G Protein Coupled Receptors

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.