G protein-Coupled Receptors - Online Tutor, Practice Problems & Exam Prep

G protein-coupled receptors (GPCRs) are integral membrane proteins characterized by seven transmembrane alpha helices. Upon ligand binding, GPCRs undergo a conformational change, activating associated G proteins, which can be stimulatory (G_s) or inhibitory (G_i). G proteins consist of three subunits: alpha, beta, and gamma. The activated alpha subunit interacts with effector enzymes to produce secondary messengers, crucial for signal transduction pathways that lead to cellular responses. Understanding these components is essential for grasping cellular communication mechanisms.

G protein-Coupled Receptors

In this video, we're going to begin our lesson on G protein coupled receptors. And so already in our previous lesson videos, we briefly introduced G protein coupled receptors. And so from those older videos, we know already that G protein coupled receptors are commonly referred to as just GPCRs for short. And so we can go ahead and put GPCR here in this blank. Now these G Protein Coupled Receptors or GPCRs, as their name implies with the receptor right here, are really just receptors themselves. But more specifically, these are receptors that will associate themselves or couple themselves with what's known as a G protein. Now we'll introduce exactly what a G protein is a little bit later in this video, but for now bear with me here, that the G protein coupled receptors are just receptors themselves that associate or couple themselves with something called a G protein. Now the G protein coupled receptor or GPCR, because it is a receptor itself, of course, we know that it is an integral membrane protein. But more specifically, these GPCRs are integral membrane proteins that consist of 7 transmembrane alpha helices or 7 transmembrane segments or TMS for short. And so sometimes you'll see that these GPCRs are referred to as 7 TMS proteins, because again, they have these 7 transmembrane alpha helices. And so if we take a look at our images down below over here on the left-hand side, notice that we're showing you 3 different representations of a GPCR. Notice that we're showing you one up here, we're showing you another right here, and we're showing you our third down below, and so we'll explain this here very shortly.

Now the top left representation of the GPCR, clearly you can see that the GPCR has these 7 transmembrane alpha helices right here. And recall that the alpha helices can actually sometimes be abbreviated as these cylinders that you see right here. And so, you can see that we've colored these 7 transmembrane alpha helices different colors just to help you guys distinguish them a little bit easier. And so again because GPCRs have 7 transmembrane alpha helices, they're sometimes called 7 TMS proteins. Now what's also important to note about these GPCRs is that they actually have an extracellular N terminal and an intracellular C terminal. And so if you take a look down below at this same representation right here, what you will notice is that the outside of the cell is this blue background up above and the inside of the cell is this yellow background down below. And so, of course, we know that the extracellular space is going to contain the N terminal domain. And so we can go ahead and fill in the N terminal here to remind us that it's going to be on the extracellular side on the outside of the cell. And of course, the intracellular side, the inside of the cell, is going to contain the C terminal domain of this GPCR protein.

Now, down below, what we have is our third representation of the GPCR, and really this representation that you see down below is the representation that we're going to use here at Club Clutch Prep to symbolize the GPCR because it's a more simplified, clean looking version. And later, once things start getting more and more complicated, you're going to appreciate having a more simplified version here. But just because we're using this more simplified version of the GPCR moving forward in our course, does not mean that you can forget about these important features of the GPCR. Again, having 7 transmembrane alpha helices, an N terminal that is extracellular, and a C terminal that is intracellular. Now in our third representation of the GPCR down below, what you'll notice is that the GPCR here in the tan color is actually associated with or coupled with this green structure down below, which is our G protein. And so that transitions us perfectly into the G proteins.

So the G proteins are called G proteins because, really, they are GTP binding proteins. And so these are intracellular lipid-linked proteins that can hydrolyze, as their name implies, GTP. And so not only do they hydrolyze GTP into GDP, but these G proteins, specifically the ones that are associated with the G protein coupled receptors, have three different subunits that are termed the alpha, the beta, and the gamma subunits. And so if we take a look at our image down below, notice that the green structures are the subunit. And, really, the alpha subunit. And really the alpha subunit is going to be the one that is most important for us to know as we'll see when we move forward in our course, and that's why it's the one that is interactive here.

Now because there are three different subunits in this G protein, it is known as a heterotrimeric G protein, hetero meaning different because there are three different subunits. The tri, of course, in here means three, and the -meric is referring to the subunit. So this is a heterotrimeric G protein. Now there are other types of G proteins that are not heterotrimeric. And moving forward in our course, we're actually going to see some examples of G proteins that are not heterotrimeric, so that's important to keep in mind here. But the G proteins that we're talking about that are associated with the GPCRs, they are heterotrimeric G proteins.

Now, what in the world is this GTP here that we were talking about that these G proteins actually hydrolyze? Well, GTP stands for guanosine triphosphate, and so you can see the GTP embedded in here. And so GTP really serves a similar type of function to adenosine triphosphate or ATP. And so, of course, we know all about ATP, and so down below over here in our image on the right-hand side here, what you'll notice is that we're showing you ATP hydrolysis on the top image, and down below what we're showing you is GTP hydrolysis in the bottom image. And so what you'll notice is that ATP, we know is the high energy molecule, and, so is GTP. And so you can see that we have these little yellow backgrounds behind these to represent that they are high energy. And so when the G protein is bound to the GTP version, that means that it's going to be in its active state. And, of course, when GTP is hydrolyzed down to GDP, we know that it's going to be the inactive form or the low energy form, just like we know that ADP is the low-energy form of ATP. And so, really, you can think ATP and GTP are both the high energy active form, whereas ADP and GDP are the low energy inactive forms. And so you can see that hydrolysis is going to remove a phosphate group. And so really, the G protein that we see here, as we mentioned up above, is capable of hydrolyzing the GTP. So when we say GTP hydrolysis moving forward, what we really mean is this reaction right here. Taking the GTP and hydrolyzing it, which of course, is going to utilize water since hydrolysis we know has the hydro- prefix in it. It will hydrolyze it so that the phosphorus, one of the phosphates is removed, and it becomes a GDP molecule. Now you can see, really, the difference between GDP and ATP is the nitrogenous base here that is attached. And so comparing the differences here, you can see that that is really what distinguishes ATP from GTP. But other than that, their structures are incredibly similar and so hopefully by just keeping in mind that the GTP is very similar in function to ATP, then you guys will be good.

Now one thing to note is that over here on the left-hand side, notice that our G protein is bound to GDP. It's bound to the low-energy inactive form. And so what that means is that this heterotrimeric G protein must be in the inactive form, since it's bound again to GDP. And so this is exactly how the G protein starts in the beginning of our G protein-coupled receptor pathway. And so this is a perfect transition to our next video.

This here concludes our introduction to the G protein-coupled receptors. And again, we'll talk more and more about these as we move forward in our course. And I'll see you guys in our next video.

G protein-Coupled Receptors

In this video, we're going to talk about the 3 essential components of GPCR signal transduction pathways. And you can see that we have these three essential components numbered down below. Now, as we move forward in our course and talk about very specific GPCR signal transduction pathways, we'll see that there are a lot more than just 3 components involved in those pathways. But really the 3 components that we're going to talk about here in this video are the ones that we'll see are the most consistent across the different GPCR signal transduction pathways that we're going to talk about in our course. And so that being said, let's get started with number 1 here, our first essential component, and that is, of course, the GPCR itself or the G protein coupled receptor itself, which, of course, we already know is a transmembrane receptor that will actually undergo a conformational change upon ligand binding. And ultimately, this conformational change is going to activate the G protein that we know the GPCR is associated with. And so down below in our image, notice that we're showing our first essential component, the GPCR here as this tan structure, and so we can go ahead and fill in the GPCR right here in our image. And of course, upon ligand binding, so when the ligand actually binds to our GPCR, notice that it actually undergoes a conformational change, as we see here in our image. So now, of course, we know that this GPCR undergoes a conformational change in order to activate the G protein, and that leads us to our second essential component, which is the G protein itself. And so recall that the G protein is an intracellular lipid linked peripheral membrane protein that actually can, bind to GDP and GTP. And so it will actually replace GDP, the low energy inactive form, with GTP, the high energy active form, when it's actually activated, which makes sense since, like, of course, GTP is the active version, and so when the G protein's activate it, it will bind GTP. And the G protein, we know, has the ability to hydrolyze the GTP, and so it will actually slowly hydrolyze the GTP. Now again, we know that the G proteins that we're talking about here in this context contain 3 different subunits, an alpha subunit, a beta subunit, and a gamma subunit, and these subunits will actually dissociate to form an alpha subunit and a beta gamma subunit upon GTP binding. And so essentially, the alpha subunit is dissociating away from the beta gamma subunits. And so if we take a look at our image down below, notice over here in green, what we have is our G protein, our heterotrimeric G protein, since it has 3 different subunits, which we know are the alpha subunit over here, the beta subunit, and the gamma subunit. And so notice that here we're showing that it is bound to the GDP molecule, the low energy inactive form. But, of course, upon binding of the ligand, once the ligand binds, it causes a conformational change in the GPCR, and that conformational change in the GPCR ultimately causes GTP to replace the GDP. And so down below here, we can say that upon ligand binding, again, GTP is going to replace the low energy GDP. And so if it's, if GTP is binding, the high energy active form, that is going to activate the G protein. And, of course, as we said, that the activated G protein is going to dissociate into the alpha subunit and the beta gamma subunits. And so notice that the beta gamma subunits are here upon ligand binding, and, of course, the alpha subunit is going to dissociate, and so we can go ahead and label this the alpha subunit. And notice that it is GTP bound now because it is in its high energy active form. And so, notice that this, G protein alpha subunit right here in its active form is actually now bound to this other structure that we see over here, and this is really the third component here of the GPCR signal transduction pathways. And this is going to be the effector enzyme. And so the effector enzyme is another membrane-bound protein. And more specifically, as its name implies, it is an enzyme. And so this is a membrane-bound enzyme, and its job is to produce what's known as a secondary essenger upon activation by the alpha G protein subunit. And so ultimately, this alpha G protein subunit, which is active itself, is actually binding and activating this other membrane protein here that we're calling the effector enzyme. And again, the effector enzyme is responsible for producing the secondary messenger that we can label down below. And the secondary messenger is actually going to be variable in different pathways that we cover moving forward.

A G protein-coupled receptor is comprised of ____ transmembrane α-helix/helices:

• A. 7.
• B. 8.
• C. 1.
• D. 10.
• E. 6.
• F. 14.

G protein-coupled receptors (GPCRs) are transmembrane proteins with ligand binding sites on the extracellular side of the membrane (near its N-terminal). What is the role of the G-protein in the GPCR signaling pathway?

• A. G proteins phosphorylate GPCRs.
• B. G proteins bind extracellular ligands and facilitate the transport into the cell.
• C. G proteins activate enzymes that transduce the signal throughout the cell.
• D. G proteins activate transcription of genes.
• E. G proteins facilitate dimerization of receptor monomers.

G protein-Coupled Receptors

So in our last lesson video, we mentioned that the role of the G protein is to activate the effector enzyme. But really, that's only part of the full story because there are some G proteins that do activate the effector enzyme. But there are also other G proteins that inhibit the effector enzyme. And so here in this video, we're going to distinguish between the stimulatory and the inhibitory G proteins or G_s versus G_i. And so, really, there are 2 types of G proteins that you guys should know that are classified according to their effect on the effector enzyme. And so we have these 2 G proteins listed down below, and so the first one is going to be the stimulatory G protein. And so the stimulatory G protein is also known as G_s, where the s here is for the s in stimulatory. And so these stimulatory G proteins, or G_s, as their name implies, will stimulate or activate the effector enzyme to create even more secondary messenger than normal. And the second type of G protein, on the other hand, are referred to as inhibitory G proteins. And these inhibitory G proteins are abbreviated as G_i, where, of course, the i is for the i in inhibitory. And so these inhibitory G proteins, or G_i, as their name implies, will inhibit or inactivate the effector enzyme to create even less secondary messenger than normal.

And so if we take a look at our image down below over here on the left hand side, notice that we're saying that the stimulatory G protein G_s is like the gas pedal in a car. And that's because the stimulatory G protein pretty much stimulates, activates, or accelerates the production of secondary messenger, just like the gas pedal in a car will accelerate the speed of a car. And of course, the G_i protein, the inhibitory G protein, is like the brakes in a car. And so just like the brakes in a car will slow down or decelerate the speed of a car, the inhibitory G proteins are going to decelerate, slow down, the production of secondary messenger. And so notice over here on the left-hand side, we're showing you the alpha subunit of the G protein that has dissociated and is bound to GTP. And notice that here it is actually activating the effector enzyme. And so because it's activating the effector enzyme, we know that this is going to be the stimulatory G protein or G_s. And then notice over here on the other side, what we have is another alpha subunit of a G protein, except notice that it has a red border here, but it's still going to be bound to GTP, same exact thing, still bound to GTP. However, this time, instead of activating, activated G protein here bound to GTP, it's actually going to inhibit the effector enzyme. And so that means that this is going to be the inhibitory G protein or G_i.

And so moving forward in our course, we're going to see examples of stimulatory G proteins or G_s, and we'll also see examples of inhibitory G proteins or G_i. And so this here is just an introduction to the stimulatory and inhibitory G proteins, but we will revisit this again as we move forward in our course. But for now, this concludes our introduction to the stimulatory and inhibitory G proteins, and I'll see you guys in our next video.

G_i is the inhibitory G protein of various effector enzymes. If a toxin released from a bacterial infection enters cells & covalently modifies the α-subunit of G_i so that it can no longer bind GTP, which of the following is a likely result?

• A. Increase in the synthesis of the secondary messenger molecule.
• B. Decrease in the synthesis of the secondary messenger molecule.
• C. The inhibitory G protein α-subunit will not dissociate from the β-γ subunits.
• D. Only A and C are true.
• E. Only B and C are true.

Here’s what students ask on this topic:

What are G protein-coupled receptors (GPCRs) and their main structural features?

G protein-coupled receptors (GPCRs) are integral membrane proteins characterized by seven transmembrane alpha helices. These receptors are also known as 7 TMS proteins due to their seven transmembrane segments. GPCRs have an extracellular N-terminal and an intracellular C-terminal. Upon ligand binding, GPCRs undergo a conformational change, which activates associated G proteins. These G proteins are intracellular lipid-linked proteins that can bind and hydrolyze GTP. The activation of G proteins leads to various cellular responses through signal transduction pathways.

How do G proteins associated with GPCRs function?

G proteins associated with GPCRs function by binding and hydrolyzing GTP. They consist of three subunits: alpha, beta, and gamma. Upon activation by a GPCR, the G protein exchanges GDP for GTP, causing the alpha subunit to dissociate from the beta and gamma subunits. The activated alpha subunit then interacts with effector enzymes to produce secondary messengers, which propagate the signal within the cell. This process is crucial for various cellular responses and signal transduction pathways.

What are the three essential components of GPCR signal transduction pathways?

The three essential components of GPCR signal transduction pathways are: 1) the GPCR itself, which undergoes a conformational change upon ligand binding; 2) the G protein, which binds and hydrolyzes GTP, and consists of alpha, beta, and gamma subunits; and 3) the effector enzyme, a membrane-bound enzyme activated by the G protein's alpha subunit. The effector enzyme produces secondary messengers that affect downstream targets, leading to the cell's response.

What is the difference between stimulatory and inhibitory G proteins?

Stimulatory G proteins (Gs) and inhibitory G proteins (Gi) differ in their effects on effector enzymes. Stimulatory G proteins activate effector enzymes, increasing the production of secondary messengers, similar to pressing a gas pedal in a car. In contrast, inhibitory G proteins inhibit effector enzymes, reducing the production of secondary messengers, akin to applying brakes in a car. Both types of G proteins play crucial roles in regulating cellular responses through GPCR signal transduction pathways.

What role do secondary messengers play in GPCR signal transduction pathways?

Secondary messengers play a crucial role in GPCR signal transduction pathways by propagating the signal initiated by the ligand binding to the GPCR. Once the GPCR activates the G protein, the G protein's alpha subunit activates an effector enzyme, which then produces secondary messengers. These secondary messengers, such as cAMP or IP3, amplify the signal and activate downstream targets within the cell, ultimately leading to a specific cellular response. This process ensures that the initial extracellular signal is effectively transmitted and amplified within the cell.