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

Adenylate cyclase GPCR signaling involves two main pathways: stimulatory and inhibitory. In the stimulatory pathway, epinephrine binds to the beta adrenergic GPCR, activating a G protein that stimulates adenylate cyclase to convert ATP into cAMP, a secondary messenger that activates protein kinase A. The inhibitory pathway, activated by an inhibitory GPCR, prevents adenylate cyclase from producing cAMP. Termination of signaling involves GTP hydrolysis and phosphodiesterase activity, which converts cAMP to AMP. Understanding these mechanisms is crucial for grasping cellular responses and the effects of toxins like cholera and pertussis.

Recap of Adenylate Cyclase GPCR Signaling

In this video, we're going to do a recap or a review of adenylate cyclase GPCR signaling. There are no new learning objectives in this video since everything that we're going to discuss has already been covered in our previous lesson videos. If you're already feeling confident about adenylate cyclase GPCR signaling, feel free to skip this entire video. However, if you're struggling with adenylate cyclase GPCR signaling and looking for a good way to recap or review the information, then stick around because this video could be really helpful for you. So, with that said, let's get started. Down below, we have a large image that recaps everything we talked about in our previous lesson videos regarding adenylate cyclase GPCR signaling.

The name of this pathway, adenylate cyclase, tells us that the effector enzyme adenylate cyclase is the one being affected by the G protein. Recall that we discussed a stimulatory pathway and an inhibitory pathway for adenylate cyclase GPCR signaling. First, we'll recap the stimulatory pathway. We know that the hormone epinephrine or adrenaline will bind to the GPCR, specifically the beta-adrenergic GPCR, causing a conformational shift. This shift activates a heterotrimeric G protein, promoting the GDP-GTP exchange. The GTP-bound alpha subunit of the stimulatory G protein dissociates towards adenylate cyclase to activate it. Adenylate cyclase then converts the substrate ATP into the secondary messenger cAMP. cAMP acts as an allosteric activator to protein kinase A, which is a heterotetrameric structure in its inactive form. Once cAMP binds the regulatory subunits, it releases the catalytically active PKA subunits, which can phosphorylate their targets, ultimately leading to the cell response.

Recall from our previous lessons the termination of the stimulatory signaling pathway involves alpha subunit's GTP hydrolysis, converting GTP back to GDP, allowing the alpha subunit to reassociate with the beta gamma subunits. Epinephrine can also dissociate from the beta-adrenergic GPCR. Additionally, cAMP phosphodiesterase lowers the concentration of cAMP within the cell by converting cAMP into AMP, and phosphatases can reverse the activity of protein kinase A by removing phosphate groups added to its substrates, helping to terminate the signal.

In terms of the inhibitory pathway, an inhibitor ligand will bind to an inhibitory GPCR, causing a conformational shift that activates the inhibitory G protein, GI. This activates the GDP-GTP exchange, where GTP binds to the inhibitory alpha subunit GI, inhibiting adenylate cyclase from converting ATP into cAMP. The stimulatory pathway acts like a gas pedal, accelerating adenylate cyclase, while the inhibitory pathway functions like brakes, slowing down adenylate cyclase activity.

We also discussed desensitization, which involves two proteins: the beta-adrenergic receptor kinase (BRC) and beta-arrestin. BRC phosphorylates the beta-adrenergic GPCR, and beta-arrestin binds to the phosphorylated GPCR, leading to desensitization and inhibiting the GPCR signaling pathway. Additionally, we discussed specific drugs that affect GPCR signaling, such as the bacterial toxin cholera toxin, which inhibits GTP hydrolysis in the alpha subunits of the stimulatory G protein, leading to overactivation of adenylate cyclase and the disease cholera. Pertussis toxin affects the inhibitory G protein GI, preventing its activation. This toxin inhibits the inhibitor, leading to adenylate cyclase activation, but in a different way, likened to broken brakes on a car.

This concludes the recap of adenylate cyclase GPCR signaling, and we'll be able to apply these concepts in practice problems as we move forward in this lesson. See you in our next video.

Recap of Adenylate Cyclase GPCR Signaling Example 1

Alright. So here we have an example problem that is asking which of the following statements about the beta adrenergic receptor signaling system is correct. And we've got these 4 potential answer options down below. Now what we need to realize is that the beta adrenergic receptor signaling system is really just referring to the adenylate cyclase GPCR signaling system, the one that we've discussed already in our previous lesson videos. And so we could have identified that because we know that the beta adrenergic GPCR is the specific receptor that's found in the adenylate cyclase signaling pathway. They're referring to the same thing. Now what we need to realize is that options c and d both indicate that insulin is the ligand in this signaling system. However, this is actually not the case. Insulin conducts its signaling transduction through a receptor Tyrosine Kinase or an RTK, which we have not yet covered in our course, but we will discuss these later in our course. But for now, because we have not discussed anything about insulin, we should have identified options c and d as being incorrect. And then notice that both options a and b include epinephrine, which is the correct ligand associated with the beta adrenergic receptor signaling system.

Taking a look at option a, it says that epinephrine binding the beta adrenergic receptor activates G_s alpha, which is the alpha subunit of the stimulatory G protein, by replacement of GDP for GTP. Activated alpha subunit of the stimulatory G protein activates phospholipase C resulting in the release of inositol triphosphate (IP₃), and calcium is released. So all of these things here, we actually have not discussed yet in our previous lesson videos. We have not mentioned anything about phospholipase C or inositol triphosphate or much about calcium or diacylglycerol or anything like that. And really, this is actually referring to another GPCR signaling pathway known as the phosphoinositide GPCR signaling pathway, which we'll talk about later in our course. But for now, because we have not introduced any of these molecules, we should have identified this as being the incorrect answer for this problem. And so, of course, this leaves answer option b, which is the correct answer here:

Epinephrine binding to the beta adrenergic GPCR activates the alpha subunit of the stimulatory G protein by replacement of GDP for GTP, and the activated alpha subunit of the stimulatory G protein activates adenylate cyclase resulting in the synthesis of the secondary messenger cAMP, and cAMP then activates protein kinase A.

This concludes this practice question. I'll see you guys in our next video.

Which of the following does not bind to G-proteins?

• A. GTP.
• B. GDP.
• C. GPCRs.
• D. cGMP.

Here’s what students ask on this topic:

What is the role of adenylate cyclase in GPCR signaling?

Adenylate cyclase is an effector enzyme in GPCR signaling that converts ATP into cyclic AMP (cAMP), a secondary messenger. In the stimulatory pathway, the binding of a hormone like epinephrine to the beta adrenergic GPCR activates a G protein, which in turn activates adenylate cyclase. This leads to an increase in cAMP levels, which activates protein kinase A (PKA). PKA then phosphorylates various target proteins, leading to a cellular response. In the inhibitory pathway, an inhibitory GPCR prevents adenylate cyclase from producing cAMP, thereby reducing the cellular response.

How does the stimulatory pathway of adenylate cyclase GPCR signaling work?

In the stimulatory pathway, the hormone epinephrine binds to the beta adrenergic GPCR, causing a conformational change. This activates a heterotrimeric G protein by promoting the exchange of GDP for GTP on its alpha subunit. The GTP-bound alpha subunit then activates adenylate cyclase, which converts ATP into cAMP. cAMP acts as a secondary messenger, activating protein kinase A (PKA). PKA phosphorylates target proteins, leading to various cellular responses. Termination of the signal involves GTP hydrolysis by the alpha subunit, dissociation of epinephrine from the GPCR, and conversion of cAMP to AMP by phosphodiesterase.

What mechanisms terminate the adenylate cyclase GPCR signaling pathway?

Termination of the adenylate cyclase GPCR signaling pathway involves several mechanisms. First, the GTP bound to the alpha subunit of the G protein is hydrolyzed to GDP, allowing the alpha subunit to reassociate with the beta and gamma subunits. Second, the hormone (e.g., epinephrine) dissociates from the GPCR. Third, cAMP phosphodiesterase converts cAMP to AMP, reducing cAMP levels. Finally, phosphatases remove phosphate groups added by protein kinase A (PKA) to its target proteins, reversing their activation and thus terminating the signal.

How do cholera and pertussis toxins affect adenylate cyclase GPCR signaling?

Cholera toxin affects the stimulatory G protein by inhibiting its GTPase activity, preventing the conversion of GTP to GDP. This leads to continuous activation of adenylate cyclase, resulting in excessive cAMP production, which causes severe diarrhea and dehydration. Pertussis toxin affects the inhibitory G protein by preventing the GDP-GTP exchange, thereby inhibiting its activation. This inhibition of the inhibitor leads to increased adenylate cyclase activity and elevated cAMP levels, contributing to the symptoms of whooping cough.

What is the difference between the stimulatory and inhibitory pathways in adenylate cyclase GPCR signaling?

The stimulatory pathway involves the activation of adenylate cyclase by a G protein, leading to the conversion of ATP to cAMP and subsequent activation of protein kinase A (PKA). This pathway is typically initiated by hormones like epinephrine binding to beta adrenergic GPCRs. In contrast, the inhibitory pathway involves the activation of an inhibitory G protein, which prevents adenylate cyclase from converting ATP to cAMP. This reduces cAMP levels and decreases PKA activity. The stimulatory pathway acts like a gas pedal, while the inhibitory pathway acts like brakes, modulating cellular responses accordingly.