- [Voiceover] Hey guys.
This is Dr. Joel with medimmersion.com.
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All right, let's jump into it.
We're gonna talk about the G protein-linked receptors today.
All right, in this lecture we are going to talk about
the G protein-linked receptors
and I'm gonna start off with an introduction,
then go into the structure and function.
I'll talk about the two most important pathways
that you have to know
and then give you a couple of mnemonics
and then a couple of knowledge challenge questions,
and that will be that.
Let's get started.
I'm sure that you've talked about
the G protein-linked receptors in school,
however, you might not have called them
G protein-linked receptors.
They go by other names like
G protein-linked second messengers
or G protein-coupled receptors,
that's a pretty common one.
Even conversationally, a lot of people just say
the G proteins.
I'm gonna break down those words a little bit later
and tell you what each part of it means
and why we use those names
to refer to these proteins.
But first off, what does the G stand for?
Why is it G protein?
Well, the G stands for guanine.
These are guanine nucleotide-binding proteins,
meaning that they bind guanine nucleotides.
Like for example guanosine triphosphate
or its slightly shorter little brother,
guanosine diphosphate.
These receptors are extremely important physiologically.
We use them all over our body
and they do all kinds of different functions.
These receptors are only found in eukaryotes
and are the target of about 40%
of all the drugs we use in medicine today.
I just told you that they're very diverse in function
however, there's two main signal transduction pathways
that you got to know, you have to know them for your boards
and that is the cyclic AMP-dependent pathway
and the phosphatidylinositol signal pathway, okay?
I'll talk about those more in a little bit.
First, let's jump into the structure
and function of these things, it's pretty cool.
I told you that I was going to breakdown the names
so that you can understand the concepts
a little bit better.
First off, let's get started with
what does the word "G proteins" mean?
Well, the G proteins are a component
of this receptor system.
The G proteins are heterotrimeric GTP-binding proteins
made of three subunits, hence, heterotrimeric.
First there's the alpha subunit, then the beta subunit
and then the gamma subunit.
And you should also notice from my illustration here
that the beta and gamma subunits
are more tightly linked together
than the two are to the alpha subunit.
Actually the beta and the gamma stay connected
where the alpha subunit separates itself in normal function.
These G proteins live on the
intracellular side of the cell membrane
and are attached to or connected to
the cell membrane itself by lipid anchors.
The next thing for us to talk about is to define
what are the G protein-coupled receptors?
Well, these are receptors that live in the membrane
and in fact, they pass through the membrane
seven times which is an important number,
you might be tested on it.
All right, so these G protein-coupled receptors
interact with the G proteins
and cause oftentimes a confirmational change
so that the alpha subunit of the G protein
can accept different nucleotides.
What about the term G protein-linked second messengers?
Well, that's another component of this system
which are cellular target-proteins or enzymes
that perform some kind of function
when they interact with the G proteins
that we've already talked about.
Now they are very diverse but as I said in the beginning,
there's two main pathways or two main targets
that cause a pathway that you have to understand.
And those two are the cyclic AMP-dependent pathway
and the phosphatidylinositol signal pathway,
which I abbreviate here as IP3/DAG pathway.
Right now you're probably thinking,
Dr. Joel, I have no idea what you're talking about.
Don't worry, I will show you the whole thing working
and we'll talk about the parts as we go,
and I'm pretty sure that it will make sense
after we go through it.
First, we have to set the stage a little bit.
The G proteins or more specifically,
the alpha subunit of the G proteins
is bound in its resting state to
guanosine diphosphate or GDP.
In this state, the receptor is just sitting and waiting.
On the extracellular side of the cell membrane,
a ligand comes and it binds with the
G protein-coupled receptor causing a confirmational change.
The confirmational change allows the alpha subunit
to bind with guanosine triphosphate
and release the guanosine diphosphate.
Now, the G proteins are active
and as active G proteins, they do a couple of things.
First off, the alpha subunit separates itself
from the beta gamma complex.
This kind of frees it up a little bit
so it's free to move around.
It's still attached to the membrane by a lipid anchor
but the lipid anchor can kind of swim through the membranes.
It's able to move to the target.
It moves the target and it causes the target
protein or enzyme to change in some way.
Either the G protein interaction causes the target to
speed up what it's doing or slow down what it's doing
or stop what it's doing.
It does something to the target protein.
In this case, I'm gonna say that this target enzyme
gets activated by the alpha G protein here.
And once it's activated, it produces a product
and that product goes off and does another job
so it becomes a second messenger.
All right?
The next logical question would be
what stops this process?
Obviously, it doesn't run on forever.
Well, inside the cell there's GTPases and they come
and they hydrolyze the GTP back into GDP
which deactivates the target enzyme,
and separates it from the alpha subunit.
Which allows the alpha subunit to go back to its friend,
the beta gamma complex
and the G protein-coupled receptor,
resetting itself and the process can now start all over.
In order to understand the pathways,
let me first show you that there is a difference
in some of the G proteins, specifically the alpha subunits.
Depending on which pathway that we're talking about,
we're actually using different G proteins.
In the cyclic AMP dependent pathway
which I'll use as my first example,
we'll use two, two different kinds of
G alpha proteins.
The first one is G alpha sub s
and in conversation, most people will just call this
the Gs or the Gs protein.
It's stimulatory so it increases
the activity of this pathway.
The next one on the cyclic AMP-dependent pathway
is the G alpha sub i
and we just call that Gi most of the time.
That particular G protein is inhibitory to this pathway.
It decreases the activity.
On the other side, with IP3/DAG,
the G alpha protein we're using there
is G alpha sub q or just Gq.
Let's get into a little bit more detail
on both of the pathways
and how they work exactly
starting with the cyclic AMP pathway.
I've already told you that the Gs is stimulatory
and the Gi is inhibitory.
But the rest of the pathway is the same.
We start with our G protein-coupled receptor
as the whole unit.
When that receptor is stimulated,
we know that the alpha subunit
exchanges GDP for GTP
and then migrates the membrane
to act on its target enzyme.
What target enzyme is that?
Well, that's adenylyl cyclase.
Does that make sense?
What does that do?
Well, this enzyme converts ATP into cyclic AMP
and then cyclic AMP goes on
to activate protein kinase A
which is an important enzyme in
several other metabolic pathways.
And I'll show you a little bit more detail on
protein kinase A in just one second.
What about Gi, what does the Gi protein do?
Well, it would also begin with a receptor.
It would be slightly different remember
because it would be a GI receptor,
but it would just have an inhibitory effect
on adenylyl cyclase which would decrease
the production of cyclic AMP.
And thus, decrease the activation of protein kinase A.
You just need to know that one increases it
and the other decreases it, it's easy.
How are you gonna remember this diagram?
Well, I think of it as a gigantic D and an L.
Why D and L?
Because adenylyl has both a D and an L.
Next in our discussion is the IP3/DAG pathway
or the IP3/DAG pathway,
or you might hear it called
the phosphatidylinositol signal pathway.
We go what? That's a big name.
Yeah, so let's just say IP3/DAG.
The IP3/DAG pathway uses
Gq protein-coupled receptors
and the target enzyme is a membrane-bound enzyme
called phospholipase C.
What does phospholipase C do?
Well, it is bound to the cell membrane
and it actually uses parts of the cell membrane
to make its second messengers.
It takes some of those molecules called PIP2
or phosphatidylinositol 4 5-bisphosphate,
and it breaks that molecule down into two parts.
The first part is IP3
inositol 1,4,5-trisphosphate.
IP3 is released into the cytosol of the cell
and it goes long and activates receptors
in the smooth endoplasmic reticulum,
which opens calcium channels
and thus liberating calcium.
And we all know that calcium has a very strong
role in changing the physiology
in a lot of things in a cell.
That's one mechanism by which this receptor works.
The second half is the DAG half or diacylglycerol.
Diacylglycerol remains in the cell membrane,
it doesn't migrate to the cytosol like the IP3.
However, now that its structure has been changed
by the phospholipase C,
it can interact with another enzyme called protein kinase C.
And protein kinase C for its part
activates other pathways by phosphorylating
different cytosolic proteins.
And I will show a little bit more detail on that
in the next slide
but for now, how do I remember this?
Well, I think of a fork like a dinner fork,
like what you would eat with
because that's just what it looks like to me.
And now for a couple of real quick words
on the IP3/DAG pathway just so that you can see it.
As we've already talked about,
our Gq protein comes and it activates phospholipase C.
Phospholipase C takes PIP2
which is already in the membrane
and it cleaves it making IP3 and DAG.
IP3 is free to roam through the cytosol
where it eventually activates calcium channels
on the endoplasmic reticulum.
This releases calcium and calcium
has an effect on a lot of different things in the cell.
DAG on the other hand, it stays in the membrane
because it still has those hydrophobic chains
or tails which keep it anchored to the membrane.
DAG helps to activate protein kinase C
and protein kinase C can phosphorylate
other proteins or substrates,
and the signal process is perpetuated.
Okay? Cool.
And now into the mnemonics about
how you're gonna remember all these stuff
and vomit it back up on your tests, okay?
Starting with the IP3/DAG pathway.
You absolutely have to know
that the Gq protein is associated with this pathway.
What about all the receptors that use a Gq protein?
This is also high yield.
I like the mnemonic and I used
the mnemonic when I was in school, "HAVe 1 M&M"
which is written out like this.
For the histamine receptors, the adrenergic receptors,
the vasopressin receptors and the M is for muscarinic,
a.k.a, the cholinergic receptors.
On the other side.
The cyclic AMP two G proteins, what are they?
Gi and Gs, you got to know it.
You have to know it, very, very important.
For the Gi, you're gonna remember "MAD 2s," okay?
For the cholinergic, adrenergic
and dopamine2 receptors, sub type twos.
For the Gs, it's everything that's left over.
Beta-1, beta-2, dopamine1, histamine2
and vasopressin2.
If you need to review what those receptors are
or what they do, here are some links.
Let's go check out the next mnemonic.
All right, so now into mnemonic number two
and what you're gonna need to do on your scrap paper
or in your mind is write out
all of the receptors that are high yield which are these.
The alphas, the betas.
Those two together being the adrenergics.
The muscarinics or the cholinergics,
whatever you want to call them.
Dopamine receptors, histamine receptors
and vasopressin receptors.
Using the first mnemonic that I taught you,
you could fill in each one of the Gq proteins
that are associated with each of these receptors.
But here's another way just in case you like it better
and the mnemonic here is
KISS and KICK until you're SICK of SEX.
which is written our like this.
See that?
KISS and KICK until you're SICK of SEX.
And there you have it.
Each receptor lined up with the type
or the sub type of Gq protein that goes with it.
And for your added viewing pleasure
here are a couple of shortlists about what
each of these receptors contribute to
in our bodies physiologically.
Okay, knowledge challenge number one.
A 16-year old male presents to your emergency room,
he's short of breath and wheezing.
His mother's with him and she's frantic,
and she tells you that he recently lost his inhaler
but she can't remember what it was.
However, because you are such an awesome medical student,
you immediately identify this medical condition as asthma,
and you realize that the inhaler
was a beta2-agonist
used to cause bronchodilation.
Which G protein-coupled receptor are we talking about?
Gs is the correct answer
so if that's what you picked, good job.
Remember, you can write it out
by either of the two mnemonics that we used.
Knowledge challenge number two.
Which membrane associated enzyme
is the target of the Gs protein?
Well, that would be C, adenylyl cyclase.
It also happens to be the associated enzyme
with the Gi protein, right?
What about protein kinase A?
Well, protein kinase A is the final step
in the cyclic AMP pathway.
Any idea about protein kinase C?
Well, that's one of the final steps in the IP3/DAG pathway.
How about phospholipase C?
Phospholipase C is the target of the Gq protein
and it is a membrane-bound enzyme
that cleaves PIP2 into IP3 and DAG.
All right. Good job.
Hey guys, thanks for watching this video.
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Good luck.