Stimulatory Adenylate Cyclase GPCR Signaling - Video Tutorials & Practice Problems
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1
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Stimulatory Adenylate Cyclase GPCR Signaling
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16m
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Video transcript
Alright. So here we're going to revisit our map of the lesson on biosignalling pathways, which is down below right here. And, of course, we know that we're exploring this map by exploring the leftmost branches first. And so already in our lesson, we've talked a little bit about the g protein coupled receptors or the GPCRs. And as we move forward in our course, we're going to continue to talk more and more about these GPCR pathways. And so now we're going to move forward in our map to talk about a very specific GPCR signaling pathway, which is the adenylate cyclase GPCR signaling pathway. And more specifically, we're going to be focusing on the stimulatory adenylate cyclase GPCR signaling pathway. And so here in this interactive box right here, you can write in the word stimulatory. And so now that we know where we are within our map, specifically the stimulatory adenylate cyclase GPCR signaling pathway, we can get started on our lesson. So here we're going to introduce stimulatory adenylate cyclase GPCR signaling, which is also commonly referred to as the adenylate cyclase GPCR system. Now this is a classic 6 step example slash prototype of a GPCR signal transduction pathway that's found in all of your textbooks. Now notice down below in our text, we're actually numbering each of these 6 steps that are found in our adenylate cyclase GPCR systems. And also notice that each of these numbers in our text that corresponds with each step also corresponds with all of the numbers that we see throughout our large image down below of our adenylate cyclase GPCR signaling pathways. And so again the numbers up above correspond with the numbers that we see down below in this image. Now another important thing to note here is that this adenylate cyclase GPCR signaling pathway is actually a cycle that begins and ends in the same place, and so that's something important to keep in mind as we move forward in this lesson. Now in terms of what exactly this adenylate cyclase GPCR system does, it turns out that it's actually linked to a wide variety of cell responses. However, that being said, it's usually associated with the ability to allow cells to generate a fight or flight response. What you might recall from your previous Human Anatomy and Physiology courses is just a response that gears your body for an emergency or a threat to your survival. For example, if you were to take a look to your left in your bedroom and see a bear or a lion right there in your bedroom, What would your body do? Would it prepare for a fight so that you would fight that lion or bear, or would it prepare for a flight straight out of the room where you're just booking it and trying to get out of the way? I can tell you I'd be booking it right out of that room if I saw a bear or lion in my bedroom. But what would you do? And so again, this adenylate cyclase GPCR system is what allows your cells to generate this fight or flight response to that emergency situation. And really this fight or flight response is going to be initiated by the hormone that's known as epinephrine. And epinephrine is just the fancy name for the hormone adrenaline. And of course you guys have heard your adrenaline is pumping and of course that's referring to the ability for your bodies to get ready for something that might require a lot of energy. And so now we can move on to talking about each of these 6 steps in this pathway. But before we get started, I wanna point out that in the text for each of these 6 steps, there are some words that are color coded to the image down below. And so in order to make sure that you're getting a complete understanding of this pathway, make sure that you're taking advantage of the color coding in these words. And so I'll make sure to point out the color coding in the text as well. And so here in our very first step of this pathway, the hormone signaling ligand epinephrine or adrenaline is going to bind to the gPCR. And in this case specifically, the GPCR is a beta adrenergic GPCR. And you can see that the adrenergic has the root in it for adrenaline, and so that connection is there. And so when this hormone signaling Ligand, Epinephrine, binds to the GPCR, Beta Adrenergic GPCR, it actually causes a conformational shift in the GPCR structure. And so what you'll notice is that in step number 1, we actually have the ligand and epinephrine color coded with this blue background, and that's because down below in our image we're actually color coding epinephrine with this blue, background here. And also notice that the GPCR is color coded with this background, more specifically the beta adrenergic GPCR, and that's because down below in our image, you'll see that the beta adrenergic GPCR is colored with that same tan background color. And so if we take a look at step number 1 down below in our image right here, what you'll notice is that the extracellular ligandepinephrine is actually binding to the GPCR, the beta adrenergic GPCR, Again, causing a confirmational shift in this beta adrenergic GPCR. And so really here in step number 1, what we can say is that there is ligand binding to the GPCR, again causing a conformational shift in this GPCR. And so really that leads us to step number 2 of this signaling pathway. And in step number 2, we pick up right where we left off with, which is with the g p c r confirmational shift. And so in step number 2, this g p c r confirmational shift that occurred in step number 1 is actually going to activate a stimulatory g protein, g s. And by activate, what we mean is that it's going to promote the alpha subunit of that protein to release GDP, the low energy form and inactive form, and bind GTP, the high energy active form. And so if we take a look down below at our step number 2, right here, what you'll notice is that GTP is coming into play. And so originally, what you'll see is that the g protein down here is bound to the low energy GDP. So originally this is actually the inactive form of the g protein, and you can see the same up above in step number 1. However, once this Beta Adrenergic GPCR undergoes its conformational shift, it allows the g protein here in step number 2 to replace its GDP with the high energy GTP. And so in step number 2, what we can say is that GTP replaces GDP, and that is going to activate this g protein here. And that leads us to step number 3, which is, of course, that with the bound GTP, again, the alpha subunit of the stimulatory g protein gs is going to dissociate from the other subunits of the g protein, the beta gamma subunits. And when the alpha subunit dissociates from the beta gamma subunits, it's actually going to diffuse towards a nearby effector enzyme. And so notice that the effector enzyme, we have color coded with this reddish background, and that's because down below you can see that the effector enzyme is this protein that we see throughout. And so in step number 3 down below, what you'll notice is that once the, alpha subunit obtains that high energy GTP, it's actually going to dissociate. And so that alpha subunit, the dissociation of the alpha subunit is what we see in step number 3. And so if you take a look, notice that the alpha subunit, with the bound GTP is dissociating from the beta gamma subunits and diffusing towards the Effector Enzyme that we see over here. And the Effector Enzyme, as you can see in this image, is Adenylate cyclase, which is really where this entire pathway gets its name from, from the effector enzyme. And so this leads us into step number 4, And in step number 4, what you'll notice is that the activated GTP bound alpha subunit of the stimulatory g protein, g s, is actually not only going to diffuse to the nearby effector enzyme, but it's actually going to bind to that effector enzyme and activate that effector enzyme as well since it is indeed the stimulatory g protein. And so when it activates the effector enzyme, again, the effector enzyme is adenylate cyclase, which is again where this entire pathway gets its name from from the effector enzyme. And so if we take a look at step number 4 way down below in our image, notice that the, alpha subunit of the g protein not only diffuses away, it diffuses towards the adenylate cyclase, but ultimately it ends up binding to the adenylate cyclase effector enzyme. And so, what we see is that in step number 4, we will see the activation of the adenylate cyclase protein. And so you can see that the activated adenylate cyclase has this yellow border around it to distinguish it from the inactive version over here, which does not have the yellow border around it. And so this leads us into step number 5 of this pathway, and in step number 5, what you'll see is that now that the effector enzyme is activated, the activated effector enzyme adenylate cyclase is going to be able to convert ATP, its substrate, into the secondary messenger that's called cAMP, cyclic AMP. And we'll talk more about this secondary messenger later in our course. But ultimately what happens is the production of cAMP leads to the activation of a protein known as Protein Kinase a or PKA for short, and so, PKA is ultimately going to lead to the cell response. And the cell response would be, for example, increasing the breakdown of glycogen and fat. And of course, increasing the breakdown of glycogen and fat is going to give our cells more energy. And more energy is what we're going to need if we're going to generate a fight or flight response. And so if we take a look down below at our step number 5 down below over here, notice that ATP is now coming into play. And so now that the alpha subunit of the g protein is stimulating and activating the effector enzyme right here, the effector enzyme can now produce or convert its substrate ATP and convert it into the secondary messenger cAMP, cyclic AMP here. And of course cAMP is going to lead to the activation of PKA, and then PKA will ultimately lead to the cell response that, leads to our fight or flight response. And so here in step number 5, what we can say is that it leads to the generation of the secondary messenger cAMP, and then cAMP leads to the activation of k a, and p k a ultimately leads to the cell response. And again, as we move forward in our course, we're going to talk a lot more about this particular process right here. But, moving on to our final step, what you'll see is that it's, step number 6 is what takes us back to the original position. It allows us to go back to step number 1 and make this entire thing a cycle. And so in step number 6, our final step of this pathway, the g protein, alpha subunit is actually going to slowly inactivate itself. And so the way that it does this is by hydrolyzing its g t p, the high energy form, into g d p, the low energy form. And of course, if the g protein alpha subunit inactivates itself, it's also going to inactivate the effector enzyme as well since the g protein is what was stimulating the effector enzyme. And so, ultimately, when the g protein hydrolyzes its GTP into GDP, the low energy state, the alpha subunit can then reassemble its original inactive form with its beta gamma subunits, and the ligand can actually dissociate from the GPCR in order to reset this pathway back to the beginning and again make this in an a complete cycle. And so if we take a look at our step number 6 down below right here, notice that, the g protein alpha subunit right here has, the ability to hydrolyze the GTP. So you can see GTP hydrolysis is occurring here. And so GTP gets, cleaved into GDP releasing an inorganic phosphate, and then this, Alpha subunit is able to go back and reform its original inactive form with its Beta Gamma subunits, and the ligand here, epinephrine, is going to dissociate, from the beta adrenergic GPCR in order to reset the pathway back to what we see in step number 1. And so really, in step number 6, what we can see is that, we have the GPCR signal, is terminated or GPCR signal termination. And again we'll talk more about this idea here later in our course as well. But for now what you'll see is that we've completed our entire adenylate cyclase GPCR signaling pathway and we've talked about all 6 of these steps. Now I'll admit this is quite a lot of information to commit to memory. So how in the world could I expect you guys to remember all of these different steps? Well, in our very next lesson video, we're going to talk about a specific way that you guys can memorize all 6 of these important events that take place in this pathway. And so I'll see you guys in that video.
2
concept
Stimulatory Adenylate Cyclase GPCR Signaling
Video duration:
10m
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Video transcript
So when it comes to stimulatory adenylate cyclase GPCR signaling, as you guys probably noticed from our last lesson video, there's quite a lot for you guys to remember. And so how in the world are you guys supposed to remember all of the different components and events in the correct order for stimulatory adenylate cyclase GPCR signaling? Well, that's exactly what this video is all about, helping you guys remember the most important components and events in the correct order. And so I'm really excited to share the memory tools that we've created here at Clutch Prep because I can tell you right now, I've tried searching and you won't find anything like these memory tools anywhere on any resource. So notice what we have right here in the middle is an ordered list of the most important components and the most important events that occur in stimulatory adenylate cyclase GPCR signaling. And so over here on the far left, we know that the extra cellular ligandepinephrine or adrenaline is going to bind to the GPCR, more specifically the beta adrenergic GPCR, and that's going to cause a confirmational shift in the GPCR. Now that confirmational shift in the GPCR is ultimately what allows the g protein to exchange its GDP, the low energy inactive form, for GTP, the high energy active form, and so that activates the G Protein. Now the activated G Protein Alpha Subunit will then dissociate from the Beta Gamma Subunits and that alpha subunit will diffuse towards the effector enzyme adenylate cyclase and bind to it in order to activate it. And so the adenylate cyclase effector enzyme will convert its substrate into the secondary messenger cAMP, and cAMP will then activate the protein kinase a enzyme over here or PKA, which ultimately leads to the cell response. And so, really, this here is what you guys need to know. And so how is it that you can go about memorizing again, these particular components and these events in this exact order? Well, that's exactly why we came up with this creative but fictional story to help you guys remember this particular signaling pathway. Now bear with me here just a little bit because this story is not fully bulletproof. It's not a perfect story to help you memorize all of the different details. Instead, this story was intentionally designed to help you guys memorize the most important components and the most important events in the correct order. And so keep that in mind as we move forward. And so the plot of our story is that the cell wants to go on a camping trip and, of course, within the word camping there is the secondary messenger c amp and so going camping is going to represent our secondary messenger c amp or cyclic amp. And, of course, what is a camping trip without cooking some s'mores? And so cooking s'mores is going to represent the cell response. And so notice down below, we have all of these numbers to label the steps of our story. And what's important to note is that these numbers for the steps of our story correspond with the numbers that you see up above as well as the numbers that you see down below throughout our image. And all of these numbers correspond with the numbers from our previous lesson video for the steps of the signaling pathway. And so in the very first step of our story of course how could you go on a camping trip without first packing the luggage for the camping trip? And so packing the luggage is going to represent ligand binding to the g pcr. And so you can think that the l in luggage is for the l in ligand. And so of course we know that once the ligand binds to the GPCR, it will cause a conformational shift in the GPCR that will ultimately activate the g protein. And so let's take a look at our image down below and what you'll notice is that right in the middle what we have is our biological membrane. And so of course above the membrane here represents the outside of our cell and below the membrane represents the inside of our cell. And so notice that on the outside of a cell what we have is the luggage for the camping trip or the ligand And, of course, we know that the ligand is going to bind to this beta adrenergic GPCR. And so, when the ligand or the luggage binds to the GPCR, it will cause a conformational shift in the GPCR that will ultimately activate the g protein. And so notice that we're symbolically representing our g protein as this superhero with his beta blaster and his gamma gadget. And so recall that the g protein is a heterotrimeric g protein, which means that it has 3 different subunits. It has the alpha subunit, which you can see the symbol alphas in the belly of our superhero, so the superhero here represents the alpha subunit. Then we also have the beta subunit represented by our beta blaster here. And then we have the gamma gadget, which represents the gamma subunit. And so notice that when we go to step number 2 of our story, it starts off with the alpha hero, which we know represents the g protein alpha subunit. And so, this alpha hero wants to go on this camping trip and so the alpha hero or the g protein alpha subunit is going to take charge of this camping trip situation. And so what he's going to do is he's going to exchange the empty gas can that he has with a full gas can so that he can go on this camping trip. And so the exchange of the empty gas can with a full gas can is going to represent GTP exchange, where the low energy GDP is going to be exchanged with the high energy GDP. And so GDP, the low energy form, is going to be associated with the empty gas can and the high energy form, GTP, is associated with the full gas can. And so if we take a look at our image down below, notice that our heterotrimeric g protein is initially associated with an empty gas can. And so notice that we have this gas meter here, and it is on empty. And, of course, the empty gas can is associated with the low energy GDP. But again, when the ligand binds to the GPCR, it causes a conformational shift in the GPCR, and that conformational shift in the GPCR allows the g protein to exchange the low energy GDP with the high energy GTP. And so the high energy GTP is associated with the full gas can, and so notice that the gas meter is on full and our gas can is now filled with gas. And so in step number 3 of our story, the alpha hero or the g protein alpha subunit is going to go to rent a car in order to go on this camping trip. And so notice that a car is going to represent the effector enzyme adenylate cyclase. Now when the alpha hero goes to rent a car, he actually forgets his beta blaster and his gamma gadget behind. And so the beta blaster and the gamma gadget are not coming along. And so this reminds us that only the g protein alpha subunit is going to be dissociating towards the effector enzyme adenylate cyclase. And so if we take a look at our image down below, notice that in step number 3, it's only the alpha subunit, the alpha hero here that is going to dissociate from the beta, subunit and the gamma subunit. And this alpha subunit is now associated with the high energy GTP, which is this full gas can, and he has gone to go rent a car. And again, a car represents the effector enzyme adenylate cyclase. And so in step number 4 of our story, the alpha hero then uses his full gas can to fill up a car's gas tank and to start the engine of a car. And so this represents the activation of the effector enzyme adenylate cyclase. And so, if we take a look at our image down below, notice that the Alpha Hero is going to use his GTP or his full gas can in order to fill up the gas tank of a car and to start the engine of a car. And once the engine has been started of a car, that represents the activation of the adenylate cyclase enzyme. And so once a car's engine has been started up, we can go to step 5 a. And so, of course, a car is going to go to the campsite. And so, the campsite, going to the campsite represents the production of the secondary messenger c amp or cyclic AMP. And so again, if we take a look at our image down below, notice that once a car's engine has been started, it can go to the campsite. And again, the campsite here represents the production of our secondary messenger, cyclic AMP or c AMP. And then, of course, in step 5 b of our story, upon arrival to the campsite, of course, before they can engage in any camping activities, they need to park a car. And, of course, parking a car is going to be associated with PKA, protein kinase a. And then, of course, once PKA, is activated, once they have parked the car, they can now engage in those, campsite activities and they can begin cooking s'mores and, again, cooking s'mores represents the cell response.
3
Problem
Problem
Which of the following represents the best order of signal transduction for the β-adrenergic receptor?
A
Hormone → receptor tyrosine kinase → G-protein → protein kinase A → cAMP → cellular effects.
B
Ligand → receptor → secondary messenger → G-protein → protein kinase A → cellular effects.
C
Hormone → G-protein → receptor → cAMP → protein kinase A → cellular effects.
D
Hormone → receptor → G-protein → second messenger → protein kinase A → cellular effects.
4
Problem
Problem
Which of the following molecules is NOT involved in signal transduction of the β-adrenergic GPCR?
A
GTP.
B
ATP.
C
cAMP.
D
cGMP.
E
GDP.
5
Problem
Problem
Which of the following reactions does the enzyme adenylate cyclase catalyze?
A
cATP to cAMP.
B
GTP to cGMP.
C
ATP to cADP.
D
cGMP to GTP.
E
ATP to cAMP.
6
Problem
Problem
In response to a ligand binding a GPCR, a particular G protein (G s) activates adenylate cyclase. If a cell has a mutation where the G protein can no longer hydrolyze GTP, which of the following would be the result?
A
Cellular levels of cAMP would go down in response to ligand binding.
B
Cellular levels of cAMP would go up independent of ligand binding.
C
The ligand would not be able to bind to the receptor.
D
Cellular levels of cAMP would not change.
E
Adenylate Cyclase would always remain inactive.
7
Problem
Problem
When epinephrine binds to its GPCR activating the cAMP cascade, all of the following happen EXCEPT:
A
GDP dissociates from the G protein as GTP associates.
B
The alpha-subunit of the G protein activates adenylate cyclase and cAMP is produced.
C
G protein is activated and diffuses away from the cell membrane into the nucleus.
D
The alpha-subunit of the G protein hydrolyzes GTP and becomes inactive.
E
The alpha-subunit of the G protein bound to GDP reassociates with the beta & gamma-subunits.