Parasympathetic nervous system - also in Neuro

Okay, so this lecture then is all about the parasympathetic nervous system. So what we will be doing is looking at the synthesis of acetylcholine, or ACH, in autonomic nervous system nerves. We'll look at the metabolism of acetylcholine when it's released from autonomic nervous system nerves. We'll look at the main types of cholinergic receptors. So these are the receptors for acetylcholine. And we'll see that there are three different types of muscarinic receptors. And we'll look at how they are differently distributed in target tissues. And then we will look at the parasympathetic control of the heart and the eye. And we will see how you can use drugs clinically to treat disorders of the eye. And then we will finish by just... Introducing you to a co-transmitter that acts together with acetylcholine, and that's known as vasoactive intestinal polypeptide, or VIP for short. So just a quick recap then of the parasympathetic division. It's also known as the craniosacral division. Are you happy you know why it could also be known as the craniosacral division, based on the information given in the previous lecture? Lots of nods there, that's good. So for anybody who's not sure, it's because the cell body of the first neuron in the series of two lies within the cranial or sacral regions of the spinal cord. And that's what defines a nerve as being a parasympathetic nerve. The role of the parasympathetic division is in keeping our body energy use low. So it predominates in individual... individuals with relaxed states. It keeps your blood pressure and your heart rate and your respiratory rates low. And it keeps your gastrointestinal activity high. And that's why it's sometimes known as being involved in the rest and digest response. And it has an inhibitory effect on many tissues and organs, not always, but usually. So, this shows then the organization of the parasympathetic nervous system, which we've just looked at. So, I might be a little bit, try to be more concise when I'm describing this. So, what we've got... is for the parasympathetic division as a part of the autonomic nervous system, we have two neurons in series. For the first neuron in the series, the cell body... lies either within the cranial region of the spinal cord or in the sacral region of the spinal cord, and that's what defines the nerves as being parasympathetic. For the cranial region, we have many different nerves. Some of these have names, they're very important, so they're given names. So there's the oculomotor nerve, or the third nerve, which innervates smooth muscles of the eye. There's the facial or seventh nerve, which innervates facial glands. And there's glossopharyngeal nerve, which innervates the salivary glands. And then the very famous vagus or tenth nerve, which innervates many target tissues throughout the body. And then in terms of the sacral outflow, these sacral nerves form synapses in ganglia that are scattered in networks of nerves within the pelvic region. And then the sacral outflow is the sacral nerve. And then we have the postganglionic nerves that innervate the target tissue, and these form the second nerve in the series of two nerves. We can simplify that in this way to show for our parasympathetic pathway, we've got the two nerves in series. There's the preganglionic nerve shown in red and the postganglionic nerve shown in blue. And I've deliberately made the preganglionic nerve longer than the postganglionic nerve because you may remember that these travel all the way to ganglia that are in the target tissue or near to the target tissue. Preganglios nerves tend to be longer than the postganglios nerves. The cell bodies of the preganglios nerves sit in the spinal cords, specifically in the cranial or sacral regions, and they receive information from the brain. So within the central nervous system, they get information about... the environment from the brain that triggers a response in this pathway. And then the preganglionic nerve then forms a synapse with the cell body of the postganglionic nerve within the ganglion. And remember, the ganglia are collections of these cell bodies. Because they're grouped together, they form these swellings that are known as ganglia. And then for the postganglionic neuron, this travels. It's the nerve fibers travel to the effector cell, which could be anything, your heart, your lungs, your eye. And it can branch to increase contact, the surface area for contact with the target tissue. And then on it, we have swellings known as varicosities. And it's from these that neurotransmitter is released. So we're moving on then to think about the neurotransmitters that are involved in this pathway. And for the parasitic... sympathetic nervous system, it's really easy to remember because the main neurotransmitter that is used throughout, so for both the pre-ganglionic neuron and for the post-ganglionic neuron, is acetylcholine, or ACH for short. So you've got acetylcholine being released here to act at the cell body and being released from the varicocytes to act at the effector cells. So that's easy, acetylcholine in both cases. What's different is the receptors at which the acetylcholine acts. So at the ganglia, the receptors are a type of acetylcholine receptor known as nicotinic receptors, and at the target tissue, the receptors are receptors known as muscarinic receptors. So these are the two main types of acetylcholine receptors, and they are different depending on the location. I've deliberately used different symbols for these, and we'll look at this in the next few slides, to indicate that the nicotinic receptors act as ion channels. This is supposed to be a channel. So these are ion channels. These are receptors act as our own channels. The muscarinic receptors, and again, we'll look at that in a moment, are G protein coupled receptors with a very distinct structure that looks a little bit like this. Okay. So the main thing to get from this is that acetylcholine is used throughout, but acts at two different types of receptors, which are nicotinic at the ganglion and muscarinic everywhere else, so everywhere else on the target tissues throughout your body. Okay. So we're first of all going to look at the synthesis and the action and the degradation of acetylcholine. at the cholinergic synapse at the ganglia, but also within the varicocytes. And this should be a bit familiar to you because the pathway is very, very similar to that which we met for the neuromuscular junction. So when we looked at the acetylcholine synthesis and actions and metabolism at the neuromuscular junction, it's essentially very similar to this. So just as a reminder then, at the terminals of the cell or at the varicosities, what we've got is the synthesis of acetylcholine. So we've got acetyl-CoA from the Krebs cycle and choline from dietary sources is synthesized into acetylcholine under the influence of an enzyme present in the cytosol. And that enzyme is known as choline acetyltransferase. The acetylcholine is... packaged into vesicles that are within the terminal of the axon and within the varicosages. And we have heard previously that these vesicles are small but contain many thousands of molecules of acetylcholine. And these acetylcholine molecules are released when an action potential invades either this nerve terminal here, or the varicosities. And that acetylcholine that's released then travels across the synapse or the synaptic cleft and acts at cholinergic receptors. And the acetylcholine can be broken down by an important end. enzyme known as acetylcholine esterase, which removes it from the synapse, and some of the choline that's formed can be taken back up into the terminals and used for resynthesis of acetylcholine. So we've heard all that previously. So just to draw your attention to the fact that we are now thinking about the receptors at which the acetylcholine acts, and we've just heard that when it... comes to the ganglion the receptors are nicotinic acetylcholine receptors so NACHR is the abbreviation And when it comes to the effector tissue, so that's all of the tissues in your body, your lungs, your heart, your smooth muscle, they are muscarinic receptors, so MACHR for short. So there are two different types of receptors. And that's written out in text there for you down below. So we've got muscarinic receptors are on your smooth muscle, your glands, etc. there. Okay, so here are the two types of acetylcholine receptors that we've just talked about. These are the main two families of acetylcholine receptors. We've got our nicotinic receptors and our muscarinic receptors. heard that the nicotinic receptors are the ones that are present at the ganglia. They're also present in the brain. They're also present at the neuromuscular junction, but we're concerned with the autonomic nervous system. considering the effects in ganglia. And these nicotinic receptors, they are inotropic receptors, so they act as ion channels, which allow the transport of, for example, sodium and potassium ions. The muscarinic receptors are present everywhere else, so throughout all of the target tissues, which the autonomic nervous system innervates, so your lungs, your heart, your eye. Your kidneys, everywhere else, your endocrine glands, exocrine glands. They're also present in the brain, but that's part of the central nervous system, so it's not what we're considering at the moment. We're thinking about the autonomic nervous system. And these muscarinic receptors are metabotropic receptors, so they are G-protein coupled receptors. And what they do is couple to second messengers to alter movement of ions across the cell membrane. There are subdivisions of muscarinic receptors. There are M1, M2, and M3 receptors, which are relevant to autonomic function. There are also M4 and M5 within the... brain so we're not going to consider these here so m1 muscarinic receptors are found within the gastrointestinal tract and they can promote gastric acid secretion M2 receptors are found within the heart, and they function to reduce heart rate and force, they reduce heart function. And then the M3 receptors are present everywhere else, so glands, smooth muscle, and so on. So what we're going to do now is just to help with understanding, is just show you the structures of what these two receptors. look like. So what an inotropic receptor looks like and what a metabotropic receptor looks like. So starting then with the nicotinic receptor. So here's our cell membrane. And bang in the middle, here we have our nicotinic receptor. So it's a receptor for acetylcholine. It's one of the two main types of receptor, the other being muscarinic. And what we know is that, well, it acts as an ion channel. So when you have two acetylcholine... molecules binding to this receptor. You can just about see acetylcholine there. When two acetylcholine molecules bind, it causes a shape change within this protein. It opens up to allow an influx of sodium or potassium, and that goes into the cell to typically cause a depolarization of the postsynaptic cell. But in other words, it elicits a response. So that's our nicotinic receptor. iron channels. The other type of acetylcholine receptor are the muscarinic receptors, often known as, well, they are metabotropic receptors. There's a whole range of different metabotropic receptors and muscarinic receptors. Receptors belong to this super family of receptors. So you can see straight away they're very different in structure to the nicotinic receptors. They consist of a single protein. That's what these amino acids here denote. And this protein winds backwards and forwards through the cell membrane. So it crosses backwards and forwards. And as it does so, it forms what are known as transmembranes. domains, that's these, and there are seven. If you count them up, you'll see there's seven. So it crosses seven times, and it also forms loops as it does so. So there are extracellular loops, and there are intracellular loops. And basically what happens is that when acetylcholine comes along and binds to one or more of these extracellular loops, that causes a change in the protein, a conformational change. And that then causes the intracellular loops to attach to G proteins to trigger a second messenger system, which can involve enzymes or ion channels, but basically to release the protein. elicit a response. If you are interested, this is somewhere where you could do wider reading if you are interested, but it's beyond the scope of this module to go into this in any greater detail. So that's for wider reading if you're interested in exactly how this works. All I need you to know for this module is that the muscarinic receptors are metabotropic, they are a type of acetylcholine receptors, and they... They also are known as G-protein coupled receptors because they're attached to G-proteins. And that's the start of the cascade to elicit a response. Okay, now, it's really useful to know about these different types of receptors because that knowledge can be exploited clinically to manipulate signaling of the autonomic nervous system. So we can tweak it up, inhibit it, do various things. And that's very, very powerful when it comes to drugs and medicines to help with various diseases. And so just... just want to introduce you to a number of different types of drugs which act at the parasympathetic nervous system. So what we've got is a category of drugs known as parasympathomimetic. And what these do is they mimic the actions of acetylcholine at its receptors. So they're also known as cholinomimetic agonists. There are some examples given here, pilocarpine, muscarine, nicotine. You don't necessarily need to know all these. these names. But clearly what they would do as agonists, so an agonist is something that acts at a receptor, they would mimic the effects of the parasympathetic nervous system so they would promote parasympathetic activity. There is a class of drugs known as parasympatholitic and these include muscarinic antagonists so they would block, well in this case the antagonists would block muscarinic receptors. Antagonist is the term given to compounds which block receptors. Muscarinic antagonists would block muscarinic receptors. And an example of one such compound is atropine, which I'll be saying a little bit more about, in fact, in later slides, because it's actually very interesting. So I'll tell you more about atropine as a muscarinic antagonist and what it does. But clearly, that's going to block the effect. of the parasympathetic nervous system. Then there are a class of drugs known as choline esterase inhibitors. These block the enzyme that breaks down acetylcholine, so they block acetylcholine esterase. And if you are blocking the breakdown of acetylcholine, acetylcholine levels are going to increase, so you are promoting the actions of the parasympathetic nervous system. And then there are a class of what are known as gaseous gases. ganglion blocking drugs. So these can include nicotinic antagonists. So they block the actions of acetylcholine at nicotinic receptors in the ganglia, and so they would inhibit both parasympathetic and sympathetic activity because both of these divisions utilize acetylcholine at the ganglia. the neurotransmitter release from the preganglionic. nerve. So we're moving on then to, I've just picked out the heart and the eye as two examples where we can look at the effects of the parasympathetic nervous system and how knowledge of its... the parasympathetic role in these tissues is useful clinically. So starting then with parasympathetic control of the heart. So here's a heart, and here are the parasympathetic... autonomic nerves. Here's our two-neuron chain, the preganglionic neuron with its cell body, which would be in the cranial or sacral regions of the spinal cord. And here's our second neuron in the chain, our postganglionic neuron. And do you remember I said that for the parasympathetic division, it's really easy to remember because acetylcholine is the neurotransmitter that's released both from the preganglionic neuron and from the preganglionic neuron. and from the postganglionic neuron. So what happens is that when this pathway is activated, acetylcholine is released from the postganglionic neuron, and it acts at muscarinic acetylcholine receptors that are present throughout the heart. And as a consequence, heart function is decreased. decreased. If you want the details, they are spelled out here. So there would be effects on heart rate, a reduction in heart rate, also known as bradycardia. There would be a decrease in contractility of the atrial muscle, so a decrease in the force and duration. There would be a reduction in the conduction of electrical impulses through the atrioventricular nodes, so a decrease in the rate of conduction. and I didn't mention the sinoatrial node is our pacemaker, so that's what's involved in heart rate. But for all of these, the effect of activation of these muscarinic receptors is a reduction in heart function. That is what the parasympathetic division does. It slows your heart rate down. Okay, so that's what it does. Now, knowing that has been really useful clinically. because in individuals have a cardiac arrest, what you can do is add atropine, which is a muscarinic antagonist, a muscarinic receptor blocker. And if you block these inhibitory effects, you will promote heart function, and therefore this can be used to resuscitate somebody. Does that make sense? A few nods. Is that okay? Is that all right? Anybody want me to just run through that quickly, or are you all right with that? Looks like we're okay with that. Okay, so that's as much as I want to say about parasympathetic control of the heart. So for the second example of the effects of the parasympathetic system on an example tissue, we're going to look at its effects on the eye. So we're going to look at the role of the parasympathetic system on the eye. parasympathetic division in controlling pupil diameter and focusing. So just to explain this diagram, which looks a little bit complicated, but it's not. Here's a brain. Here's the brain stem. And what we are considering is our parasympathetic pathway. So we've got a cell body of our parasympathetic preganglionic nerve sitting in the cranial region. There's our first nerve in our series of two. It falls into the parasympathetic brain. And what we're looking at is our parasympathetic forms a synapse within a ganglion. It's actually got a name, the ciliary ganglion. And there's the second nerve in our series of two. Some of these go to innervate ciliary muscle, and some innervate circular muscle, also known as constrictor pupillae, that sit within the eye. Just to orientate you, this is the same eye, but it's just viewed from different angles. positions. So this is looking at the eye face on. There's your pupil, that's the coloured bit of your eye, your iris. And that's the same eye, just looking at it sideways on so we can have a look at the lens. Okay? So parasympathetic fibres, chain of two neurons. What about the neurotransmitters that are released along this pathway? Well, we've already heard that for the parasympathetic pathway, it's simple to remember because it's acetylcholine being released at the ganglion, acting at nicotinic receptors, N for nicotinic, and at the post-ganglionic fibers. Again, it's acetylcholine, but this time acting at muscarinic receptors. In fact, it's M3 receptors. So that's the transmitter. Those are the receptors. Let's look at what happens when this pathway... is activated. So starting then with looking at the effects on pupil diameter. So in the eye, what we have is muscle. It's known as, well, we have two sets of muscle, one of which is the circular muscle. And this is arranged concentrically. So it's arranged in rings. And what happens is that when the parasympathetic pathway is activated, acetylcholine gets released. acts on muscarinic M3 receptors that are on that muscle. That causes the circular muscle to contract. As the muscle contracts, it moves inwards, and you get a constriction of the pupil, and that's known as meiosis. So let's have a look at that. Here's our pupil. Here's our concentrically arranged muscle. It's got parasympathetic... sympathetic fibers, innervating it. It's got lots and lots of muscarinic M3 receptors scattered all over it. So when acetylcholine is released and acts at the muscarinic receptors, that circular muscle is going to contract. It moves inwards, and the pupil constricts. And it could look something like that, pinpoint pupil. That can be quite pronounced. Now, there is some ongoing release of acetylcholine on this muscle, on this circular muscle, all the time. So all the time you have some acetylcholine being released. So if you were to put in a blocker of those receptors, a muscarinic antagonist, for example, acetylcholine, that would inhibit the effect of acetylcholine, that would inhibit the contraction, and what would happen is that the pupil would dilate. And that's known as mydriasis, pupil dilation. That's achieved through blocking endogenous acetylcholine that's released. And this can look something like that when it's pronounced. Any thoughts as... How this could be useful clinically. Why might we want to do this? Why might we want to put atropine in somebody's eye and make them look like this? Any thoughts? Clinical use? Yep. Yep, yep, very good, yeah. So you could look for tumours, you could, for general eye inspection, just have a look down. If you've got any suspicions of things going wrong, this would allow you to have a good look in and see what's going on. The other reason to do this might also be for surgery. If you needed to do some surgery, that could be useful. So, some clinical uses. Okay, so the parasympathetic system then clearly it can control your eye, control your pupil diameter, it can either constrict it or dilate it. And we've just looked at the terms meiosis and mydriasis. So just a little bit more information about atropine for you. So atropine is a muscarinic receptor. that blocked the M3 receptors to cause that dilated pupil. Atropine is a compound that's an alkaloid, so it's an alkaloid, and it can be derived naturally from... a plant known as atropa belladonna also known as deadly nightshade and this used to be an essential part of every lady's beauty makeup kit in the Middle Ages and what they would do is to put atropine into their eyes that would dilate their pupils and that would make them more attractive to the opposite sex and that they is where that name comes from. Belladonna means beautiful lady in Italian, and that's what that name comes from for the plant. It's Latin name, Atropa belladonna. So that's what they used to do, which is all very well and good. However, atropine has other effects. So as we will see, it can impair your ability to focus on things. If you block your your muscarinic receptors in your heart, that can increase your heart rate. And also, it could cause blindness. So some side effects. So a high price to pay then for that. So that's just a little bit of extra. So we are then going to just have a look now at the effects of the parasympathetic nervous system on focusing. So not only does it affect your pupil diameter, it can affect your lens shape. So affect your ability to focus. focus on near or far things. So this is the same eye, but we're looking at it sideways on because we want to look at what happens to the lens under different conditions of parasympathetic stimulation. So in your eye, you've got your lens here. You've got fluid in front of it known as the aqueous humor. This kind of clear bit at the front is your cornea. And then the colored bit is your iris. That's the bit that we've just looked at. It's contractility. Your lens is held in place, suspended by these suspensory ligaments. And they are attached to a layer of muscle known as the ciliary muscle, which is arranged in a circle around the eye. So that's colored in purple there just to highlight it. When that ciliary muscle is relaxed, it pulls out. So it's relaxed, so it's stretching out. And that's stretching. stretches these suspensory ligaments, they become taut. And as they stretch, they flatten the lens. There's a flat lens, and that allows you to focus for distant vision, that's there. When the ciliary muscle contracts, so this muscle colored in purple, when that contracts and moves in, these suspensory ligaments relax, and so the lens gets fatter, it bulges. and that's what allows you to focus for near vision, and that's shown there. And that's known, the technical term for that is accommodation. That allows you to focus for near vision. And if you impede that process, if you block it, if you paralyze it, That's known as cycloplegia. That's a loss of the ability to accommodate. And that's what the ladies putting atropine in their eye had. So just to summarize some of the clinical uses that there are, knowing about the effects of the parasympathetic system on eye function, we've got the fact that we can dilate the pupil using mydriatum. drugs, so muscarinic antagonists, and that's useful in eye inspection and surgery. That would also cause some loss of focusing, so that's something to be aware of as a side effect of cycloplegia. A common condition of the eye, one of the most common treatable causes of blindness is something called glaucoma, which is a buildup of pressure within the eye. the eye due to a buildup of the aqueous humor. And it can be because the fluid is failing to drain out from this canal of Schlem. So the fluid builds up, creates a big pressure within the eye, and it can be due to a lack of drainage. And one of the reasons can be because a dilated iris can block this canal. And so a treatment, a way to treat this is to give a muscarinic agonist. The agonist then constricts the pupil, so meiosis. The pupil moves away from the canal of Shlem as it constricts. That allows outflow of the aqueous humor, and that relieves the pressure within the eye and helps to treat the glaucoma. Another way of approaching the same condition is to give a muscarinic agonist. is through use of anticholine esterases. So these block the breakdown of endogenous acetylcholine, promoting pupil constriction, and similarly allow... allowing the fluid to flow out through the canal of Schlem. So I just want to finish then by thinking about parasympathetic co-transmission. So thus far we've talked about acetylcholine as the neurotransmitter of the parasympathetic nervous system. it is. It's the main neurotransmitter used throughout, used by both the pre- and the post-ganglionic neurons. It's not the only transmitter. There are a number of different neurotransmitters that are used as co-transmitters. One of the best known is vasoactive intestinal polypeptide, or VIP as short. The classic experiments demonstrating its co-transmitter role were carried out in salivary glands of the cat. And basically, the two neurotransmitters are released at different frequencies and can have different effects. Yes. Yes, there are other co-transmitters. So, for example, ATP and nitric oxide are examples. Okay. So, just to finish then, we have what we've done, what you've learned, is about the synthesis of acetylcholine. We've looked at its metabolism. We've looked at acetylcholine receptors. We've focused on parasympathetic control of the heart and eye and finished by looking at co-transmission of acetylcholine. our colon with VIP. Okay, thank you.

We'll look at the main types of cholinergic receptors. So these are the receptors for acetylcholine. And we'll see that there are three different types of muscarinic receptors.

And we'll look at how they are differently distributed in target tissues. And then we will look at the parasympathetic control of the heart and the eye. And we will see how you can use drugs clinically to treat disorders of the eye. And then we will finish by just... Introducing you to a co-transmitter that acts together with acetylcholine, and that's known as vasoactive intestinal polypeptide, or VIP for short.

So just a quick recap then of the parasympathetic division. It's also known as the craniosacral division. Are you happy you know why it could also be known as the craniosacral division, based on the information given in the previous lecture?

Lots of nods there, that's good. So for anybody who's not sure, it's because the cell body of the first neuron in the series of two lies within the cranial or sacral regions of the spinal cord. And that's what defines a nerve as being a parasympathetic nerve. The role of the parasympathetic division is in keeping our body energy use low.

So it predominates in individual... individuals with relaxed states. It keeps your blood pressure and your heart rate and your respiratory rates low. And it keeps your gastrointestinal activity high.

And that's why it's sometimes known as being involved in the rest and digest response. And it has an inhibitory effect on many tissues and organs, not always, but usually. So, this shows then the organization of the parasympathetic nervous system, which we've just looked at. So, I might be a little bit, try to be more concise when I'm describing this. So, what we've got...

is for the parasympathetic division as a part of the autonomic nervous system, we have two neurons in series. For the first neuron in the series, the cell body... lies either within the cranial region of the spinal cord or in the sacral region of the spinal cord, and that's what defines the nerves as being parasympathetic.

For the cranial region, we have many different nerves. Some of these have names, they're very important, so they're given names. So there's the oculomotor nerve, or the third nerve, which innervates smooth muscles of the eye. There's the facial or seventh nerve, which innervates facial glands. And there's glossopharyngeal nerve, which innervates the salivary glands.

And then the very famous vagus or tenth nerve, which innervates many target tissues throughout the body. And then in terms of the sacral outflow, these sacral nerves form synapses in ganglia that are scattered in networks of nerves within the pelvic region. And then the sacral outflow is the sacral nerve. And then we have the postganglionic nerves that innervate the target tissue, and these form the second nerve in the series of two nerves. We can simplify that in this way to show for our parasympathetic pathway, we've got the two nerves in series.

There's the preganglionic nerve shown in red and the postganglionic nerve shown in blue. And I've deliberately made the preganglionic nerve longer than the postganglionic nerve because you may remember that these travel all the way to ganglia that are in the target tissue or near to the target tissue. Preganglios nerves tend to be longer than the postganglios nerves.

The cell bodies of the preganglios nerves sit in the spinal cords, specifically in the cranial or sacral regions, and they receive information from the brain. So within the central nervous system, they get information about... the environment from the brain that triggers a response in this pathway. And then the preganglionic nerve then forms a synapse with the cell body of the postganglionic nerve within the ganglion. And remember, the ganglia are collections of these cell bodies.

Because they're grouped together, they form these swellings that are known as ganglia. And then for the postganglionic neuron, this travels. It's the nerve fibers travel to the effector cell, which could be anything, your heart, your lungs, your eye. And it can branch to increase contact, the surface area for contact with the target tissue. And then on it, we have swellings known as varicosities.

And it's from these that neurotransmitter is released. So we're moving on then to think about the neurotransmitters that are involved in this pathway. And for the parasitic... sympathetic nervous system, it's really easy to remember because the main neurotransmitter that is used throughout, so for both the pre-ganglionic neuron and for the post-ganglionic neuron, is acetylcholine, or ACH for short.

So you've got acetylcholine being released here to act at the cell body and being released from the varicocytes to act at the effector cells. So that's easy, acetylcholine in both cases. What's different is the receptors at which the acetylcholine acts. So at the ganglia, the receptors are a type of acetylcholine receptor known as nicotinic receptors, and at the target tissue, the receptors are receptors known as muscarinic receptors.

So these are the two main types of acetylcholine receptors, and they are different depending on the location. I've deliberately used different symbols for these, and we'll look at this in the next few slides, to indicate that the nicotinic receptors act as ion channels. This is supposed to be a channel.

So these are ion channels. These are receptors act as our own channels. The muscarinic receptors, and again, we'll look at that in a moment, are G protein coupled receptors with a very distinct structure that looks a little bit like this.

Okay. So the main thing to get from this is that acetylcholine is used throughout, but acts at two different types of receptors, which are nicotinic at the ganglion and muscarinic everywhere else, so everywhere else on the target tissues throughout your body. Okay. So we're first of all going to look at the synthesis and the action and the degradation of acetylcholine. at the cholinergic synapse at the ganglia, but also within the varicocytes.

And this should be a bit familiar to you because the pathway is very, very similar to that which we met for the neuromuscular junction. So when we looked at the acetylcholine synthesis and actions and metabolism at the neuromuscular junction, it's essentially very similar to this. So just as a reminder then, at the terminals of the cell or at the varicosities, what we've got is the synthesis of acetylcholine.

So we've got acetyl-CoA from the Krebs cycle and choline from dietary sources is synthesized into acetylcholine under the influence of an enzyme present in the cytosol. And that enzyme is known as choline acetyltransferase. The acetylcholine is...

packaged into vesicles that are within the terminal of the axon and within the varicosages. And we have heard previously that these vesicles are small but contain many thousands of molecules of acetylcholine. And these acetylcholine molecules are released when an action potential invades either this nerve terminal here, or the varicosities. And that acetylcholine that's released then travels across the synapse or the synaptic cleft and acts at cholinergic receptors.

And the acetylcholine can be broken down by an important end. enzyme known as acetylcholine esterase, which removes it from the synapse, and some of the choline that's formed can be taken back up into the terminals and used for resynthesis of acetylcholine. So we've heard all that previously.

So just to draw your attention to the fact that we are now thinking about the receptors at which the acetylcholine acts, and we've just heard that when it... comes to the ganglion the receptors are nicotinic acetylcholine receptors so NACHR is the abbreviation And when it comes to the effector tissue, so that's all of the tissues in your body, your lungs, your heart, your smooth muscle, they are muscarinic receptors, so MACHR for short. So there are two different types of receptors. And that's written out in text there for you down below.

So we've got muscarinic receptors are on your smooth muscle, your glands, etc. there. Okay, so here are the two types of acetylcholine receptors that we've just talked about. These are the main two families of acetylcholine receptors. We've got our nicotinic receptors and our muscarinic receptors. heard that the nicotinic receptors are the ones that are present at the ganglia.

They're also present in the brain. They're also present at the neuromuscular junction, but we're concerned with the autonomic nervous system. considering the effects in ganglia.

And these nicotinic receptors, they are inotropic receptors, so they act as ion channels, which allow the transport of, for example, sodium and potassium ions. The muscarinic receptors are present everywhere else, so throughout all of the target tissues, which the autonomic nervous system innervates, so your lungs, your heart, your eye. Your kidneys, everywhere else, your endocrine glands, exocrine glands. They're also present in the brain, but that's part of the central nervous system, so it's not what we're considering at the moment.

We're thinking about the autonomic nervous system. And these muscarinic receptors are metabotropic receptors, so they are G-protein coupled receptors. And what they do is couple to second messengers to alter movement of ions across the cell membrane.

There are subdivisions of muscarinic receptors. There are M1, M2, and M3 receptors, which are relevant to autonomic function. There are also M4 and M5 within the... brain so we're not going to consider these here so m1 muscarinic receptors are found within the gastrointestinal tract and they can promote gastric acid secretion M2 receptors are found within the heart, and they function to reduce heart rate and force, they reduce heart function.

And then the M3 receptors are present everywhere else, so glands, smooth muscle, and so on. So what we're going to do now is just to help with understanding, is just show you the structures of what these two receptors. look like. So what an inotropic receptor looks like and what a metabotropic receptor looks like. So starting then with the nicotinic receptor.

So here's our cell membrane. And bang in the middle, here we have our nicotinic receptor. So it's a receptor for acetylcholine.

It's one of the two main types of receptor, the other being muscarinic. And what we know is that, well, it acts as an ion channel. So when you have two acetylcholine...

molecules binding to this receptor. You can just about see acetylcholine there. When two acetylcholine molecules bind, it causes a shape change within this protein. It opens up to allow an influx of sodium or potassium, and that goes into the cell to typically cause a depolarization of the postsynaptic cell.

But in other words, it elicits a response. So that's our nicotinic receptor. iron channels. The other type of acetylcholine receptor are the muscarinic receptors, often known as, well, they are metabotropic receptors.

There's a whole range of different metabotropic receptors and muscarinic receptors. Receptors belong to this super family of receptors. So you can see straight away they're very different in structure to the nicotinic receptors.

They consist of a single protein. That's what these amino acids here denote. And this protein winds backwards and forwards through the cell membrane. So it crosses backwards and forwards. And as it does so, it forms what are known as transmembranes.

domains, that's these, and there are seven. If you count them up, you'll see there's seven. So it crosses seven times, and it also forms loops as it does so. So there are extracellular loops, and there are intracellular loops. And basically what happens is that when acetylcholine comes along and binds to one or more of these extracellular loops, that causes a change in the protein, a conformational change.

And that then causes the intracellular loops to attach to G proteins to trigger a second messenger system, which can involve enzymes or ion channels, but basically to release the protein. elicit a response. If you are interested, this is somewhere where you could do wider reading if you are interested, but it's beyond the scope of this module to go into this in any greater detail.

So that's for wider reading if you're interested in exactly how this works. All I need you to know for this module is that the muscarinic receptors are metabotropic, they are a type of acetylcholine receptors, and they... They also are known as G-protein coupled receptors because they're attached to G-proteins. And that's the start of the cascade to elicit a response.

Okay, now, it's really useful to know about these different types of receptors because that knowledge can be exploited clinically to manipulate signaling of the autonomic nervous system. So we can tweak it up, inhibit it, do various things. And that's very, very powerful when it comes to drugs and medicines to help with various diseases. And so just... just want to introduce you to a number of different types of drugs which act at the parasympathetic nervous system.

So what we've got is a category of drugs known as parasympathomimetic. And what these do is they mimic the actions of acetylcholine at its receptors. So they're also known as cholinomimetic agonists.

There are some examples given here, pilocarpine, muscarine, nicotine. You don't necessarily need to know all these. these names.

But clearly what they would do as agonists, so an agonist is something that acts at a receptor, they would mimic the effects of the parasympathetic nervous system so they would promote parasympathetic activity. There is a class of drugs known as parasympatholitic and these include muscarinic antagonists so they would block, well in this case the antagonists would block muscarinic receptors. Antagonist is the term given to compounds which block receptors. Muscarinic antagonists would block muscarinic receptors. And an example of one such compound is atropine, which I'll be saying a little bit more about, in fact, in later slides, because it's actually very interesting.

So I'll tell you more about atropine as a muscarinic antagonist and what it does. But clearly, that's going to block the effect. of the parasympathetic nervous system.

Then there are a class of drugs known as choline esterase inhibitors. These block the enzyme that breaks down acetylcholine, so they block acetylcholine esterase. And if you are blocking the breakdown of acetylcholine, acetylcholine levels are going to increase, so you are promoting the actions of the parasympathetic nervous system.

And then there are a class of what are known as gaseous gases. ganglion blocking drugs. So these can include nicotinic antagonists. So they block the actions of acetylcholine at nicotinic receptors in the ganglia, and so they would inhibit both parasympathetic and sympathetic activity because both of these divisions utilize acetylcholine at the ganglia.

the neurotransmitter release from the preganglionic. nerve. So we're moving on then to, I've just picked out the heart and the eye as two examples where we can look at the effects of the parasympathetic nervous system and how knowledge of its...

the parasympathetic role in these tissues is useful clinically. So starting then with parasympathetic control of the heart. So here's a heart, and here are the parasympathetic...

autonomic nerves. Here's our two-neuron chain, the preganglionic neuron with its cell body, which would be in the cranial or sacral regions of the spinal cord. And here's our second neuron in the chain, our postganglionic neuron.

And do you remember I said that for the parasympathetic division, it's really easy to remember because acetylcholine is the neurotransmitter that's released both from the preganglionic neuron and from the preganglionic neuron. and from the postganglionic neuron. So what happens is that when this pathway is activated, acetylcholine is released from the postganglionic neuron, and it acts at muscarinic acetylcholine receptors that are present throughout the heart. And as a consequence, heart function is decreased.

decreased. If you want the details, they are spelled out here. So there would be effects on heart rate, a reduction in heart rate, also known as bradycardia. There would be a decrease in contractility of the atrial muscle, so a decrease in the force and duration.

There would be a reduction in the conduction of electrical impulses through the atrioventricular nodes, so a decrease in the rate of conduction. and I didn't mention the sinoatrial node is our pacemaker, so that's what's involved in heart rate. But for all of these, the effect of activation of these muscarinic receptors is a reduction in heart function. That is what the parasympathetic division does.

It slows your heart rate down. Okay, so that's what it does. Now, knowing that has been really useful clinically.

because in individuals have a cardiac arrest, what you can do is add atropine, which is a muscarinic antagonist, a muscarinic receptor blocker. And if you block these inhibitory effects, you will promote heart function, and therefore this can be used to resuscitate somebody. Does that make sense? A few nods. Is that okay?

Is that all right? Anybody want me to just run through that quickly, or are you all right with that? Looks like we're okay with that.

Okay, so that's as much as I want to say about parasympathetic control of the heart. So for the second example of the effects of the parasympathetic system on an example tissue, we're going to look at its effects on the eye. So we're going to look at the role of the parasympathetic system on the eye.

parasympathetic division in controlling pupil diameter and focusing. So just to explain this diagram, which looks a little bit complicated, but it's not. Here's a brain.

Here's the brain stem. And what we are considering is our parasympathetic pathway. So we've got a cell body of our parasympathetic preganglionic nerve sitting in the cranial region. There's our first nerve in our series of two.

It falls into the parasympathetic brain. And what we're looking at is our parasympathetic forms a synapse within a ganglion. It's actually got a name, the ciliary ganglion. And there's the second nerve in our series of two.

Some of these go to innervate ciliary muscle, and some innervate circular muscle, also known as constrictor pupillae, that sit within the eye. Just to orientate you, this is the same eye, but it's just viewed from different angles. positions.

So this is looking at the eye face on. There's your pupil, that's the coloured bit of your eye, your iris. And that's the same eye, just looking at it sideways on so we can have a look at the lens. Okay? So parasympathetic fibres, chain of two neurons.

What about the neurotransmitters that are released along this pathway? Well, we've already heard that for the parasympathetic pathway, it's simple to remember because it's acetylcholine being released at the ganglion, acting at nicotinic receptors, N for nicotinic, and at the post-ganglionic fibers. Again, it's acetylcholine, but this time acting at muscarinic receptors.

In fact, it's M3 receptors. So that's the transmitter. Those are the receptors. Let's look at what happens when this pathway...

is activated. So starting then with looking at the effects on pupil diameter. So in the eye, what we have is muscle. It's known as, well, we have two sets of muscle, one of which is the circular muscle.

And this is arranged concentrically. So it's arranged in rings. And what happens is that when the parasympathetic pathway is activated, acetylcholine gets released.

acts on muscarinic M3 receptors that are on that muscle. That causes the circular muscle to contract. As the muscle contracts, it moves inwards, and you get a constriction of the pupil, and that's known as meiosis. So let's have a look at that. Here's our pupil.

Here's our concentrically arranged muscle. It's got parasympathetic... sympathetic fibers, innervating it. It's got lots and lots of muscarinic M3 receptors scattered all over it.

So when acetylcholine is released and acts at the muscarinic receptors, that circular muscle is going to contract. It moves inwards, and the pupil constricts. And it could look something like that, pinpoint pupil. That can be quite pronounced.

Now, there is some ongoing release of acetylcholine on this muscle, on this circular muscle, all the time. So all the time you have some acetylcholine being released. So if you were to put in a blocker of those receptors, a muscarinic antagonist, for example, acetylcholine, that would inhibit the effect of acetylcholine, that would inhibit the contraction, and what would happen is that the pupil would dilate. And that's known as mydriasis, pupil dilation. That's achieved through blocking endogenous acetylcholine that's released.

And this can look something like that when it's pronounced. Any thoughts as... How this could be useful clinically.

Why might we want to do this? Why might we want to put atropine in somebody's eye and make them look like this? Any thoughts? Clinical use?

Yep. Yep, yep, very good, yeah. So you could look for tumours, you could, for general eye inspection, just have a look down.

If you've got any suspicions of things going wrong, this would allow you to have a good look in and see what's going on. The other reason to do this might also be for surgery. If you needed to do some surgery, that could be useful. So, some clinical uses.

Okay, so the parasympathetic system then clearly it can control your eye, control your pupil diameter, it can either constrict it or dilate it. And we've just looked at the terms meiosis and mydriasis. So just a little bit more information about atropine for you. So atropine is a muscarinic receptor. that blocked the M3 receptors to cause that dilated pupil.

Atropine is a compound that's an alkaloid, so it's an alkaloid, and it can be derived naturally from... a plant known as atropa belladonna also known as deadly nightshade and this used to be an essential part of every lady's beauty makeup kit in the Middle Ages and what they would do is to put atropine into their eyes that would dilate their pupils and that would make them more attractive to the opposite sex and that they is where that name comes from. Belladonna means beautiful lady in Italian, and that's what that name comes from for the plant. It's Latin name, Atropa belladonna. So that's what they used to do, which is all very well and good.

However, atropine has other effects. So as we will see, it can impair your ability to focus on things. If you block your your muscarinic receptors in your heart, that can increase your heart rate.

And also, it could cause blindness. So some side effects. So a high price to pay then for that.

So that's just a little bit of extra. So we are then going to just have a look now at the effects of the parasympathetic nervous system on focusing. So not only does it affect your pupil diameter, it can affect your lens shape.

So affect your ability to focus. focus on near or far things. So this is the same eye, but we're looking at it sideways on because we want to look at what happens to the lens under different conditions of parasympathetic stimulation. So in your eye, you've got your lens here.

You've got fluid in front of it known as the aqueous humor. This kind of clear bit at the front is your cornea. And then the colored bit is your iris. That's the bit that we've just looked at. It's contractility.

Your lens is held in place, suspended by these suspensory ligaments. And they are attached to a layer of muscle known as the ciliary muscle, which is arranged in a circle around the eye. So that's colored in purple there just to highlight it.

When that ciliary muscle is relaxed, it pulls out. So it's relaxed, so it's stretching out. And that's stretching. stretches these suspensory ligaments, they become taut.

And as they stretch, they flatten the lens. There's a flat lens, and that allows you to focus for distant vision, that's there. When the ciliary muscle contracts, so this muscle colored in purple, when that contracts and moves in, these suspensory ligaments relax, and so the lens gets fatter, it bulges.

and that's what allows you to focus for near vision, and that's shown there. And that's known, the technical term for that is accommodation. That allows you to focus for near vision. And if you impede that process, if you block it, if you paralyze it, That's known as cycloplegia. That's a loss of the ability to accommodate.

And that's what the ladies putting atropine in their eye had. So just to summarize some of the clinical uses that there are, knowing about the effects of the parasympathetic system on eye function, we've got the fact that we can dilate the pupil using mydriatum. drugs, so muscarinic antagonists, and that's useful in eye inspection and surgery. That would also cause some loss of focusing, so that's something to be aware of as a side effect of cycloplegia.

A common condition of the eye, one of the most common treatable causes of blindness is something called glaucoma, which is a buildup of pressure within the eye. the eye due to a buildup of the aqueous humor. And it can be because the fluid is failing to drain out from this canal of Schlem. So the fluid builds up, creates a big pressure within the eye, and it can be due to a lack of drainage.

And one of the reasons can be because a dilated iris can block this canal. And so a treatment, a way to treat this is to give a muscarinic agonist. The agonist then constricts the pupil, so meiosis.

The pupil moves away from the canal of Shlem as it constricts. That allows outflow of the aqueous humor, and that relieves the pressure within the eye and helps to treat the glaucoma. Another way of approaching the same condition is to give a muscarinic agonist. is through use of anticholine esterases.

So these block the breakdown of endogenous acetylcholine, promoting pupil constriction, and similarly allow... allowing the fluid to flow out through the canal of Schlem. So I just want to finish then by thinking about parasympathetic co-transmission.

So thus far we've talked about acetylcholine as the neurotransmitter of the parasympathetic nervous system. it is. It's the main neurotransmitter used throughout, used by both the pre- and the post-ganglionic neurons.

It's not the only transmitter. There are a number of different neurotransmitters that are used as co-transmitters. One of the best known is vasoactive intestinal polypeptide, or VIP as short.

The classic experiments demonstrating its co-transmitter role were carried out in salivary glands of the cat. And basically, the two neurotransmitters are released at different frequencies and can have different effects. Yes.

Yes, there are other co-transmitters. So, for example, ATP and nitric oxide are examples. Okay.

So, just to finish then, we have what we've done, what you've learned, is about the synthesis of acetylcholine. We've looked at its metabolism. We've looked at acetylcholine receptors. We've focused on parasympathetic control of the heart and eye and finished by looking at co-transmission of acetylcholine.

our colon with VIP. Okay, thank you.

Transcript for:Parasympathetic nervous system - also in Neuro

Transcript for:
Parasympathetic nervous system - also in Neuro