G Protein Coupled Receptors | Nervous system physiology | NCLEX-RN | Khan Academy
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G Protein Coupled Receptors | Nervous system physiology | NCLEX-RN | Khan Academy

November 10, 2019


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.

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  1. I HAVE SPENT 2 YEARS IN MED SCHOOL MANEUVERING MY WAY THROUGH COUJTLESS EXAMS AND VIVAS WITHOUT EVER REALLY UNDERSTANDING THIS! UNTIL TODAY! THANK YOU

  2. From how this is presented, I get the impression that the ligand itself, is not internalized. Is that correct? What happens to it in most GPCRs? Is the most common mechanism that it is released and dependent on other transporters to be terminated as a signal? If anyone has some knowledge about it, I'd appreciate your thoughts. Especially if you have some references to back it up. Kind regards.

  3. Besides the VERY MINOR flaw in remaining zoomed in during a certain segment this was a very succinct and well presented lesson on GPCRs. Thanks for posting it up, it's been a great overview to revising the key concepts.

  4. How hours of boring lectures are made into a 12 min riveting knowledge is always going to be a mystery to me #Khanacademy.
    Thank You for saving my life btw <3

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