Voiceover: In this video we're gonna talk about
G-protein coupled receptors.
Also known as GPCRs.
G-protein coupled receptors
are only found in eukaryotes
and they comprise of the largest known class
of membrane receptors.
In fact humans have more than 1,000 known
different types of GPCRs,
and each one is specific to a particular function.
They are a very unique membrane receptor
and they are the target of around
30 to 50% of all modern medicinal drugs.
In fact, the ligands that bind
range from things like light sensitive compounds
to odors, pheromones, hormones
and even neurotransmitters.
GPCRs can regulate the immune system, growth,
our sense of smell, of taste,
visual, behavioral and our mood.
Including things like serotonin and dopamine.
Even now many G-proteins and GPCRs
still have unknown functions
and is a topic heavily researched.
In fact, in just 2012, a Nobel Prize in chemistry
was awarded for research on GPCRs.
To start off let's talk a little bit about
the structure of GPCRs.
It's impossible to really have a discussion about
how GPCRs work without having an understanding of
what they look like.
The most important characteristic of GPCRs
is that they have seven transmembrane alpha helices.
If we have this being our cell membrane
and we have this being the extracellular side,
and this being the intracellular side,
if we have a GPCR, a G-protein coupled receptor
it will span this membrane seven times.
Let's say it starts here
and we got one, two, three, four, five, six, seven.
This is one of the most important characteristics
of a GPCR.
They have seven transmembrane alpha helices.
Since this is such a unique
and interesting structural characteristic,
we often also call GPCRs "7 transmembrane receptors."
Just to quickly label this is our GPCR here.
As the name implies GPCR interact with G-proteins.
They're coupled with G-proteins.
Now it's important to talk a little bit
about the structure of G-proteins also.
G-proteins in general are specialized proteins
which have the ability to bind GTP and GDP.
In other words they are able to bind guanosine triphosphate
and guanosine diphosphate.
Hence the name G-proteins.
Now some G-proteins are small proteins
with the single subunit.
However when we talk about GPCRs
all of G-proteins that associate with GPCRs
are heterotrimeric.
Meaning that they have three different subunits.
Three sections.
I'm gonna go ahead and draw this out.
The first section we call the alpha subunit.
The first subunit or section of this protein
we call the alpha subunit.
The second we call beta
and the third we call gamma.
All three of these together
they are alpha, beta and gamma subunits together
is our G-protein.
You'll notice that I drew the alpha and gamma subunits
with a little tail-looking thing in our cell membrane
and the reason why is because these are two subunits,
our alpha and gamma
which are attached to the cell membrane
by what we call lipid anchors.
Now the final thing about this picture
that I need to draw in
is our GDP or GTP.
As we remember, the whole point of a G-protein
is because it binds GTP or GDP.
Right now this protein is inactive
and so it binds GDP, guanosine diphosphate.
This GDP binds to the alpha subunit.
When this protein becomes activated
and we'll talk in just a second how that happens,
it will actually bind GTP instead.
Now that we've drawn out
our actual picture of our G-protein
let's talk a little bit about
how our signalling pathway actually happens.
That's the whole point of membrane receptors
is that they respond to signalling molecules and ligands
and they respond to the environment.
As we mentioned before,
G-protein coupled receptors
interact with a wide variety of molecules
on the outer surface of cells.
Each receptor binds to usually one
or just a few very specific molecules
fitting together like a lock and key.
If we pretend that our signalling molecule is
a circle like this,
the shape in which it should bind to the GPCR
should be complementary.
When this green signalling molecule
binds to our GPCR,
our GPCR will actually undergo what we call
a conformational change.
Its shape of this GPCR will change
which in turn triggers a complex chain of events
which will ultimately influence different cell functions.
As we mentioned, our first step here
is of course the ligand,
the signalling molecule has to bind to our GPCR.
Once this ligand binds
our GPCR is going to undergo
a conformational change.
Let's just go ahead and redraw our GPCR.
Again, one, two, three, four, five, six, seven.
Our seven alpha helices.
Now it's a little tougher to draw a conformational change
but the protein is actually gonna
look completely different.
Here, because of this binding
we're gonna have a conformational change.
The protein confirmation of a GPCR will alter.
Let's just write out our first two steps real quick.
Step one, we have the ligand binds to our GPCR.
Step two, we said that we undergo
a conformational change.
Our GPCR undergoes conformational change.
What happens next is because of this conformational change
our alpha subunit which I'm gonna draw in here
is actually going to exchange this GDP for GTP.
Just keep track step three.
Our alpha subunit exchanges GDP for GTP.
The molecule is swapped out.
Instead of GDP we have GTP.
Now because we have GTP bound to this alpha subunit
it will now cause our alpha subunit to dissociate
and move away from our beta and gamma subunit.
Now once this happens,these two different sections,
our alpha subunit and our beta-gamma dimer,
these two together
are actually going to find a protein in the membrane.
It's going to alter and regulate the function
of that protein.
We could have another protein for example here
that the alpha subunit will find
and regulate the function.
Let's go ahead and write this up.
Step four, our alpha subunit
dissociates and regulates target proteins.
Now during the step there are a few things I like to note.
The first is that both the alpha subunit
and the beta-gamma dimer
can interact with other proteins to relay messages.
We're gonna focus in on the alpha subunit
because it tends to be more common and more ...
However, the beta-gamma subunits can still
regulate functions of other proteins.
The target proteins can be enzymes
that produce second messengers
which we'll talk a little more about in a second,
or ion channels that also let ions be second messengers.
As we mentioned G-proteins are incredibly diverse.
Some G-proteins can stimulate activity
while others can also inhibit.
Now step five.
Once this alpha subunit activates a target protein,
this target protein can then relay a signal.
As long as this ligand is bound to the GPCR
this process whereas alpha subunit dissociates,
looks for a protein and regulates that target protein
causing a whole chain of events can happen repeatedly
as long as this ligand is bound.
Now how can we actually make this thing
go back to normal?
Well, step six is that our GTP is hydrolyzed to GDP.
Our GTP loses a phosphate in hydrolysis
and becomes GDP.
Once this happens, everything goes back to normal
and the ligand will leave,
and everything will go back to looking the way it was
and ready to combine with another ligand in the future.
This often happens on its own.
Eventually the GTP will be hydrolyzed and become GDP
though our body actually has a few ways to regulate this.
One common way out of a few is the RGS protein.
Which is regulation of G-protein signalling
and this can accelerate the step.
Now that we actually know the steps to this
let's talk about an example.
A very common example of GPCR function in our cell
actually involves epinephrine or adrenaline.
This is our fight or flight response.
Let's pretend that this green ligand,
this green signalling molecule is epinephrine,
and let's pretend that our GPCR
is our adrenergic receptor.
Once this epinephrine binds to our adrenergic receptor
our GPCR in our body that binds epinephrine,
this adrenergic receptor
will undergo a conformational change.
It will swap out this GDP on this alpha subunit for GTP
and this alpha subunit will now seek out this other protein
and regulate its function.
It just so happens that the protein that it seeks out
is going to be called adenylate cyclase.
Now we have adenylate cyclase being activated
stimulated by our alpha subunit.
What the adenylate cyclase will do
is it will take ATP, adenosine triphosphate
and it will produce cAMP.
Cyclic adenosine monophosphate.
It will take away two phosphates from our triphosphate
and it will make it monophosphate.
Once this happens, our cyclic AMP here
is what we call a second messenger.
Our signal or epinephrine goes through this entire process
and the signal is transformed into another signal.
The cyclic AMP which is now inside our cell.
This cyclic AMP will now tell our cell to do other things.
For example is that it will increase our heart rate.
It will also dilate our skeletal muscle blood vessels.
Remember fight or flight.
We need to start running or fighting.
Our muscles are going to have their blood vessels dilate.
Finally, all of these process
is gonna require a lot of energy
so we're gonna actually breakdown glycogen to glucose.
Now remember this is our biggest group
of cell membrane receptors.
It's a pretty complicated process.
Just go over it again.
For example, our epinephrine binds to our GPCR.
This GPCR then changes its shape
and undergoes a conformational change.
It switches out the GDP to GTP on the alpha subunit
which causes our alpha subunit to dissociate
which will then regulate another protein
and this protein will turn ATP into cyclic AMP
which is our second messenger
and this second messenger will now tell our body
to do other things for example increase heart rate,
dilate blood vessels, breakdown glycogen into glucose.
Now other GPCRs in our body,
the other 1,000 are going to do other things
but undergo a similar process.
In summary, GPCRs are a large, diverse family
of cell surface receptors
that respond to many different external signals.
Binding of our signalling molecule or our ligand
to our GPCR results in G-protein activation
which then triggers the production
of other second messengers.
Using these sequence of events,
GPCRs can regulate an incredible range
of bodily functions from sensation to growth
to even hormone response.