β-adrenergic Receptor Signaling

by Kevin Ahern, PhD

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    00:01 Now if we look at what’s happening with this system, and by the way this system is known as the β-adrenergic receptor.

    00:07 What’s happening in this system? We can actually see the overall process.

    00:11 There’s the hormone that binds to the receptor, there is the activation of the G-protein with the α subunit getting a GTP.

    00:19 The interaction of the α subunit with the adenylate cyclase.

    00:23 The formation of cyclic AMP.

    00:25 The activation of protein kinase A, the activation of phosphorylase kinase.

    00:32 The inactivation of glycogen synthase.

    00:35 The activation of glycogen phosphorylase-a.

    00:37 And the breakdown of glycogen.

    00:40 This process happens very rapidly.

    00:44 Everything that we see here is an enzymatic reaction.

    00:46 And enzymes work really, really quickly.

    00:49 You notice that in this pathway, there’s no movement into the nucleus.

    00:54 This is important because movement into the nucleus and activation of gene expression is a very slow process.

    01:02 In our cells it takes about 24 hours for that to happen.

    01:05 Well it’s important if you’re in a dark alley for example because imagine that someone’s chasing you.

    01:10 You need to have energy and you need to have that energy right now.

    01:14 You can’t wait 24 hours for gene expression to occur so that you can make something that can make you some glucose.

    01:20 This pathway which regulates the activity of enzymes and doesn’t have anything to do with gene expression is an example of one that works very, very quickly.

    01:31 Now, when we think about turning on a system which I’ve described here, that’s pretty straightforward.

    01:36 But we think, cells can’t continually have the system turned on because if they left the system turned on all the time, they would be continually breaking down their glycogen.

    01:45 They wouldn’t have any glycogen.

    01:46 And glycogen’s a pretty important storage molecule for energy.

    01:50 So just like they’ve got to be able to turn on glycogen breakdown quickly, they’ve also got to be able to turn it off quickly when the need for glucose from the glycogen breakdown diminishes.

    02:02 So there are several things that have to be deactivated in this process.

    02:06 So I’m going to step you through the process of deactivation of the β-adrenergic receptor.

    02:11 The receptor itself has to be deactivated.

    02:14 The G-protein that I described with the α subunit has to be deactivated.

    02:18 The cyclic AMP, the small molecule has to either be destroyed or hidden in some way so that it can’t exert its effects. Protein kinase A needs to regain the regulatory subunits. Phosphorylase kinase needs to lose its phosphate. Glycogen phosphorylase A needs to be inactivated. And when this all happens, glycogen synthase, the synthesis of-- the enzyme involved in the synthesis of glycogen has to be activated. So all these things have to happen, and the reversal of that process. Well let’s look to see how that happens. We’ll start with the receptor.

    02:52 The receptor is shown here as we saw before.

    02:54 The receptor is depicted with the exterior part of the cell being up and the interior part being below which is where the G-protein interacts with it.

    03:04 One of the things that happens in the inactivation process of the receptor, is the receptor gets phosphorylated.

    03:11 It gets a phosphate attached to it.

    03:13 And this happens as a result of action of a protein known as G-protein receptor kinase.

    03:19 You can see the addition of the phosphate to the bottom of the receptor.

    03:23 That phosphate is target for binding of a protein known as arrestin.

    03:28 Now arrestin sees that phosphate, grabs a hold and covers it up.

    03:32 And the effect of arrestin being there prevents the G-protein from interacting with its receptor.

    03:39 This therefore blocks the receptor and prevents it from communicating further signals into the cell.

    03:45 It also favors the process of endocytosis, that is the pulling in of the receptor into the cell, so that cell can either break it down or do something with it.

    03:55 So we’ve inactivated the receptor as a result of this action I’ve just described here.

    04:01 Next we think about-- and by the way, I’m describing these in an order.

    04:04 There is not an order associated with them for the most part.

    04:07 But I will talk about them in the way that they happen during the overall signaling process.

    04:13 The next thing is that the G-protein has to itself be inactivated.

    04:17 And that turns out to be a really interesting phenomenon.

    04:20 We see here first of all, the G-protein can’t interact with the receptor.

    04:23 But we remember that cells have hundreds of copies of a receptor, and we’re looking at one.

    04:29 So just because we block one receptor, doesn’t mean that the other receptors aren’t available.

    04:35 This means that the G-protein has to itself be deactivated.

    04:39 And that deactivation process is something that it does to itself which is kind of cool.

    04:44 Well how does that happen? Well it turns out that the α subunit of the G-protein is a very bad enzyme.

    04:52 Yeah, I said that right.

    04:52 It’s a very bad enzyme.

    04:55 What does that mean? It means that it catalyzes a reaction but it doesn’t catalyze a reaction very well or very fast.

    05:02 The reaction that it catalyzes is it breaks down GTP.

    05:06 And in breaking down GTP, the product is GDP.

    05:10 Well why is that important? Well of course, remember when the GDP was bound to the α subunit, it was no longer in the active state.

    05:17 It will no longer interact with adenylate cyclase.

    05:20 So the α subunit in this reaction has turned itself off.

    05:24 And it being a very inefficient or a very bad enzyme, means that it didn’t turn itself off as soon as it got the GTP.

    05:33 If it was a good enzyme, it would break down the GTP immediately and no signal will be communicated.

    05:38 This process of breaking down the GTP can take from a few seconds to a few minutes which allows enough time to communicate that signal but not allow the signal to continue to propogate.

    05:48 Pretty cool.

    05:51 Once the GDP is back in the α subunit as we see here, the β and γ subunits can then interact with it again.

    05:58 And this will then ultimately go to another β-adrenergic receptor or GPCR and wait for the next signal.

    06:07 The next molecule that I’ll describe, the elimination of, is that of cyclic AMP.

    06:12 Cyclic AMP you recall was necessary to activate protein kinase A.

    06:17 Cyclic AMP is broken down by an enzyme known as phosphodiesterase.

    06:21 Now the cell is full of phosphodiesterase.

    06:23 Phosphodiesterase is usually present and it’s usually present in an active form.

    06:30 So cyclic AMP, once it’s been made, usually also doesn’t hang around for very long because it gets found by phosphodiesterase and cleaved to make AMP.

    06:40 Well as AMP it can’t do anything, so this phosphodiesterase being present allows cyclic AMP to rapidly be degraded.

    06:50 Well cyclic AMP was necessary for of course activating protein kinase A.

    06:54 And you’ll see the green form there.

    06:55 So without the cyclic AMP being present, the regulatory subunits can now come back and replace what little cyclic AMP was associated with the protein kinase A, and recreate the inactive protein kinase A bound to the regulatory subunit.

    07:11 The protein kinase A has therefore been turned off.

    07:16 Alright, well the next process in the scheme, is removing phosphates.

    07:20 And it turns out this is actually the simplest step that happens.

    07:24 There’s an enzyme known as phosphoprotein phosphatase.

    07:27 And phosphoprotein phosphatase is an enzyme that’s stimulated by the addition of insulin to the outside of a cell. Insulin causes this protein to become active and what this protein does is it removes phosphates from other proteins. Well we can imagine what’s going to happen here.

    07:45 The removal of phosphate from phosphorylase kinase causes the phosphorylase kinase to move from the active to the inactive form.

    07:55 We see the removal of the phosphate from the glycogen phosphorylase-a causes it to flip into the glycogen phosphorylase-b form which is also inactive.

    08:03 And the removal of the phosphate from glycogen synthase causes it to flip into the green form which is the active form of glycogen synthase.

    08:12 So with this last step, now all of the processes that got activated during the binding of the epinephrine have been reversed. There’s one other thing I want to say something about. And that one thing I want to say something about is to take you back to this slide right here. This slide you remember still showed active cyclic AMP being present. And when cyclic AMP was present, we saw all these other proteins being active and glycogen synthase being inactive. But why am I coming back to this slide? I’m coming back to this slide because remember the phosphodiesterase breaks down cyclic AMP. A really cool fact is that phosphodiesterase breaking down cyclic AMP to make AMP is inhibited by caffeine. So that morning cup of coffee that you had, you said it gave you a little buzz, well the little buzz that it gave you came from the fact that with cyclic AMP levels present in your cells, you’re putting out more glucose. So that little buzz that you had was a little bit of sugar that came from the inhibition of phosphodiesterase by caffeine.

    About the Lecture

    The lecture β-adrenergic Receptor Signaling by Kevin Ahern, PhD is from the course Hormones and Signal Transduction. It contains the following chapters:

    • β-adrenergic Receptor Signaling
    • G-protein Inactivation
    • cAMP

    Included Quiz Questions

    1. cAMP is broken down by phosphodiesterase.
    2. Arrestin favors exocytosis.
    3. Caffeine inhibits glycogen phosphorylase.
    4. The α-subunit of the G-protein turns itself off.
    5. Phosphoprotein phosphatase converts GTP to GDP.
    1. The arrestin protein after phosphorylation on its intracellular part by G-protein receptor kinase enzyme.
    2. The G-protein receptor kinase, under the guidance of arrestin protein.
    3. The phosphate group on its extracellular domain part.
    4. The cAMP molecule on its intracellular domain sites.
    5. The GDP-αβγ molecular entity under the guidance of G-protein.
    1. It breaks down GTP.
    2. It synthesizes ATP.
    3. It breaks down GDP.
    4. It digests adenylate cyclase.
    5. It autodigests itself.
    1. Phosphodiesterase
    2. G-protein receptor kinase enzyme
    3. Phosphatase
    4. Protein kinase A
    5. Phosphorylase kinase

    Author of lecture β-adrenergic Receptor Signaling

     Kevin Ahern, PhD

    Kevin Ahern, PhD

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    By Rina Alejandra R. on 21. July 2021 for β-adrenergic Receptor Signaling

    Thank you so much This video helped me so much en my sesions of study

    By Juan G. on 09. June 2021 for β-adrenergic Receptor Signaling

    Thank you Dr. Ahern for this very comprehensive lecture. Going through the biochem book makes this topic very complicated. It is amazing how you can simplify this topic to get to the point and what we actually need to understand.

    shallow lectures
    By gioia b. on 06. February 2018 for β-adrenergic Receptor Signaling

    the lectures is shallow; i think that more details are needed. it is ineffectual for the level required from the biochemestry course of the Med University of Florence. cordially gioia