- [Voiceover] The Cholinergic Receptors.
This is a high-yield topic.
You really need to understand this when you're going into
your boards or exams.
These receptors are found in the central and peripheral
nervous systems, and they use Acetylcholine
as their neurotransmitter.
Thus, they can also be referred to
as Acetylcholine Receptors, and their abbreviation
is ACh for Acetylcholine and R for Receptor.
There are two main types of these Cholinergic Receptors:
the Nicotinic Acetylcholine Receptors
and the Muscarinic Acetylcholine Receptors.
The Nicotinic Acetylcholine Receptors are named such
because they are responsive to both Acetylcholine
and Nicotine.
They are ionotropic receptors, meaning that they are
ligand-gated ion channels.
When stimulated by their neurotransmitter,
they themselves become an ion channel.
The Muscarinic Acetylcholine Receptors, on the other hand,
are named such because they are responsive
to Acetylcholine and Muscarine.
They are a different kind of receptor.
They're what's called a Metabotropic Receptor,
meaning that they act through a second messenger system,
which in this case refers to the fact that they
are G protein-coupled receptors.
Let's talk about the Nicotinic Cholinergic Receptors first,
and this is abbreviated the same as what we've seen,
AChR, except now with an "n" in front of it
to denote Nicotine.
So the Nicotinic Cholinergic Receptors, they're directly
linked to ion gated channels, as I previously said.
There is no second messenger system here.
The receptor is a physical part of the ion channel.
These ion channels are made of five subunits,
and they're arranged symmetrically around
a central pore through which ions travel when opened.
Also, each of these five subunits is made of four domains,
which we might talk about later.
However, it's not necessarily high-yield right now.
When stimulated by either Acetylcholine or,
remember, these are Nicotinic Cholinergic Receptors,
so either Acetylcholine or Nicotine can stimulate them,
there is an initial stimulation, an initial opening,
followed by a blockage or a refractory period.
This is important and interesting to talk about
because it's related to how some of the drugs work
that we will talk about in other lectures.
Let me give you a quick visual example of what is happening
when these receptors are stimulated.
I am going to place two molecules of Acetylcholine
on the screen and then two separate ions,
and these ions can be Sodium, Potassium, Calcium,
and so forth.
So what is going to happen is that the Acetylcholine
molecules are going to come down and interact
with the receptor/ion channel.
This is going to cause a conformational change in the shape
of the ion channel, which is going to open the central pore
to allow ions through.
Let's take a look.
Kind of interesting, isn't it?
Let me repeat this a couple of more times.
Kind of neat how that works, huh?
Well, as if we didn't have enough abbreviations to remember,
I have to add two more, unfortunately.
There are two sub-types
of the Nicotinic Acetylcholine Receptors:
the Neuronal-type, abbreviated Nn,
and the Muscle-type, abbreviated Nm.
The Neuronal-type is found in both the central
and peripheral nervous system, and it is most often
found "Up-Stream" in the nervous system,
from other receptor types.
So take for example the sympathetic nervous system
and the associated Adrenergic Receptors.
For a sig to get through to the Adrenergic Receptors,
it must first travel through
a Neuronal-type Nicotinic Receptor
in an "Up-Stream" ganglion or nerve.
The Muscle-type Nicotinic Receptors are found
post synaptically in the Neuromuscular Junctions,
and they are responsible for our skeletal
muscle contraction.
They are what let us move and breathe consciously.
So keep these two subtypes in mind.
At the end of this lecture, I will give a picture
and an example and walk you through where they are.
But for now, let's skip on to the Muscarinic Receptors.
Okay, so the Muscarinic Receptors are a little bit different
than the Nicotinic Receptors.
First of all, they're named Muscarinic Receptors because
they are responsive to Acetylcholine and Muscarine.
Also, they use a second messenger system
to propagate the signal.
In this case, it's the G protein-coupled receptors.
I am not going to go into great detail
on the G protein-coupled receptors.
There will be a separate lecture for that.
However, just as an overview, let me walk through
what's happening.
This picture on the right represents six basic steps
of a G protein-coupled receptor.
Let's zoom in on step one.
Okay, what we have here is the receptor within the membrane
of the cell.
The brown oval near the top represents the ligand.
In this case, we're talking about Acetylcholine
or Muscarine.
The ligand binds to the receptor and induces
a conformational change.
This conformational change activates the alpha sub unit,
which then exchanges its GDP for GTP.
This allows the alpha subunit to disassociate
from the beta and gamma subunits and interact
with other intracellular proteins which continues
the signal transduction.
Then the next step to reset the receptor is that the ligand
is released from the receptor, and the alpha subunit
reattaches to the receptor.
So you can see that this receptor works completely different
from the Nicotinic Cholinergic Receptors.
And, again, just as a reminder, this was in no way
a detailed explanation of the G protein-coupled receptors.
If you need more information, another video is coming.
So just as there were two subtypes
of the Nicotinic Cholinergic Receptors, there are subtypes
for the Muscarinic ones as well.
There's actually five subtypes
of Muscarinic Cholinergic Receptors.
However, only three of those are high-yield,
so those are the only three that I'm going to cover.
M1, M2, and M3 are the high-yield Muscarinic Receptors.
Starting with M1, M1 is a Gq protein-coupled receptor.
It increases exocrine gland secretions,
such as increasing the saliva that we produce in our mouth,
and also increasing the stomach acid that we produce.
M1 receptors are also found in the central nervous system
where they're thought to play a role in the way
that we form memory.
M2 receptors are Gi protein-coupled.
What I want you to think of when you think M2
is increased heart parasympathetic effects,
and that would be a decrease in the chromotropy,
inotropy, and dromotropy of the heart.
M3 receptors, well, they're Gq protein-coupled,
so the odd numbers here: one, three, and five,
are Gq protein-coupled receptors, while M2 and M4
are Gi protein-coupled.
What I want you to think of when you think of M3
is an increase in the classic parasympathetic effects,
such as an increase in bronchoconstriction,
an increase in endocrine and exocrine secretions.
So that's the rest and digest of the parasympathetic system.
Increase in eye accommodation, and an increase
in vasodilation.
So next, how about we put all of these receptors,
including the Nicotinic Receptors, on one picture
and talk about where all of them are?
All right?
All right, let's do it.
Let's put it together.
These two pictures, I think, are really cool pictures.
They've got a lot of good detail, and I think they're great
to study from.
I didn't create these images.
If you want to go find them yourself for printing them
and studying from them, I've got some links
on the side for you.
The picture on the left represents
the parasympathetic nervous system,
and the picture on the right is kind of an overlay
of the same picture, but it represents
the sympathetic nervous system or the sympathetic fibers.
Now, remember, we're talking about receptors.
We're not necessarily talking about nerve types,
just receptors.
So starting with the parasympathetic nervous system,
the picture on the left, let's zoom in on a couple
of these organs: the heart, the bronchial tree,
and the stomach.
So starting with the heart,
which of the Cholinergic Receptors are found here?
At this location, you're going to find
the Nicotinic Receptors.
Which subtype of Nicotinic Receptors?
The Neuronal Nicotinic Receptors.
What about here?
Remember, this is the parasympathetic nervous system
that we're talking about right now.
These are going to be Muscarinic Receptors, okay?
But which subtype of Muscarinic Receptors?
Well, that's a little bit of a tricky question.
It's not cut and dry.
But generally, if you remember the previous slide,
we talked about the M2 receptors, you can generally
think of as increasing the parasympathetic tone
on the heart.
So an increase in parasympathetic tone equates
to a decrease in chromotropy, inotropy,
and dromotropy.
Next, how about the bronchial tree,
which receptor is found here on this new green dot?
Again, this is a Nicotinic Receptor.
Nicotinic Receptors are found before Muscarinic Receptors.
Which subtype of Nicotinic?
Neuronal, Neuronal Nicotinic Receptors.
What about here?
Again, there will be a little bit of variation,
but generally, but think back to the previous slide.
M3, the M3, the Muscarinic Acetylcholine Receptor,
subtype M3, are generally associated with the classic
parasympathetic effects, one of those being
bronchial constriction.
Next, which is this?
There's a pattern here.
I hope you're picking up on the pattern.
This is a Nicotinic Receptor again.
Which kind?
A Neuronal Nicotinic Receptor.
Again, Nicotinic Receptors always come before
other types of receptors.
What about this one?
Okay, so this is a little bit tricky.
If you remember the previous slide, there were two
different subtypes of Muscarinic Receptors
that could increase the production of exocrine secretions.
That was M1 or M3 of the Muscarinic type.
Pretty cool, huh?
Now, let's move over and talk about
the sympathetic nervous system, and I'm going to pick
on the same organs, okay?
So which receptors are found here?
Nicotinic, Neuronal Nicotinic.
It's a pattern.
Neuronal Nicotinic Receptors are found first
in the chain.
Other types of receptors are found later.
What about here, on the heart?
Remember, this is the sympathetic nervous system.
A little bit of a trick question.
I need you to think outside of the box.
These are going to be the Adrenergic Receptors,
not covered in this lecture.
Do you remember those?
Alphas and beta receptors, usually stimulated
by Norepinephrine, okay?
Next, which receptor is this?
Easy, right?
Neuronal-type Nicotinic.
And here?
Well, again, this is the sympathetic nervous system,
so it's going to be an Adrenergic Receptor.
That's going to decrease the production
of stomach acid so that more energy can be used
for the fight or flight response.
Lastly, something that isn't shown very well,
the skeletal muscle system.
Which receptors are found here?
Nicotinic Receptors, but what kind of Nicotinic Receptors?
Those are going to be the Muscle-type Nicotinic Receptors.
That's pretty cool, huh?
All right, good job, guys.
Okay, guys, time for a little friendly Knowledge Challenge.
No pain, no gain, right?
So the way this is going to work is I am going to flash
a drug name on the screen, and I want you to think about
what that drug does, as far as its mechanism of action,
its therapeutic use, and also its side effects.
If you don't know all the answers, that's okay.
You can pause the video.
You can think about it, or you can just learn from it.
You don't have to know the answers.
Okay, are you ready?
Let's go.
First drug: Bethanechol.
Bethanechol is used for post-op neurogenic ileus
and also urinary retention in the case of an atonic bladder.
What is its mechanism of action?
Well, Bethanechol is a muscarinic agonist.
Structurally, it's very similar to Acetylcholine.
However, there are some small changes
to some side groups that allow it to be selective
from Muscarinic Receptors and also blocks it
from being hydrolized by Acetylcholinesterase.
Let's zoom in on our picture and see the location
of the mechanism of action.
All right, there it is, the little green circles.
This is where it's working.
It is stimulating things.
It's making things move.
It's making things contract.
Can you see how that would work for both
post-operative ileus and also an atonic bladder?
Okay, so the side effects now, and I'm going
to read this list off from a well-known drug reference.
I'm not making this up, folks.
Urinary urgency.
Isn't that why we're taking the drug?
Diarrhea.
Again, isn't that why we're taking the drug?
How about abdominal cramping, increased gastric motility,
bronchial constriction, hypotension.
Are you starting to see something interesting here?
This is the cool thing about understanding drugs
and their mechanism of action.
If you really understand the mechanism of action,
you don't have to memorize all the side effects.
They intuitively make sense.
We gave this person or this imaginary patient
a muscarinic agonist.
There are Muscarinic Receptors all over the body
in a lot of different systems.
We're stimulating all of them.
There is also increased salivation, lachrymation,
and myosis.
Isn't that cool?
Just taking the extra work to really understand
what a drug does and where it works can save you
a lot of headache in memorizing side effects.
Hey, guys, this is Joel.
Thanks for all the good comments on the other videos,
and the emails, and your support.
Hey, look, if you've got something to say,
if you've got a question, leave me a comment.
I'll get back to you as soon as I can.
Like me, subscribe to me, and as always,
good luck in school.