in this video, we're going to revisit our map of the lesson on bio signaling pathways, which we have down below right here. And of course, we know that we've been exploring this map by following the left most branches first. And so we've talked about G protein coupled receptors or GPC. Ours, and we've talked more specifically about a specific GPC are signaling pathway the A dental It cycles. GPC are signaling pathway in terms of the stimulatory pathway that involves C amp and Peek A, as well as the inhibitory pathway that we introduce in our previous lesson videos. And so now in this video, we're going to continue to talk about the inhibitory pathway as we talk about drugs and toxins that can affect the identical it cycles. GPC are signaling and so let's get started talking about that. So here we're going to introduce some drugs and toxins affecting GPC are signaling, and more specifically, we're going to talk about two bacterial toxins that you guys should know and we have both of these bacterial toxins number down below number one and number two now these two bacterial toxins will both target G proteins, although they target different G proteins. One of them targets the stimulatory G protein and the other targets the inhibitory G protein. And both of these bacterial toxins will also indirectly increase the activity of the effect er enzyme a dental. IT cyclists. However, they will increase the activity of a dental it cycles in different ways that will get to talk about here very shortly. Now the very first bacterial toxin that you guys should know is cholera toxin and cholera toxin inhibits the GTP ace activity of the G s G protein, which is the stimulating G protein Alfa sub unit. And this causes the disease cholera, which is characterized by extreme diarrhea and dehydration. And so it's definitely not something that you want to have. Now. What we need to recall from our previous lesson videos is that the GTP ace activity of a G protein is when it cleaves the high energy GTP into the low energy G, D P. And so GPS activity in activates the G protein. But if we inhibit something that in activates the G protein, then essentially what we're doing is permanently activating or we have a permanently active G protein. Alfa sub unit and this permanently active G protein. Alfa sub unit will then thus be able to overstimulate a dental IT cyclists activity, essentially increasing the activity as we already mentioned. And so if we take a look at our image down below, over here on the left hand side, notice that we're focusing in on cholera toxin and it's a bit and its ability to overstimulate the G protein and so notice that we have our extra cellular lie again are hormone epinephrine that binds to the beta Andrew Energy. GPC are causing a confirmation. I'll shift in this G p c r, and that is going to activate the G protein because it's going to cause it to exchange the low energy G d. P with the high energy GTP and then the G protein Alfa Sub unit will associate and be able to activate a dental it cyclist so it can create. Essentially, it can catalyze the reaction that converts a TPM to see amp are Secondary Messenger now, normally, the G protein Alfa sub unit for G s, the stimulating G protein would only remain active for a relatively short period of time because over time, eventually this GTP would get cleaved down to G d. P. The low energy, um inactive form. However, notice that the bacterial toxin cholera toxin will actually inhibit this GTP ace activity. So it will not allow the G protein to convert GTP into G d. P. And so that means that GTP will remain associated with this Alfa sub unit and it will continue to activate a dental it cyclists. Essentially, it will continue to overstimulate um, the A dental it cyclist. And so what we can say is that the stimulatory g protein Alfa sub unit gs and therefore a dental it cyclists a c are always going to remain active in the presence of cholera toxin. And again, uh, this will lead to the disease cholera, which is characterized by extreme diarrhea and dehydration, which is why we have this toilet over here. And so really, you can think of the bacterial toxin cholera toxin almost like having the gas pedal down to the metal. So it's almost like having the pedal to the metal where you're pretty much accelerating the activity of a dental. It cycles to its maximum again because, uh, the GTP, uh, GPS activity is being inhibited by collar toxic. And so if we move on to our second bacterial toxin that we're gonna cover here it is. The toxin called pertussis toxin and pertussis toxin differs from cholera toxin really in two major ways. The first is that it doesn't inhibit GTP ace activity. Instead, it inhibits the GDP GTP exchange, which is different, and also it does not inhibit the stimulating G protein Alfa sub unit GS. Instead, protesters toxin inhibits the inhibiting G protein Alfa sub unit, or G Ay. So it's almost like inhibiting and inhibitor. And so this causes a different disease called whooping cough instead of causing cholera. Now, recall from our previous lesson videos that the GDP GTP exchange is really what activates the G protein. And so if we inhibit something that activates the G protein, then that means it's going toe permanently. Remain an active and so we have a permanently inactive G i protein Alfa sub unit. But recall that when g I is active, what it does is it inhibits a dental it cyclists. And so if we have an inactive G I, that means that we're inhibiting an inhibitor, and so what we're doing is we're preventing a dental it cyclist from being inhibited, which is kind of a strange way of increasing its activity. And so it's increasing the activity in a different way than what cholera toxin increases the activity. So let's take a look down below at our image, and we're focusing this time on the right hand side of our image, and we can see that the bacterial toxin pertussis toxin is really going to inhibit the inhibitor, and the inhibitor is again the inhibiting G protein Alfa sub unit, G. I. And so what we have is our inhibiting ligand up here that's going to bind to the inhibitory. GPC are causing a confirmation. I'll shift that would normally allow for GTP to come in and replace G. D. P. And then when that would happen, what would normally happen is the Alfa sub unit would then dissociated to inhibit the A dental it cyclists, essentially causing it to create less. See amp, however, noticed that in the presence of per Tutsis bacterial toxin here, it actually inhibits the GDP GTP exchange. And so GTP is never actually able to get in and replace G d. P. So that means that the G protein Alfa sub unit is going to remain in its inactive state, and it will never be able to disassociate to inhibit a dental it cyclists so down below. What we can say is that the G I is always going to remain inactive and because it is the G I protein. If we have an inactive G, I. Of course, that means that the A dental it cyclist is never going to be inhibited. And so that's almost like a way of again increasing the activity of a dental it cyclists again by inhibiting the inhibitor. And so you could think of pertussis toxin almost like broken brakes on a car. You won't be ableto slow down the rate, However, as long as the gas pedal is working properly, then it's going to create a different effect than pedal to the metal over here. And so again, pertussis toxin is associated with the disease whooping cough, which is why we have this character over here coughing. And so really, this concludes our lesson on these two bacterial toxins, cholera toxin and pertussis toxin, and as we move forward in our course, will be able to get some practice applying these concepts so I'll see you guys in our next video
Drugs & Toxins Affecting GPCR Signaling Example 1
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All right. So here we have an example Problem that says cholera toxin blocks GTP. Hydraulics is of the stimulating G protein Alfa sub unit, whereas pertussis toxin prevents the interaction of the inhibiting g protein Alfa sub unit with a dental it cyclists. What is the effect of these toxins on the intracellular concentration of C. Amp. And we've got these four potential answer options down below? And so what we need to recall from our last lesson video is that both cholera toxin and pertussis toxin will increase the activity of the effect er, enzyme a dental it cyclists. Now they do it in different ways, but ultimately they both lead to an increase in the activity. And so, of course, a dental it cycles is responsible for converting a teepee into see AMP. And so increasing the activity of a dental it. Cyclists will increase the concentration of Cmte within the cell. And so we would expect that both cholera toxin and pertussis toxin should lead to an increase in the sea and concentration. And so we could go ahead and indicate that See, here is the correct answer, and all of these other ones are just trick answers that are trying to tempt you. But see here is correct. And that concludes this practice. So I'll see you guys in our next video.
Cholera toxin increases the cellular cAMP levels by:
Binding to and activating GPCRs.
Altering the activity of stimulatory Gs proteins.
Inhibiting phosphodiesterase activity.
Binding to and inhibiting adenylyl cyclase.
Altering the activity of inhibitory Gi proteins.
Pertussis toxin is produced by Bordetella pertussis, the bacterium that causes whooping cough. Pertussis toxin catalyzes the addition of ADP-ribose to Gi which ‘locks’ it in the GDP-bound state. If the uninhibited, toxin free GPCR pathway normally results in decreased glycogen synthesis, then what would be the effect of pertussis toxin?
It would decrease contraction.
It would decrease glucose production.
It would further decrease glycogen production.
It would increase the rate of endocytosis.
Drugs & Toxins Affecting GPCR Signaling
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in this video, we're going to distinguish between agonists and antagonists and so many clinical drugs are developed to act either as agonists or antagonists to various receptors. But what exactly are these agonists and antagonists? Well, an agonist can be defined as a structural analog to a ligand or a molecule that is going to very closely resemble the structure of the ligand and this structural analog is going to bind receptors and mimic the effect of the original or natural ligand. Now, antagonists, on the other hand, are also structural analogs that resemble the structure of the original Liggan. However, the antagonist is going to bind the receptor without triggering the normal effect. And so if the normal effect is not going to be triggered, then that means that it is going to be blocking the effects of the agonist or the lichen. And so really you can think of antagonists as functioning very, very similarly to competitive enzyme inhibitors. And so recall that competitive enzyme inhibitors would compete with the substrate for a binding position to the active site and therefore it would block the active site and block the substrate from binding the active site. And so antagonists can work in a very similar way where they bind to the receptor and block the original Ligon or the agonists from binding to the receptor. And so if we take a look at our image down below, we can look at an example of how caffeine a molecule found in your typical coffee actually acts as an antagonist to the adenosine receptor. And so notice on the left hand side over here, what we're showing you is the chemical structure of the molecule Adina scene, which is actually going to be the ligand. The original Ligon to the edina seen receptor. And then on the right notice that we're showing you the chemical structure of the molecule caffeine which again you can find in your typical coffee that you might drink in the morning. And so notice that the caffeine molecule right here in this red region is going to very, very closely resemble the structure of the ligand. However, it is not identical. You can see that the branching units here are going to be different and so on the right side of the image, uh notice that we have two regions we have the top half and then we have the bottom half of the image and notice that the top half of the image is showing you the adenosine molecule binding to the adenosine receptor. And so here you can see the adenosine molecule binding to the adenosine receptor and of course Adina scene is the normal or natural ligand for the adenosine receptor. And so when the adenosine molecule binds the adenosine receptor, it's going to trigger the normal effect. And the normal effect of the adenosine molecule binding to the adenosine receptor is going to be decreased heart rate. And this decreased heart rate is actually going to lead to a drowsiness type of effect, where you're going to feel somewhat tired and sleepy. Now, down below In the bottom half of the image we're showing you caffeine this antagonist binding to the same adenosine receptor. And so because caffeine is an antagonist, it's going to function very similarly to a competitive enzyme inhibitor. And so when caffeine binds to the adenosine receptor it will block a dina scene from binding. And so therefore when caffeine binds it will block the normal effect that adenosine usually has. And so instead of decreasing heart rate when caffeine binds, it is actually going to lead to an increased heart rate. And this increased heart rate is going to lead to a more wakefulness type of effect where you're going to feel more awake and more energized. And so this is why a lot of you drink coffee in the morning is to get that caffeine stimulation that leads to increased heart rate and a more wakefulness effect. And so this year concludes our brief example of how caffeine acts as an antagonist to the identity and receptor. And it includes, concludes our brief discussion on agonist and antagonist. So we'll be able to get some practice applying these concepts as we move forward. So I'll see you all in our next video
Caffeine is a molecule that binds to ______________ receptors, inhibiting their response.
Caffeine is a(n) __________ of adenosine that blocks its receptors from activation.