening up your airways. But if you have a chemical that blocks the beta-2 receptor, that's going to keep those airways constricted and not let epinephrine do its job. Okay?
So far, so good on how to read this. Yeah? Was the power of the obvious on the sympathetic side? So when it says epinephrine... You're reading my mind.
I'm sorry, go ahead. No, you're going to get there. No. No, go ahead, finish. So if it's the epinephrine or epinephrine part, would that kind of be like a cheat?
Like alpha 1 can either be epinephrine or epinephrine? Correct. So alpha 1, so what this means is that, notice that if I were to draw a line like this, kind of breaking up all these different receptor types, and you can do it on both of them, that epinephrine can bind to alpha and beta. Norepinephrine can only bind to alpha 1, alpha 2, and beta 1. This chemical here, dopamine, only binds to alpha 1 and beta 1. So if I say, okay, I can't even read this.
If I said, whatever that says. The only place that that actually binds is to the M1. cells. You're not going to have to know M1.
And it would act as an antagonist, so it's going to block the receptor site, prevent acetylcholine from binding to it, and having the opposite effect that acetylcholine would if it was attached. So what I'm going to ask you on the exam is I'm going to say, this particular chemical causes this to happen. You got to find it and then you have to read the rest of the question then to answer it. So for example then norepinephrine binds to alpha-1. This is going to cause smooth muscle contraction in the blood vessels.
If this labetalol Attached to the alpha-1 receptor that's going to block the effects of norepinephrine Which would actually cause that vascular smooth muscle to relax? Causing the blood vessel to dilate reducing the blood pressure. That's the style of question you're gonna have Some of them are bolded and some of them aren't. I'm not sure. I found this on the internet probably 15 years ago.
And I've been using it ever since because it's great. So I'm not sure why some are bolded and some are not. Maybe because it binds to more than one?
Yeah, that kind of looks like the pattern. If it binds to more than one receptor, it's bolded, I think. If it binds to just one receptor in that particular class, then it's not bolded, I guess. All right, so let's focus then a little more detail on adrenergic simulation. So what do I mean by adrenergic?
Am I talking sympathetic or parasympathetic? Sympathetic, good. that's that all right so let's look at i'm missing a page in here somewhere All right, so we know that epinephrine comes from the adrenal medulla.
If you look at the table, we know that epinephrine is going to bind to alpha-1. Now, you can ignore, I will not ask you anything about alpha-2 or beta-3 receptors. And I will not ask you anything about M1 receptors.
And honestly, I probably won't ask you anything on the exam about the nicotinic receptors either. So epinephrine, as you can tell, will bind to the alpha-1 receptors, beta-1, and beta-2 receptors. You can see that alpha-1 vascular Those receptors are only going to be found on the smooth muscle in blood vessels. You're going to want to make a note of that.
Smooth muscles associated with arterioles. Very small blood vessels. Which tells us that these play a big role in regulating blood pressure.
Basal constriction and dilation. Can you repeat what you said we should make a note of? That the alpha-1...
Vascular, what that means is that these are only found on the smooth muscle associated with the arterial blood vessels. Those are the ones that play the biggest role in regulating your blood pressure. They constrict and they dilate. Beta-1, those are only associated with the heart. So in other words, the beta-1...
depending on what attaches to it. If it's sympathetic, what does sympathetic do to the heart? Sympathetic increases heart rate. So when norepinephrine and epinephrine bind to beta-1 receptors, they will increase the heart rate. But if any of those antagonists bind to the beta-1 receptors, they block.
They're beta blockers. They block. the epinephrine and norepinephrine from the beta-1 receptors, which then allow the heart rate to decrease, to slow it down. These can be used as blood pressure medications too, as beta blockers. That's how you read this chart.
Now notice that norepinephrine, and we can make a note here that norepinephrine, this is from the nervous system. Yes, we get a small percentage from the adrenal medulla as well. This will only bind to the alpha one and the beta one.
Again, we're eliminating, we're not going to do anything with alpha two. So if you find norepinephrine on that chart, Okay, so here's norepinephrine. Now we're skipping this alpha-2 stuff. We can see that norepinephrine binds to the alpha-1, and we can see that it binds to the beta-1.
It does not bind to beta-2, which means that any of the smooth muscle associated with the beta-2 receptors can only respond to epinephrine. That's what that means. Now, these epinephrine and norepinephrine, depending on the receptor, it can stimulate something or can inhibit something. So we can say that they're either going to be an excitatory or an inhibitory receptor.
or an excitatory or inhibitory response. And I already mentioned alpha and beta receptors many times already. Okay, so let's dive in and start looking at the specific physiology of these receptors.
So you should have some large sheets somewhere in your packet. It's in the back by the charts someplace. What? 207. Not sure what that is. So we're going to look at the alpha-1s first.
And hopefully that will help us understand why when the alpha-1s are stimulated by epinephrine or norepinephrine. They will cause blood vessel dilation or constriction. Yeah, you have a question?
Let me find my other ones here. If you look at where those tables go. There it is. If you look at page 214, you'll see this on the test.
So I give you the organ. And I put a header on there, sympathetic stimulation, parasympathetic stimulation. And I tell you that...
Sympathetic will cause the heart rate to go up. It increases the force of contraction and increases the conduction velocity of the blood as it moves through the circulatory system. I even give you the receptor types. You'll notice that under arteries, under constriction, we have alpha-1.
Those will cause the blood vessel arteries to get smaller, causing an increased blood pressure. But also notice... that we have beta 2 in dilation. Now there is a mistake on this chart.
Under parasympathetic stimulation artery dilation. Cross that off. That should not be there. I'm not sure how it got there.
Page 214. Find the organ artery. Go all the way over to the parasympathetic column. Cross off dilation. So what this means is that when an alpha-1 receptor is stimulated, it's going to cause the blood vessels to constrict.
But when the beta-2 receptors on those same cells are stimulated, specifically by epinephrine, it's going to cause that smooth muscle to relax. And I will show you why. And we'll compare what the beta-2s do and what the alpha-1s do. Also notice that under the gastrointestinal tract, We have certain sphincters with alpha receptors. There's certain alpha receptors in the liver, in the smooth muscle of the urinary bladder, and so on.
So pretty much when we have an alpha-1 receptor, we're looking at several different places. Obviously, we're looking at vascular smooth muscle. That's really how we're gonna focus on this but according to our chart there are alpha receptors on other smooth muscles.
So let's look and you have where those other ones are, but let's at least look at, and this would be location. That's the main thing we're going to focus on. So let's look at how it works.
So alpha one, what neurotransmitter, notice I said neurotransmitter, what neurotransmitter is going to bind to the alpha one receptors? What's the normal chemical that's going to bind to the alpha one receptors? Well, norepinephrine is a neurotransmitter. That's what's released from the second neuron.
We also notice, according to that table on 213, epinephrine, which is a hormone because it's released into the blood and travels the body via the blood, that will also bind to the alpha-1 receptors. And so they have the same response. So this is how it works.
So if this is our chemical, so let's say that's epinephrine or norepinephrine. Notice that there's a G protein here. We talked about those before. Here's our receptor.
This is the alpha-1 receptor. There's a G protein here. Well, when that epinephrine and norepinephrine binds to the receptor, that G protein gets released.
Now, this is embedded in that plasma membrane. Now, it's not shown, and we're going to add a couple of things. is that also embedded in the membrane is an enzyme and this enzyme is called phospholipase C and attached to that phospholipase C is kind of a special phospholipid that's that's in one configuration.
So it ends in ASE, phospholipase C, it ends in ASE, that tells you what about it? It's an enzyme. So when that G protein is released, it activates the enzyme. which in turn causes this phospholipid to essentially break in half.
Now I'm simplifying it. And what we end up getting is two additional molecules. One is called IP3, inositol triphosphate.
and the other one is called DAG, diacylglycerol. I don't think you need to know the names on the exam, but that's what the names mean. Now both of these do different things that are important for changing the behavior of the smooth muscle cells.
Now they're muscle cells. We want them to contract, they get shorter, and when they get shorter they do something. In this case we're focusing on the constriction of a blood vessel.
Now inside the cell we have smooth endoplasmic reticulum. Remember that stuff? And inside this is calcium ions. Well calcium ions are required for muscle contraction, all muscle contraction, skeletal, cardiac, or smooth.
If we want these smooth muscles to contract, we have to release that calcium from that smooth endoplasmic reticulum. And so what the IP3 does is this ends up opening the channels. that allow that calcium to diffuse into the cytoplasm of the smooth muscle cells. That then triggers the contraction of the smooth muscles.
And that's something we address in more detail in chapter 12, unit 3. So the IP3 is what triggers the release of calcium from the smooth endoplasmic reticulum. What haven't we looked at yet? The DAG. What the DAG does is it actually opens an ion channel in the membrane. And when that ion channel is open, it lets calcium into the cell from the extracellular fluid.
adding additional calcium to allow the smooth muscle cells to get shorter and contract. So when the diacylglycerol is activated, it binds to this ion channel, which in turn opens the channel and lets calcium move into the smooth muscle cell from the extracellular fluid. Remember, we said way back in chapter six, if there's more calcium outside the cell than inside the cell, free calcium. This calcium that comes in is gonna be important for causing those smooth muscle cells, the actin and the myosin inside the smooth muscles to actually interact and cause that cell to shorten.
And because smooth muscles are in sheets, typically in tubular organs, when they contract, That's going to cause the diameter of that organ, hollow tubular organ, to get smaller. This is why we get vasoconstriction, blood vessels getting smaller in diameter. I'm debating whether or not to provide a little bit more detail about exactly what calcium does, how it does it. I'll just say this. Let's number these so that you can go back and kind of put this in a sequential order.
Now remember, on the exam, I'm not going to ask you, even though we're numbering these, I'm not going to ask you, what's step two? What's step three? You can break this down into 100 steps if you want.
I'm going to break it down probably into six. Okay? So here's step one. Neurotransmitter binds to the receptor.
Step two, that in turn releases the G protein and activates the phospholipase C. We have 3A. So this phospholipid splits into IP3.
And 3B splits into IP3 and the DAG, diacetylglycerol. Now this isn't a traditional phospholipid. That's beta of the membrane.
This is kind of different. It's the same basic structure, but it's got more stuff on it. Do you think it's being like a transgenic enzyme?
No. It breaks off and kind of travels through the membrane and attaches to the phospholipase C, which in turn activates the phospholipase 3. So right now, the phospholipase C as an enzyme is inactivated. So this G protein is acting as what we would call a coenzyme.
That without the G protein, the phospholipase C won't work. It's like a switch. Yes, it would attach to it in a certain spot.
Turning a switch on activates the enzyme, which then splits that phospholipid into the IP3 and the DAG. So for A, we could say then the DAG opens the calcium channel. And then 5A, calcium flows in. It's all being recorded.
You can go back and watch it. 4, sorry, I guess I should call those Bs. I don't know. Whatever. So this 4A, I guess we should call it 4B because we have 3B here.
Because we have two things happening. in the third step that phospholipid splits into ip3 and dag at the same time so really this 4a should be 4b and this 5a should be 5b so the dag then goes and binds to that special channel which in turn opens the channel and lets calcium move into the cell that's 5b calcium moves into the cell This, yeah, this would be 4A. Sorry if I want to keep kind of the processes together. So 4A would be then that that IP3 that's formed binds to this smooth endoplasmic reticulum, which then opens up calcium channels and lets calcium diffuse out of the smooth ER into the cytoplasm itself. Six.
And we're just going to say six because the calcium, doesn't matter where it comes from, does the same thing. So calcium binds to something called calmodulin. And you're going to hear that again in chapter 12. So calmodulin is a protein enzyme that's inactivated. And when calcium binds to the calmodulin, it now becomes activated calmodulin. That then in turn is what triggers the smooth muscle proteins, the actin filaments and the myosin filaments inside the smooth muscle cells to interact.
It pulls on the plasma membrane and causes the cell to get shorter. Yeah? What does it do to the smooth endoplasmic reticulum?
It triggers the opening of these calcium channels in the smooth endoplasmic reticulum to let the calcium out. That calcium then binds to the calmodulin, which then initiates the smooth muscle contraction process. Now if we're talking a vascular smooth muscle, this is going to cause a constriction of the blood vessel raising the blood pressure.
So what if somebody was given as a pill an antagonist that attached to the alpha-1 receptor, what would it do to the smooth muscle contraction? It would prevent the epinephrine and norepinephrine from binding and would not allow that calcium to be released or enter the cell. Calcium's not binding to the calmodulin.
Calmodulin then doesn't initiate smooth muscle contraction. Remember I mentioned this idea of tone, sympathetic tone. What we have, if we want to maintain a certain diameter of our blood vessel, we have to constantly stimulate these alpha-1 receptors. And the level of stimulation determines the diameter of the vessel. Go way back to that first slide.
So this one right here, notice we have more stimulations in a certain unit of time. That's going to cause a lot more stimulation of that Alka-1 receptor, causing more calcium to continue being released. Because that neurotransmitter does not stay attached to that receptor very long. It's going to attach, and then an enzyme, that monoamine oxidase, is going to come in and break it down, which means that whatever's happening inside the cell stops. And if we want to continue that process, we have to continue to stimulate that cell.
So what an antagonist would do in this situation, it would come in, it would bind and block. that epinephrine and norepinephrine for a short time until that antagonist gets removed from the receptor site. So it would reduce the amount of stimulation that that receptor gets, limiting the time that those cells stay contracted and in a sense then allowing that dilation to occur and relaxation of those smooth muscles.
They're not contracting as much so the diameter isn't as small. And when your blood vessel diameter is bigger, your blood pressure gets lower. Something we address more in Unit 4. That's how an Alpha-1 receptor works. Now, Alpha-1 are also associated with the gastrointestinal tract, the liver, the urinary bladder.
The same thing is going to happen. The smooth muscle in those organs, when they're stimulated, We're going to see the same thing, and we're going to then cause constriction of your gastrointestinal sphincters or constriction of the urinary bladder, which is going to force urine out of the bladder. When that detrusor muscle in your bladder contracts, it's going to push the urine out, and you're going to get the urge to go.
So I just used the example of vascular smooth muscle, but there's a lot of places where we do find these alpha receptors and other smooth muscle cells. Okay, so this is something you're gonna have to spend a little time on I would say write these steps out practice drawing this I believe there's additional diagrams online if there's not I can make just the diagrams available so you can practice on these I Don't think you're gonna see any pictures of these But if you have a visual embedded and kind of a model in your in your mind then hopefully you can understand this process a little better. Okay.
All right, let's look at beta-1. These are much simpler. If we look at our table on 213 and we find the beta-1 receptors and look under the agonist category, we're going to see that both norepinephrine As a neurotransmitter, an epinephrine is a hormone. We'll bind to these.
These are associated with the heart, so the SA node, the AV node, and the myocardium, the actual muscle of the heart itself. So epinephrine and orpinephrine or some type of agonist binds to the beta-1 receptor. That's step one.
Notice we have a G protein. Step two is that that G protein is released, travels through the plasma membrane. And so there's the bottom, the inside portion of the membrane.
Binds to an enzyme. Anybody remember the name of that enzyme? We kind of looked at this before. It starts with an A, adenylate cyclase. Again, ASE tells you it's an enzyme.
All right, so the G protein then activates, is released, activates the adenylate cyclase. Step three is that adenylate cyclase converts ATP into Cyclic AMP, C-A-M-P. This is this. Everything we've looked at so far involved the second messenger system. The IP3 and DAGs are second messengers.
Cyclic AMP is a second messenger. This is what actually then triggers the change in the cellular behavior. So what this does is this inside. the SA node AV node cells or the myocardial cells there is something called protein kinase another enzyme protein kinase A it starts out inactive but when cyclic A and P is formed it binds to the protein kinase A.
I kind of draw it as a rectangle with a square attached to it. Now it's active. Just like we saw that the phospholipase C gets activated by the G protein, okay, well this cyclic AMP activates this particular protein.
So now we have an active protein kinase A. So let's see, 2, 3, 4, 4 again. And what this does is that in the beta-1 receptors, this is going to trigger the opening of calcium channels again. This is going to let calcium into the cell. And we're going to get more into this.
and specifically what happens in the myocardium and the SA node in unit four. But we're going to come back and we're going to look at this again. And then this calcium then does different things inside the cell.
Calcium is required for cardiac muscle contraction. Calcium is required. for the SA node to send out and generate the signal which triggers the muscle cells of the heart to actually contract which causes the heartbeat. And remember the heartbeat the SA node sends out signals all on its own. You can sever all the nervous system connections to a heart and the heart's still going to beat.
The nervous system doesn't tell the heart when to beat. It tells it when to beat faster or when to beat slower. So there's different G proteins associated. Don't worry about that. Just know it's a G protein.
It does the same type of thing as G protein we looked at in the alpha ones. Does the protein bind? Yes. So it gets released from the receptor, travels through the phospholipid bilayer, attaches to the adenylate cyclase, activates it, which then allows ATP to get converted to cyclic AMP.
Cyclic AMP binds to the protein kinase A, activates it. That opens ion channels. The other thing that could happen, depending on where, is that it could trigger the release of calcium from smooth endoplasmic reticulum.
This would happen actually in the myocardium. Both of these, we'd let calcium in from outside and we'd get calcium released from the smooth ER as well. And I come back and talk about this when we look at the physiology of the myocardial action potential.
Okay, so would this be considered excitatory or inhibitory receptor? It's an excitatory receptor. So at alpha 1, right? Because we're stimulating something to happen, we're not stopping something.
Well, guess what? Beta 2 receptors are inhibitory. What? Oh.
These are only activated by epinephrine, which is not a neurotransmitter, it's a hormone. Now these are found on smooth muscle. of involuntary effectors, which I guess is kind of a contradiction in terms. Yes, smooth muscle are involuntary.
So it's found on smooth muscles. So we're talking the bronchial smooth muscles, vascular smooth muscles. Now this would include... the blood vessels in the skeletal muscles, the vasculature, specifically the coronary arteries, and I'll look at those with you specifically in a minute, and the gastrointestinal tract, the smooth muscle of the gastrointestinal tract.
No. So if we look at the blood vessels in the skeletal muscles, that supply blood to the skeletal muscles, on those blood vessels we're going to have beta-2 receptors. Same with the coronary arteries, and I'll explain why in a minute.
And then in the gastrointestinal tract on the smooth muscles that propel the food forward and mix and churn the food, we have these receptors as well. Now let me explain what these do and then I'll come back and I'll talk about what we're seeing here. So although the epinephrine in a hormone that's not a neurotransmitter, it acts as a neurotransmitter in a way? It acts as the ligand that releases the G protein. It just comes from, it goes, gets to the cells via the blood rather than a neuron.
So it's going to, it causes a change in the cellular behavior, even though it doesn't come from a neuron. but it binds to the receptor, changes the cellular behavior. And in some instances, it acts just like norepinephrine. It binds to the alpha-1, it binds to the beta-1s, except with beta-2, norepinephrine, you might get some, but this has a much higher affinity for epinephrine than norepinephrine.
So in order to activate and stimulate this inhibitory response, The adrenal medulla has to release this epinephrine. So step one then, epinephrine from the adrenal medulla binds to the receptor. So far this is no different than beta-1, is it?
But remember, these are found in smooth muscles. So even though we're going to see a lot of the same things that we just saw in that beta-1, These are in smooth muscles. Beta-1 are associated with the heart. So step two then, the G protein is released, activates that adenylate cyclase.
And what does that adenylate cyclase do? Takes ATP, converts it to cyclic AMP. Again, second messenger. Here's where it's different than beta 1. Remember, in the beta-1, it activated protein kinase A. Now, that's in the heart.
We're looking at smooth muscles. Now, one of the things I didn't mention is that in order to get smooth muscles to contract, there is an enzyme called myosin light chain kinase. Okay, it's an enzyme. It adds a phosphate to something. This is typically going to be active because if we think about, and this is associated with smooth muscle, this myosin light chain kinase associated with smooth muscle, this is going to be active, causing the smooth muscle to stay contracted or maintaining some type of smooth muscle tone.
But if we want that smooth muscle to relax in some way and not contract, well, we have to inhibit that myosin-like chain kinase. And so the cyclic AMP then, in step four, would bind to that myosin-like chain kinase and actually inhibit it and prevent. Smooth muscle contraction.
I'm going to walk you through a couple more things. Good question. Why would we want to inhibit smooth muscle contraction?
We'll get to that in a second. That's the right question to ask. Now, are beta receptors associated with sympathetic or parasympathetic? Sympathetic.
Do we want our gastrointestinal tract to be pushing food through our digestive tract and mixing while we're in a fight-or-flight situation? Absolutely not. Do we want our sphincters to be relaxed and peeing while we're...
in a fight or flight. No, but a lot of times you'll piss your pants if you get really scared. Okay, and I haven't really spent any time researching why that happens. Maybe it's a conflict of signals. Theoretically, your sphincter, urinary sphincter should tighten up because those alpha receptors are going to be stimulated in a fight or flight.
Well, that could very well be because it could be a very primitive instinct is that you piss yourself as a... Organism and the predator runs away. I don't want to eat this now, you know Well, but that's all that's all skeletal muscles though But no, but yeah, so if your pelvic muscles aren't strong enough, you can, you know, squeeze your pelvic muscles. Women that have children are encouraged to do those kegel exercises, strengthen those pelvic floor muscles. Because remember, you have an external sphincter as well, which is smooth skeletal muscle.
And if you can, you know, squeeze those, then you can, even when that internal sphincter opens automatically, you can squeeze that external sphincter a little more with those pelvic floor muscles that keep that from leaking out. Probably because they're using different muscles and can't contract those other ones at the same time, right? Okay, interesting. Okay, so let's break this apart here. So why would we want to inhibit smooth muscle contraction?
Well, so here's our, let's say here's our blood vessel. I'm going to do it this way. So here's our blood vessel.
And let's say that this is in a skeletal muscle. Blood vessels are everywhere. And so here's our alpha-1. There's a continuous stimulation of alpha-1, maintaining a certain amount of tone and diameter, letting a certain volume of blood into the skeletal muscles, right? With me so far.
So these are constantly being stimulated by norepinephrine. Well, in a fight-or-flight situation, you're going to have to use your muscles to get away, typically, or fight. right? And so what are you going to need to bring to those skeletal muscles to make sure that they can provide you with the ability to run away or stick around and fight?
You need oxygen and you need other nutrients all used to make ATP. You want to increase the flow of blood to your skeletal muscles so that those cells then have what they need to be able to help you survive. So even though, and so in fight or flight, we know we get increased sympathetic stimulation. So that means increased norepinephrine from neurons.
We know norepinephrine binds to the alpha-1, but we also see increased epinephrine from the adrenal medulla, which we know also binds to the alpha-1. But yet, at the same time, I'll just draw it a little different shape. Okay, this is our beta-2 receptor. If this epinephrine released from the adrenal medulla in a fight-or-flight binds to this, even though this releases calcium, which is important for smooth muscle contraction, the cyclic AMP released are generated from this beta-2 receptor would actually inhibit that smooth muscle from doing anything.
Even though it's being told to contract over here, the activation of that beta-2 is going to stop it. and block it and prevent that from happening. So if our smooth muscles can't contract, what happens to the diameter of the blood vessel in your skeletal muscles? It's going to dilate, letting more blood flow into that organ, delivering more oxygen, which your breathing rate is increased, your heart rate's increased, so you're able to deliver a larger volume per unit time, but also the volume going into your cells is increased as well. This is why you inhibit.
This is why we can find both alpha and beta-2 receptors on the same tissue. This is what happens to cause the dilation of your bronchioles. You're having an asthma attack and you take your inhaler, albuterol, that's a beta-2 agonist. It binds to a beta-2 receptor. It inhibits smooth muscle contraction of the bronchial smooth muscles.
and causes those smooth muscles to relax, opening up your airway. Same with the coronary artery blood vessels. We want more blood flowing to the heart in a fight or flight because that heart needs more oxygen, more nutrients, because it has a higher demand.
It's going to have to contract more often. Does that answer your question? So that's how the beta-2 work.
Now notice if you compared an alpha-1 to a beta-2, do alpha-1s use cyclic AMP? No, they don't. Two different mechanisms. Two different mechanisms meaning you can have two different cellular behaviors when those receptors are stimulated.
Would you find a beta-1 and a beta-2 on the same cell? You shouldn't because both release cyclic AMP or both activate cyclic AMP.