Stimulatory Adenylate Cyclase GPCR Signaling - Online Tutor, Practice Problems & Exam Prep

The stimulatory adenylate cyclase GPCR signaling pathway initiates with epinephrine binding to the beta adrenergic GPCR, causing a conformational shift that activates the G protein. This leads to GDP being replaced by GTP, allowing the alpha subunit to dissociate and activate the effector enzyme adenylate cyclase. Adenylate cyclase then converts ATP into cyclic AMP (cAMP), a secondary messenger that activates protein kinase A (PKA), resulting in cellular responses like increased energy mobilization. The pathway concludes with the hydrolysis of GTP to GDP, resetting the system for future signaling.

Stimulatory Adenylate Cyclase GPCR Signaling

Alright. So here we're going to revisit our map of the lesson on biosignaling pathways, which is down below right here. And, of course, we know that we're exploring this map by exploring the leftmost branches first. Already in our lesson, we've talked a little bit about G protein-coupled receptors or GPCRs. As we move forward in our course, we're going to continue to talk more about these GPCR pathways. 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. More specifically, we're going to be focusing on the stimulatory adenylate cyclase GPCR signaling pathway. Here in this interactive box right here, you can write in the word "stimulatory". 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.

We're going to introduce stimulatory adenylate cyclase GPCR signaling, also commonly referred to as the adenylate cyclase GPCR system. This is a classic 6-step example/prototype of a GPCR signal transduction pathway that's found in all your textbooks. Notice, in our text, we number each of these 6 steps found in our adenylate cyclase GPCR systems. Also, each of these numbers in our text that corresponds with each step also corresponds with all of the numbers throughout our large image below of our adenylate cyclase GPCR signaling pathways. 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, an important point as we move forward in this lesson.

In terms of what exactly this adenylate cyclase GPCR system does, it is linked to a wide variety of cell responses. However, it's usually associated with the ability to allow cells to generate a fight or flight response. This is a response that gears your body for an emergency or a threat to your survival. For example, if you were to see a bear or a lion in your bedroom, what would your body do? Would it prepare for a fight or would it prepare for a flight straight out of the room? This adenylate cyclase GPCR system is what allows your cells to generate this fight or flight response to emergency situations. This fight or flight response is initiated by the hormone known as epinephrine, which is just the fancy name for adrenaline.

Now, we can move on to talking about each of these 6 steps in this pathway. In the text for each of these 6 steps, there are some words that are color coded to the image below; ensure that you take advantage of the color coding in these words. In our very first step of this pathway, the hormone signaling ligand epinephrine or adrenaline will bind to the GPCR, specifically, a beta-adrenergic GPCR, causing a conformational shift in the GPCR structure.

Continuing to step number 2, this GPCR conformational shift activates a stimulatory G protein, Gs, promoting the alpha subunit of that protein to release GDP, the low energy and inactive form, and bind GTP, the high energy active form. In step number 3, with GTP bound, the alpha subunit of stimulatory G protein Gs dissociates from the other subunits and diffuses towards a nearby effector enzyme. This effector enzyme is adenylate cyclase.

In step number 4, the activated GTP-bound alpha subunit binds to and activates the effector enzyme adenylate cyclase. In step number 5, now that the effector enzyme is activated, adenylate cyclase converts ATP into the secondary messenger cAMP, which leads to the activation of Protein Kinase A (PKA), ultimately leading to cell responses like increasing the breakdown of glycogen and fat.

Finally, in step number 6, the G protein alpha subunit inactivates itself by hydrolyzing GTP back into GDP, allowing the alpha subunit to reassemble with its beta-gamma subunits, and the ligand epinephrine dissociates from the GPCR, resetting the pathway to the beginning. This makes the adenylate cyclase GPCR signaling pathway a complete cycle. In our next lesson, we'll discuss specific ways you can memorize all 6 of these important events that take place in this pathway. See you in that video.

Stimulatory Adenylate Cyclase GPCR Signaling

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. 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. 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.

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. Over here on the far left, we know that the extracellular ligand epinephrine or adrenaline is going to bind to the GPCR, more specifically the beta adrenergic GPCR, and that's going to cause a conformational shift in the GPCR. That conformational 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. 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. 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.

How can you go about memorizing again these particular components and these events in this exact order? That's exactly why we came up with this creative but fictional story to help you guys remember this particular signaling pathway. 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.

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 cAMP, and so going camping is going to represent our secondary messenger cAMP or cyclic AMP. What is a camping trip without cooking some s'mores? Cooking s'mores is going to represent the cell response.

Notice down below, we have all of these numbers to label the steps of our story. 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. All of these numbers correspond with the numbers from our previous lesson video for the steps of the signaling pathway.

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? Packing the luggage is going to represent ligand binding to the GPCR. You can think that the 'l' in luggage is for the 'l' in ligand. Once the ligand binds to the GPCR, it will cause a conformational shift in the GPCR that will ultimately activate the G protein.

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. Above the membrane here represents the outside of our cell and below the membrane represents the inside of our cell. Notice that on the outside of a cell, we have 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. 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.

Notice that we're symbolically representing our G protein as this superhero with his beta blaster and his gamma gadget. Recall that the G protein is a heterotrimeric G protein, meaning that it has three 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. We also have the beta subunit represented by our beta blaster here, and then we have the gamma gadget, representing the gamma subunit.

Notice that when we go to step number two of our story, it starts off with the alpha hero, which we know represents the G protein alpha subunit. 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. What he's going to do is exchange the empty gas can that he has with a full gas can so that he can go on this camping trip. 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 GTP. 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.

If we take a look at our image down below, notice that our heterotrimeric G protein is initially associated with an empty gas can. Notice that we have this gas meter here, and it is on empty. 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. 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.

In step number three 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. Notice that a car is going to represent the effector enzyme adenylate cyclase. When the alpha hero goes to rent a car, he actually forgets his beta blaster and his gamma gadget behind. The beta blaster and the gamma gadget are not coming along. This reminds us that only the G protein alpha subunit is going to be dissociating towards the effector enzyme adenylate cyclase.

If we take a look at our image down below, notice that in step number three, it's only the alpha subunit, the alpha hero here, that is going to dissociate from the beta subunit and the gamma subunit. 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. Again, a car represents the effector enzyme adenylate cyclase.

In step number four 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. This represents the activation of the effector enzyme adenylate cyclase. 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. Once the engine has been started of a car, that represents the activation of the adenylate cyclase enzyme.

Once a car's engine has been started up, we can go to step five a. Of course, a car is going to go to the campsite. Going to the campsite represents the production of the secondary messenger cAMP or cyclic AMP. 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. The campsite here represents the production of our secondary messenger, cyclic AMP or cAMP.

In step five b of our story, upon arrival at the campsite, before they can engage in any camping activities, they need to park a car. Parking a car is going to be associated with PKA, protein kinase A. 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.

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.

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.

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.

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.

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.

Here’s what students ask on this topic:

What is the role of epinephrine in the stimulatory adenylate cyclase GPCR signaling pathway?

Epinephrine, also known as adrenaline, is the extracellular ligand that initiates the stimulatory adenylate cyclase GPCR signaling pathway. When epinephrine binds to the beta adrenergic GPCR on the cell surface, it causes a conformational shift in the receptor. This shift activates the associated G protein by promoting the exchange of GDP for GTP on the alpha subunit. The activated alpha subunit then dissociates and activates adenylate cyclase, leading to the production of cyclic AMP (cAMP) and subsequent activation of protein kinase A (PKA), which triggers various cellular responses, such as increased energy mobilization for the fight-or-flight response.

How does the G protein become activated in the stimulatory adenylate cyclase GPCR signaling pathway?

The G protein becomes activated in the stimulatory adenylate cyclase GPCR signaling pathway through a series of steps initiated by the binding of epinephrine to the beta adrenergic GPCR. This binding causes a conformational shift in the GPCR, which in turn activates the G protein. Specifically, the alpha subunit of the G protein exchanges GDP (the low-energy form) for GTP (the high-energy form). This exchange activates the alpha subunit, allowing it to dissociate from the beta and gamma subunits and interact with the effector enzyme adenylate cyclase, leading to further downstream signaling events.

What is the function of adenylate cyclase in the GPCR signaling pathway?

Adenylate cyclase is the effector enzyme in the stimulatory adenylate cyclase GPCR signaling pathway. Once activated by the GTP-bound alpha subunit of the G protein, adenylate cyclase catalyzes the conversion of ATP into cyclic AMP (cAMP). cAMP acts as a secondary messenger that activates protein kinase A (PKA). PKA then phosphorylates various target proteins, leading to cellular responses such as increased glycogen and fat breakdown, which provide the energy needed for the fight-or-flight response. Thus, adenylate cyclase plays a crucial role in amplifying the signal initiated by epinephrine binding to the GPCR.

What is the significance of cyclic AMP (cAMP) in the stimulatory adenylate cyclase GPCR signaling pathway?

Cyclic AMP (cAMP) is a critical secondary messenger in the stimulatory adenylate cyclase GPCR signaling pathway. Once adenylate cyclase is activated by the GTP-bound alpha subunit of the G protein, it converts ATP into cAMP. cAMP then activates protein kinase A (PKA), which phosphorylates various target proteins to elicit specific cellular responses. These responses include the breakdown of glycogen and fat, providing the energy necessary for the fight-or-flight response. Therefore, cAMP serves as a key intermediary that transduces the extracellular signal (epinephrine binding) into a wide range of intracellular actions.

How is the stimulatory adenylate cyclase GPCR signaling pathway terminated?

The stimulatory adenylate cyclase GPCR signaling pathway is terminated through the hydrolysis of GTP to GDP on the alpha subunit of the G protein. This hydrolysis reaction is catalyzed by the intrinsic GTPase activity of the alpha subunit. Once GTP is hydrolyzed to GDP, the alpha subunit becomes inactive and reassociates with the beta and gamma subunits, forming the inactive heterotrimeric G protein. Additionally, the ligand (epinephrine) dissociates from the beta adrenergic GPCR, resetting the receptor to its inactive state. This termination process ensures that the signaling pathway is tightly regulated and can be reactivated when needed.