Glycogen Metabolism: Regulation of Glycogen

00:00 So you have seen really all there is to see with respect to glycogen synthesis and glycogen breakdown. There is only a handful of enzymes that are involved in those entire pathways.

00:12 Now that allows for some simplicity in terms of regulation. But as we will see that regulation has a bit of complexity. But it's focused completely on the enzymes involved in the direct synthesis and the direct breakdown. These, of course, are the glycogen phosphorylase and the glycogen synthase.

00:30 Now the body works with glycogen metabolism largely through hormonal action.

00:36 And hormones are involved in transferring information of one part of body to another. So for example a muscle cell that is undergoing a lot of energy burning from contracting and so forth, can release a signal that says "Hey I am needing some glucose".

00:54 And that signal can travel to the liver, for example, and then cause a process to release glucose.

01:00 The release of hormones is an organismal function.

01:05 It's important to remember that as we talk about some of the pathways that I will be talking about here for hormones stimulation.

01:11 And the reason is that's important is because the needs of the body are quite varied.

01:16 Muscles have a different need than a liver has. Liver is there to supply, muscles are there to use glucose for example.

01:24 So what we are focusing on here are largely liver cells.

01:27 Liver cells supplying the glucose or in some cases storing the glucose for the body.

01:33 The regulation of glycogen metabolism occurs through one of hormones that you see here. Now there are couples of hormones that play role in telling the liver, "Hey, the body is needing some glucose." These include epinephrine and a peptide hormone called glucagon.

01:49 Epinephrine is also known as adrenaline, for example.

01:54 The binding of either one of these hormones to the receptor in the cell membrane that you see in the upper left causes a change in the receptor. A slight change in structure of the receptor and that change is communicated inside of the receptor to the inside of the cell.

02:10 Now that's a very critical step in this process; because, what's called signal transduction that I am talking about here is an essential way that the outside part of the world connects with inside the part of the world of a cell.

02:23 In the signal transduction, the inside of the receptor, and the receptor here that I am talking about is called the beta adrenergic receptor.

02:34 The beta adrenergic receptor interacts with a protein called a G-protein and you see that below in orange.

02:40 That's label with an α, a β and a γ.

02:44 That protein has three subunits and the functional part of that protein, for our purposes, is the part that has the nucleotide GDP located in it.

02:53 And it's the GDP that actually gives the protein the name of a "G" protein. It means it contains guanine nucleotides. The action of the binding of the hormone that changes the receptor changes the interaction between the receptor and the G protein and that two causes two things to happen.

03:13 One thing that happens, is that GDP is released from the α subunit and replaced by GTP. Second the interaction between the α subunit and the β, γ subunit is interrupted.

03:27 So the β, γ subunit is released and the release of the β, γ subunit allows the G-protein to travel from the receptor over to a membrane bound enzyme called adenylate cyclase.

03:42 Adenylate cyclase is an enzyme, as it's name suggest, and what it does is it catalyzes the conversion of ATP into a molecule called cyclic AMP.

03:52 Now cyclic AMP is an example what we call a signaling molecule.

03:55 And cyclic AMP is involved in many signaling pathways we are looking at one of the pathways right here.

04:03 Well the reason cyclic AMP is important is it is an allosteric effectors on protein kinase A.

04:11 Now as we will see in this presentation and subsequent presentations, protein kinase A is central to phosphorylation of many proteins and those proteins have significant changes that happen in their activity as a result of that phosphorylation. So the addition of cyclic AMP to protein kinase A converts it from the inactive form on the right to the active form on the left. That active form on the left then is able to start phosphorylating proteins and the inactive form it is not able to do that. So in absence of cyclic AMP, proteins kinase A will not phosphorylate anything.

04:50 The phosphorylation by proteins kinase A, I wanna focus on the arrows moving down first and then I will talk about the one that into the left later.

04:59 Protein kinase A, phosphorylates proteins, that's how it gets its name.

05:02 And the phosphorylation that it does first is on an enzyme called phosphorylase kinase.

05:09 Again whenever you see the name kinase you should think puts phosphate onto. And so what phosphorylase kinase does is when it's activated, it puts a phosphate onto another enzyme.

05:19 Phosphorylase kinase is converted from the inactive form on the right to the active form on the left by that phosphorylation.

05:26 And that active phosphorylase kinase converts glycogen phosphorylase B which is relatively inactive, into glycogen phosphorylase A which is very active.

05:38 And so what the glycogen phosphorylase A does is it goes and catalyzes the reactions that we have already seen, that is the breakdown of glycogen to make glucose-1-phosphate that can then be used later for energy.

05:50 A second thing that protein kinase A phosphorylates, is it phosphorylates the enzyme glycogen synthase that we have already seen. Now glycogen synthase, of course, is involved in the synthesis of glycogen. The effect of phosphorylating glycogen synthase it to do exactly the opposite thing.

06:10 In the case of glycogen synthase, the B form is the active form and the A form which is phosphorylated in inactive.

06:17 As a result of this, glycogen synthase is converted into an inactive form.

06:22 So what's happened here is what we call reciprocal regulation.

06:27 Protein kinase A has started what we call a phosphorylation cascade that is resulted in the different effects on catabolic and anabolic pathways.

06:37 Breakdown is activated and the synthetic pathway is inhibited.

06:42 So as we have seen this system is designed then to put phosphate onto glycogen enzymes and these additional phosphate on the glycogen enzyme is activated by the hormone stimulation and you have seen little bit of the effects that these can have on the activity.

06:56 Glycogen synthase, a synthetic enzyme, is less active with phosphate and glycogen phosphorylase it breaks down glycogen is more active with phosphate.

07:06 Now this reciprocal regulation is very very important for these metabolic pathways and reciprocal regulation as a principle is very important for catabolic and anabolic pathways in general.

07:20 Now you can see here the phosphorylation that's happened on there and the phosphorylation or the addition of those phosphates must be removed in some way; because, cells are control freaks, as I like to say, cells if they wanna do something they wanna also be to reverse what they do and they have to be able to reverse what they do; because, is really important here. Glycogen is a resource of the body and the activity of a glycogen breakdown enzyme is such that it could very readily breakdown the glycogen and waste all the glycogen if it was doing that when the glycogen was not needed.

07:54 So it's important that this breakdown be controlled and the breakdown is controlled by removal of phosphates as we shall see by an enzyme called phosphatase.

08:03 Now another interesting consideration occurs at the top. So when we are talking about reversing and stopping this pathway, if we stop the lower part of the pathway but we don't stop the upper part of the pathway, then this signaling will continue to activate glycogen breakdown.

08:21 So it's important that these internal things inside the cell be turned off at all levels.

08:26 And this is a very interesting process, the G-protein that you see on the left with a GTP bound to it. The G-protein is a very inefficient enzyme and because it's an inefficient enzyme it is able to do what it does. Now that may seem very odd but it's true.

08:43 What happens is, the G-protein besides activating adenylate cyclase has an enzymatic activity of its own.

08:51 And the enzymatic activity of its own is that it cleaves GTP and leaves behind GDP.

08:58 Well when the G-protein has GDP on it, we have already seen what happens to it. It goes back to the receptor and binds to the receptor and the β and the γ bind to it.

09:09 So the G-protein has a way of turning itself off.

09:13 But what's important is because it's an inefficient enzyme it doesn't cleave GTP too fast.

09:20 So by having an inefficient enzyme, it takes a few seconds to a few minutes for that conversion to happen. So that it's able to communicate the signal to the adenylate cyclase to be active, but it is able to turn itself off automatically by that.

09:36 Now the other molecule that is interesting in this respective, cyclic AMP; because, cyclic AMP must be dealt with.

09:40 Otherwise it will continue to activate protein kinase A, and that's what happens as we can here in the next slide.

09:46 Cyclic AMP is broken down to AMP by the enzyme phosphodiesterase.

09:52 And when that happens AMP will not stimulate the process, as I have talked about, and so the signal has been turned off.

09:58 Now you will notice above that enzyme phosphodiesterase is inhibited by caffeine.

10:04 Now caffeine has numerous effects on the body but I always like to remind people that you think about that buzz you get from caffeine. What's happening with that buzz? Well part of that buzz comes from the fact that the phosphodiesterase is being inactivated.

10:18 And when the phosphodiesterase is being inactivated protein kinase A is being activated and glycogen breakdown is being stimulated.

10:25 So what you are doing by drinking caffeine at lease to a limited extent is increasing your blood glucose. That's part of your buzz.

10:33 Now so in summary here when glucose levels are low the body signals the liver with epinephrine or glucagon and it increases the glucose concentration by favoring glycogen breakdown and inhibiting glycogen synthesis, the reciprocal regulation that I have talked about before.