Resetting cardiac concentration gradients

So one thing I wanted to do was compare two types of cells, the ones that we've been talking about most often, the pacemaker cells, and right next to them, the myocytes. And you're going to start seeing some really interesting kind of similarities, and maybe some differences as well between the two. Actually, on this side we'll do our usual millivolts scale, positive and negative, right, and we'll do the same thing over here. On the left we're going to do our pacemaker cell, and on the right we'll do our myocyte. So let's do our pacemaker cell first. And, you remember, the pacemaker cell starts out somewhere around negative 60 and creeps up, right. We've drawn this a few times now. And then it hits its action potential, and it goes up more rapidly at that point, and then finally starts coming back down again. And this is the pattern that repeats over and over. And on the other side we've got our myocyte, our muscle cell, and this is the cell that does a lot of the heavy lifting, as it were, for the heart, what you imagine the heart cell might be. So this myocyte actually starts out a little bit more negative, around negative 90, let's say, and is more flat initially, right. And then it hits its action potential and it rises much more steeply than the pacemaker cells. So now that they're kind of side by side, you can see the difference, right. And then it comes back down as the potassium begins to leak in, except there's a new phase here because the potassium and calcium offset each other, and they begin to have this plateau. And eventually the potassium wins out, and then you get repolarization, where you basically get back down to where it started. So this is kind of a very rough schematic of what it would look like, and let me actually now bring some space onto our canvas. I'm going to make some space here, and let's actually draw the two cells. So we've got a pacemaker cell over here, and I'll draw the myocyte right next to it, right, and this is our myocyte. And I'm drawing them the same size, but that's just so that you can see things clearly. So what's the first thing that happens with our pacemaker cell? Well you know that when it's rising-- when that membrane potential is rising --sodium is actually coming in. And I'm going to draw a little set of lines here to represent sodium coming in. The sodium is coming in here, and then you get a rapid rise. You get that rapid action potential, and for that I'm actually going to draw white lines to represent the voltage-gated channels. So this is my way of representing voltage-gated channels, and here you have predominantly calcium coming in, right. I'm going to take a quick moment to pause here and say, when I say sodium is coming in or calcium is coming in, I don't want you to think that that's the only ion that comes in at that point. When I say sodium is coming in, for example, that's the main ion that the cell is permeable to, but it's not the only one. In fact, we've even talked about the fact that when sodium is coming in, in phase four, that sometimes a few other ions are actually leaking in and out as well. So just keep that in mind. When I draw one ion, it's not to say that that's the only one. It's just to make things a little bit more clean and clear, so that you can get a sense for what's the overall gist of what's happening. OK. So back to our regularly scheduled program. We have now another voltage-gated channel down here, and this is our potassium that's leading. So this potassium leaves, and to make it really clear and parallel, I'm going to actually go one step further and draw on here the phases. We have phase four here. This is phase zero and this is phase one, right. These are the phases of our action potential. And phase four, the main ion we said is sodium. Phase zero, the main ion is calcium. Phase one, the main ion is potassium. Now a cardiac myocyte initially has mostly potassium leaving so the dominant ion here is going to be potassium leaving, and that's what's setting that membrane potential. And then you have in the action potential-- actually let me switch colors to a voltage-gated white channel. So these are the voltage-gated channels now. You have sodium entering the cell. So here sodium is entering the cell like that. In phase one you have now some voltage-gated potassium channels. So unlike the one at the top of the cell, now you've got potassium leaving, just as before, but these are voltage-gated so they kind of flip open and flip closed, based on voltage. And then you finally have another ion over here coming in, which is calcium. You have calcium coming in as well. And so let's do the same kind of exercise we did before, where you go through and label the phases. So we know we have phase four down here, phase zero here, one, two, and three. So this is one, two, and three, and what would this potassium be? Well this potassium is the dominant ion in phase four. Sodium coming in is happening during that action potential, during that phase zero, and then potassium-- these voltage-gated channels-- they're kind of involved in phase one, two, and three. That's kind of a unique property of those channels, and they're not the exact same channel family. They're different families of channels, but the voltage-gated potassium channels are actually involved in a few different phases, and this calcium is involved in phase two. So now you can see how the different channels are involved and also their action potentials, kind of side by side. Now one thing I should also point out is that in the myocyte-- and this is less true of the pacemaker cells-- and I say less true because they also have this, but it's unclear what the role is. They have this thing called a sarcoplasmic reticulum, and a sarcoplasmic reticulum I think of as a magnifier. Sarcoplasmic reticulum. Sometimes you'll see it as just SR, reticulum, a magnifier. Well what do I mean exactly? What happens is that this sarcoplasmic reticulum-- I think of it. It's an organelle basically. It's sitting inside of a cell. It's an organelle, and this sarcoplasmic reticulum is a bag of calcium. Literally, it is a bag of calcium. So this is sitting here with all of these little calcium ions inside, and what it's waiting for is a signal from the cell to say that some calcium has entered. So once this calcium has entered, what it does is-- it binds to a little receptor. It binds to a little receptor right here, and when it binds to the receptor, calcium from the inside of the SR, sarcoplasmic reticulum, is dumped out into the cell. So why is that necessary? If you have calcium already coming in from the outside, why would you need more calcium coming from the sarcoplasmic reticulum, this bag of calcium? What happens is that this bag of calcium can basically empty out really quickly, so you can have just a few ions trickle in from the outside. As long as they bind to that sarcoplasmic reticulum and let it dump out, then you get tons of calcium flooding into the cell. So basically it magnifies the effect of calcium. So just keep that in mind. When we talk about phase two and this calcium entering, the one thing that I haven't really talked to you about until right now, is that there's this magnification that happens because of the sarcoplasmic reticulum. All right. Now let's bring up the main reason I wanted to do this video, which is, when you have all these ions floating in and out, you may be wondering, well how in the world does the cell actually reset. Itself. I mean-- at some point doesn't it need to get things back to the way they were? Otherwise you'll just run out of sodium and calcium on the outside, and you'll just fill up the cell with that stuff. In other words, if sodium and calcium just keep coming in and potassium keeps leaving in this pacemaker cell, at some point won't you have no gradient left? And so how do you set up those gradients? That's the real question, right? So you'll remember that there are these little ATP pumps and a pink pump is basically going to be, for me, my code for using energy. And it's going to be throwing out sodium. It's going to be throwing out three sodiums and bringing in two potassiums. There's also a little pump, little pump over here, that does something very similar, but for calcium, and what it does is basically just boots out calcium. It says, see you later, buddy. So this calcium leaves over here. And actually there's another strategy. There's another pump right here-- I'm going to draw it right here-- that also gets rid of calcium, but this one is not pink. This one does not take energy. So you're thinking, well how in the world do the first two take ATP and this third one not? Well you can think about the fact that there is a sodium gradient. Sodium likes to get inside the cell. We know this, right? And it likes to be inside the cell because you set up a sodium gradient because of this right here. So if you've created a sodium gradient using energy, you can also use that sodium gradient to drive out calcium. So you have a couple of mechanisms to take care of our ion problem, For. example, we needed to figure out how to get rid of this sodium and we've got our answer right there. We had to get potassium back into the cell and we did that right there. And we also had to get rid of all of this calcium that keeps coming in, and we did that right there and there. So this is how our cell takes care of those ions. Now what about our myocyte? How does that work out? How does it reset all the concentration gradients after all this stuff happens, as I described above? It also, of course, has our two ATP-using pumps. So these two are using ATP and it's going to also drive sodium out. Let me just draw that right there. So three sodiums leave. This is all looking kind of the same, right? Two potassiums enter and already I've solved some of my problems, and, just as before, it has this sodium, calcium pump, so calcium exits right there and sodium enters right there. So kind of the same answer as to the last, but you also have this-- remember-- this sarcoplasmic reticulum, and this sarcoplasmic reticulum-- I said it was loaded with calcium. Well how did it get loaded with calcium? How did that even happen? Well the way that it happens is that there's actually a pump here. Let's draw it right here on this side. Basically pumps using energy again, using energy, pumps calcium inside. So you can actually pump calcium into the sarcoplasmic reticulum using another ATPase that's very similar to the one that's on the membrane. They look literally the same, except this one is on the sarcoplasmic reticulum. And doing our same kind of checklist, you can see that-- look --sodium is pumped out and that takes care of this guy. And then we have to bring potassium back in, and that's done there. And then we have to get rid of all of this calcium-- all this calcium that came in here and here. How do we take care of it? Well we pump it out there, we pump it back into the sarcoplasmic reticulum there, and we can exchange it for sodium there. So this is how we take care of and literally reset our cells. Now the final thing I wanted to say is that, if you actually think about it, if we're talking about permeability-- let's say we want to talk about whether more calcium is coming into a cell or out of a cell. Well usually-- under most circumstances-- we think of these guys, all of these energy-driven processes or using concentration-driven processes, operating at a certain rate. They are always operating at a certain rate, and the same is true for these guys. We only have one extra thing over here, but they're operating at a certain rate. Now if I increase the permeability-- let's talk about calcium, for example. Of calcium, let's say increase the permeability of calcium. That means more calcium is entering that space. And if I decrease the permeability of calcium-- I'm talking about this channel right here. If I decrease the permeability of calcium, that means less calcium is entering that space. Now would you accept the following? What if I told you that I'm not even going to change-- let me erase that little line I drew-- I'm not even going to change how this permeability is going to function. All I'm going to do is-- what if I change this, and this Is kind of an interesting idea-- what if I changed how fast this guy works? Well if he starts working more sluggishly-- let's say he is working more sluggishly, then you have more calcium hanging out over here. You have more calcium hanging out in the cell. And let's say you make him work really fast, really, really fast, so he is pumping that stuff back in. Well then you have even less calcium. Now you have the opposite. You'd have less calcium out here. And so you can actually now see how by changing the basal rate of these pumps you can also affect the amount of ion that's hanging out in the cell. And that, of course, is going to affect the membrane potential of that cell. So just keep that in mind as usually we think about this. We're usually thinking and talking in terms of this stuff up here. What is the permeability, what ions are coming in and out, and we kind of assume that this is static, that this stuff is not changing too much. But every once in a while you'll see that resetting the membrane, or resetting where the ions should be, you can actually tweak those mechanisms as well. You can actually make some of these pumps work harder or less hard, and that's going to have an effect on the amount of ions as well.