Welcome back, so today's going to be our third lecture in this course. And we want to talk about the division between the cell and its extracellular environment. As I said in the first First lecture that every cell has a membrane around it and that membrane forms a hydrophobic barrier and that prevents ions or any charged molecules from moving from the extracellular space into the interior of the cell. So that exit and entrance of these hydrophilic molecules, that is charge molecules is going to be regulated by the cell. And so today we're want to talk about the kinds of proteins that are used to regulate the exit and entrance of hydrophilic materials from our cells. So the learning objectives then, or one we're going to describe, how solutes are moving across the cell membranes. Two we want to explain how charge, size, and their solubility will affect the solute movement across the membranes. Three, we want to contrast how the transporters, pumps, and channels work. So these are the proteins that are going to mediate the movement of hydrophilic materials, that is charged materials, across the membranes. And lastly we want to describe how the ion channels are gated, that is the regulation of movement across these channels. So, the first thing is that you have to remember that the cells have a hydrophobic barrier and that this barrier is a bilayer of lipid. So this lipid then, this bilayer of lipid, allows hydrophobic materials to come across but not the charged entities. But our physiology, the parts of the physiological processes are controlled by a lot of signals that are coming from the extracellular space and it has to come into the cells or they have to change the property of the cell in some manner. And the kinds of physiological processes that are controlled are, one growth. Two, our metabolic processes. We have to be able to move fuel across the membranes for instance. So, glucose has to be able to enter into cells. And then, thirdly we're going to use some of this movement across membranes to signal information from the environment back into the body to the integration center, which is our brain, and then back out to the effectors. So in order to be able to govern the nervous system, we have to be able to convert chemical information, which is coming in from the environment into an ion and this ion then travels, the ion flow is going to then take information to the brain, where it can recognize the information. And then they send out also by ion flow to the effectors, to something like glands or to the muscle. The other reason that we're interested in this topic is that this is really the basis of many diseases. When we have defective transporters, such as in cystic fibrosis, then materials are not positioned correctly across the membranes. For instance in cystic fibrosis the chloride is not moving across the membrane correctly. And because the chloride ion is not moving correctly, water is not moving correctly across these membranes. Consequently the mucus, which is secreted by the lung as a protective barrier, becomes very, very thick and viscous. And there's a difficulty then for transporting gases across this mucus layer. So the oxygen then can get into the blood. The other one is that we can have defective channels and we'll talk about what channels are in a minute. But in these cases the channels can be allowing calcium or sodium or potassium to be moving across the membranes. In the long QT syndrome of the heart, we find that some of these channels are defective, and that then changes the way the heart is able to have its beat. And because the beat is prolonged, then what happens is that the heart can go into arrhythmia. The other thing that we should notice is that these channels and the pumps and the transporters often are the target sites for therapy for our drug therapies. So for instance when you have hypertension and somebody has a blood pressure that's very high, they may be treated with a diuretic. The diuretic inhibits the ability of a sodium transporter to move sodium across membranes and therefore water cannot follow sodium, and what happens then is that the sodium and the water are peed out from the body. So, we increase the amount of urine production from the body. By doing so, you decrease the volume of the ECF and by decreasing volume of the ECF, you decrease blood pressure. We also have drugs that can be used to treat stomach ulcers, so in stomach ulcers you have an erosion of the epithelial cells that line the stomach and under these conditions the acid is the causative agent. By blocking the ability to make acid in the stomach, then the ulcer can heal. And so, these are called proton pump inhibitors. And when we talk about the stomach and it's activity, the physiological role of the stomach in it building to make acid in the GI tract, that is the gastrointestinal tract, then we'll be talking about these proton pump inhibitors. All right, so let's look at the very simplest way of moving materials across a plasma membrane. And that's what's diagrammed here. So, if you can imagine that we have a plasma membrane which is here, and that this plasma membrane then again is going to be our bilayer of lipids, so it's a hydrophobic barrier. And we have the ICF is the yellow component and outside of that we have our ECF. So we have this orange material which is sitting in the ECF and the membrane is able to allow this material to cross the membrane. So this material is permeable to the membrane. So, the material then can enter into the ICF and it will enter by gunning down this concentration gradients. So, it has high concentration of the orange material in the ECF. And so the dominant movement of the material is towards the interior of the cell because the cell has very low concentrations of material. This is by what's called diffusion and that this is simply a random movement of particles going across this permeable membrane. Because the plasma membrane is a bilayer of lipids, any molecule that is soluble in a hydrophobic materials, that is a soluble in lipids, such as urea, can easily pass across the plasma membrane. So the orange material could be urea. So as the urea then enters into the cell, we also have a very small flow of the urea back towards the ECF. But this is a very small flow because we have a very high concentration of the urea in the ECF and a very low concentration in the ICF. The flux, which is going to be the random movement of this material across a surface per unit time, is going to be determined by the gradient. So the net flux is determined by the gradient. And we go from a high concentration to a low concentration. And this is called simple diffusion. And simple diffusion can also occur between two cells, for instance, in the cardiac myocyte, we have a small junction, which is called a gap junction or a nexus. And this structure is a little pore that's between the two cells. Two adjacent cells. If we have a high concentration of calcium in the first cardiac myocyte, this calcium can diffuse through the gap junction to the second cell. Which is shown here. And again, the diffusion is down the concentration gradient. So the gap junctions then are allowing the diffusion of ions and notably calcium from one cell to the other cell, and this occurs through all the cardiac myocytes of the heart that are contractual. So these cells are all connected to one another, so that when they contract, they have a wave of calcium that goes across all the cells and they all contract synchronously. So, the characteristics then of the simple diffusion is that is the molecules going to move from a high to a low concentration, that it requires no energy expenditure. And third, that it will continue until the equilibrium is reached. That is, we will have an equal concentration of the materials on wither side of the membrane. Fourth, it occurs rapidly over short distances, but very, very slowly over long distances. So we can move materials from the vasculature across the interstitial space, which is pretty narrow, and into the cells by diffusion. But it would take way too much time to move materials from the GI tract all the way to the lung or to the brain by diffusion. So we have to have the cardiovascular system which has a pump and moves material by bulk flow. Five, the simple diffusion is directly related to temperature. So if I increase temperature, the system will go faster. If I decrease temperature, the system slows. And six, it's inversely related to the size of the molecule. So if the molecule is very large, then it's going to be very slow diffusion for that molecule. If the molecules are very small like an ions, say a sodium ion, then the diffusion path can be quite rapid. And seven, we have the diffusion will be dependent on the total surface area that's available. So a large surface area, you have a lot of diffusion, very small surface area, very small amount of material that can cross at that particular point. It's also dependent on the thickness of the membrane that is going across. And this is going to be very important when we talk about the respiratory tract because if the membrane between the air space and the vasculature thickens, because we have water in that area or we have some kind of fibrosis so we have connected tissue in that area. The diffusion path for gases will be lengthen and then the diffusion of the gas across that region will be impaired. And we'll talk about that some more when we talk about the respiratory tract. So that's the simple diffusion and that works for hydrophobic molecules. But molecules that are not soluble in lipid, that is molecules that are hydrophilic, they're polar molecules, they're charged molecules, they can not move across the plasma membrane by simple diffusion. Instead, some of them are using what are called transporters, and transporters are integral membrane proteins, so they're actually stuck into the center of the membranes. So if we look at this membrane, we have our bi-layer of lipids and that's here. So this is our membrane. The bi-layer of lipids has molecule that's actually embedded within the bi-layers. When they are embedded in the bilayer, they're called integral membrane proteins. This particular integral membrane protein can be open to, in this case the ECF of the extra cellular fluid space. But ti can change its confirmation and then opens to the intracellular fluid space and it does so by simply flipping back and forth across the membrane. So a particular example of this would be the glut transporter, that is the glucose transporter or the gluts. This is the family of transporters that can move glucose into cells and all cells have glut transporters. The glucose can enter into our carrier, this transporter, and as it enters into the transporter from the extra cellular space, then there's a conformational switch and now the glucose is released into the interior of the cell. This particular transporter can move in both directions and so the net flux or the net flow of the material across the membrane is dependent upon the concentration of the material. So if the material is high concentration in the ECF, then we will have a net movement of the glucose into the cell. But the glucose that's within the cell can also enter into the transporter and move back across the membrane. So it is a system which simply is active depending upon the diffusion gradient. So this is called facilitated diffusion because we're using an integral membrane protein to move the solute across the membrane. And there's a couple of things about the facilitated diffusion that we should think about. One is, is that they're specific. These transporters are specific for a given solute. So the glucose transporter transports glucose but it does not transport an amino acid or peptide or something like that. The second thing is that there's a finite number of these on the membrane surface so that we can, under certain circumstances, saturate all of these transporters. And at that point, we can't get any further transfer of material across the membrane. That is, our net flux across the membrane, becomes constant. And that's what we can see here on this next diagram. So, here I've diagrammed then the flux versus the solute concentration. So, let's say this was our glucose. The glucose in the ECF and that the solute concentration is increasing as we go towards in this direction. The flux of course is our transport rate across the membrane itself. And if we look at this simple diffusion, the simple diffusion would be for urea for instance, then the urea as we increased the urea along the x axis. So if we increase urea along here, that the solute concentration of urea, then the urea is moving in a linear function and that never acetates. But if we look at the facilitated diffusion for the glucose, then what we is that glucose will saturate all of the receptors or all of their transporters at this point so that at that point, any concentration of glucose beyond that does not cause an increase in the transfer rate or in the flux across the membrane. Now, some of these transporters are able to take more than one solute at a time. For instance, we can have a transporter that will move glucose and sodium together. And these occur within the gastrointestinal track. They also occur within the renals tubules. This sodium glucose transporter is a co-transporter, taking two solutes across the membrane at the same time. And again,it will load on one side of the membrane, undergo confirmational change and then release the material on the other side of the membrane. And here again is our hydrophobic bi-layer. If the molecules, the sodium and the glucose in this case, are moving in the same direction, they're going from the ECF into the ICF, then it is called a symporter. They're moving in the same direction. And importantly, this only works if both the sodium is present and the glucose is present. So we have to have both solutes present in order for this transporter to work. But we do have in some instances antiporters. And the antiporters are again, we can find these in the gastrointestinal tract and within the renal system, within the renal tubules. And here, we are moving both a sodium, in this case, a sodium and a proton but they're moving in opposite directions. So this transporter, as it's moving a sodium into the cell is moving in the proton out of the cell and into the ECF. Because they're going in the opposite directions, this is called an antiporter. Again, their specificity with this transporters, they're only are binding the specific solutes and both solutes have to be present for the transporters to work. And again there's a finite number of these on the cell surfaces. And therefore, the transfer of the material from one side of the membrane to the other can be saturated. Now, we do have instances where there's actually a pore made across the plasma membrane. So again, we have our hydrophobic barrier, just our bilayer of lipid. And these are integral membrane proteins which are inserted within the membrane. But when they're open, there is an aqueous pore that goes all the way across the membrane. An example of one of these is the aquaporine. Aquaporine is a pore that is used for moving water across the membrane, and in almost all cells, aquaporines are present, and so water will almost immediately reach equilibrium across a plasma membrane. But under some circumstances, we have channels where the pore is gated, that is it's closed, and there's a regulated opening of the pore. And this regulated opening of the pore is called gating. In both cases when the pore is open then the movement of the particle across the channel will be by diffusion, and we will be moving from high concentration to low concentration. So in the case of the aquaporine, we could have water which is higher in concentration in the ECF, and the water then will move to the ICF at a very rapid rate. So how then are these channels gated? The channels can be gated by three different mechanisms. The first is a ligand gating. This simply is a chemical which will bind to the channel itself. And the channel will be in a closed position. And when this ligand binds to the channel, it will cause the channel to open. An example of this is the acetylcholine receptor. This is a neurotransmitter for the parasympathetic system, nervous system. This acetylcholine binds to a nicotinic receptor On skeletal muscle. So this nicotinic receptor on the skeletal muscle is a channel. It is a sodium channel. And when the acetylcholine binds to the channel, the channel opens and sodium can enter into the cells. It enters into the skeletal muscle. And we'll talk about what happens after the sodium enters into the skeletal muscle, when we deal with skeletal muscle. This channel will only allow sodium to cross, and the channel will only open when there is acetylcholine present, and that combined to the receptor itself. And the second type of channel, these channels are opening to voltage, and we've not really talked about how there is a charge difference of charge gradient across the plasma membranes. We said that there's a chemical gradient across the plasma membrane so that sodium is high on the outside of the cell and very small concentration on the inside. The potassium is very high on the inside of the cells and has a very small concentration on the outside of the cells. So that's a chemical gradient across the plasma membranes of all cells. But there is in fact a voltage gradient that is a charged gradient across the membranes as well. And this charged gradient is due in part to the negatively charged proteins that are inside cells. So the inside of a cell is more negative than the outside. So the ECF is more positive relative to the inside of the cell. When the voltage that is the charge across this membrane changes and it can change in certain cell types such as neurons or muscle, then if it reaches a specific difference in voltage across the membrane, it can open channels. And one of the channels that will open is a voltage-gated calcium channel. The voltage-gated calcium channels are present in muscle, in cardiac muscle, and then at a certain voltage across the membranes, these channels will open and then at a certain voltage, these channels will again close. And we'll talk about these some more when we talk about the cardiovascular system and the heart. And the last kinds of gating we see is mechanical gating. And mechanical gating is found in smooth muscle. So in smooth muscle, we have a situation where the smooth muscle has, around the artery, may have a tonic contraction, which is a basal contractile state. If more blood is delivered to that vessel, then the walls are stretched. And when the walls are stretched to open these mechanically gated channels, and calcium can enter, and the calcium causes the smooth muscles to contract. And the cells will then go back to their original contracted state so that the vessel diameter then will go back to its original basal state. And again, we'll talk about this more when we talk about the cardiovascular system. So those are our channels. So with the transporters and the channels then, the movement of materials across the membrane, once the opening is present, then the movement is going to be by diffusion. But with pumps, we are moving materials not from a high to a low concentration but in the opposite direction, and that's what's shown here. So with pumps, we're going to have a high concentration of material on one side of the membrane. And let's say that's calcium and this is in the ECF, so these little green dots are calcium. And in the intracellular space, we have calcium and it's in a very small amount of calcium. Our pumps are enzymes, and they're enzymes which will cleave, usually, ATP. So they cleave an ATP molecule which is an energy molecule within the cell. But cleaving ATP, they will undergo a different conformation and that allows the molecule to cross the membrane, and that's what's shown here. So we bind ATP to an inactive pump, the calcium ATPase, and we bind calcium to the calcium ATPase on the inside of the cell. It undergoes a conformational change, and when it does so, the calcium is extruded to the extracellular space, so removing calcium then from a low concentration to a high concentration, exactly the opposite of what we saw with simple diffusion and facilitated diffusion, and this requires energy. There are many really important pumps within the cells of the body. One, of course, we've already talked about is the sodium, potassium ATPase. This is a pump that maintains the volume of all cells, and it allows us to keep a steady state of sodium and potassium across the plasma membranes. We also have the calcium ATPases which we just talked about and these are present in muscle cells. So there we're going to move calcium across membranes, removing calcium very quickly from the inside of a cardiac myocyte, for instance, in order to be able to relax the cell and then be ready for the next contraction. We also use these pumps in other areas, such as the stomach where we make acid. So in order to make acid and extrude proton into the lumen of the stomach, and you do so by using a proton potassium ATPase. And we'll talk about that when we talk about the stomach in the GI tract. So this one last concept that we need to talk about, and this is a little difficult for students to understand sometimes. There are areas of the body where we want to move materials all the way across the cell, not just going into the cell, but across the cell and into the blood stream. We're starting with a lumen, such as the gastrointestinal tract. You just ate your Big Mac and we now have glucose sitting in the lumen of the gastrointestinal tract. And we want to move it across the epithelium into the blood on the other side, and then deliver that to the liver and to the cells of the body. And we do that, not by a primary active transport, which we just talked about, which is just a simple pump moving it across, but we use two different entities, and the two entities are working in coordination, so this is called a secondary active transport. So the secondary active transport requires a ATPase pump on one surface of the cell, and usually on the basal surface of the cell. That's the side that's facing the bloodstream. And then on the lumen, or the apical surface of the cell, we have a co-transporter, and that's what's shown here. So this happens to be the sodium glucose co-transporter that we talked about already. And in the gastrointestinal tract it's know as the SGLT, or the salt glucose transporter. Both glucose and sodium will bind to this transporter, it's a co-transporter and it's a sim porter. So both the sodium and the glucose enter into the cells. And when they enter into the cells, the glucose then is at a high concentration and it will diffuse across the cell, and leave the cell at the basal surface through a simple transporter which is by facilitated transporter for glucose. So this is just simply a glute transporter. So glucose then exits this cell and enters into the blood. Sodium, on the other hand, moves across the cell and then the sodium is pumped out of the cell actively by the sodium potassium ATPase, which moves three sodiums out for every two potassiums that enter. And this pump requires an ATP, so it's an enzyme which cleaves ATP so the energy is moving the sodium then from the interior of the cell to the outside, and we know that that's moving the sodium against its concentration gradient. The glucose in a sense gets a free ride, the glucose is using the sodium gradient. And the sodium gradient is maintained by the sodium potassium ATPase, which is on the opposite side of the cell. So we have a transporter, a co-transporter, which is linked to a active transport of one of the solutes, and that sets up the gradient where the other solute then is able to just essentially piggy back or get a free ride as it goes across the cells. And we'll talk about this trans-cellular transport in much more detail when we talk about the gastrointestinal tract and interrenal tubules. Okay, so one of our general concepts, so the first is the movement of a solute across the lipid bilayer, the cell membranes, is dependent on its size, its charge and its solubility. The second is that the net flux, or movement of the solute, will be determined by its gradient. And third, that a permeable solute crosses the membrane by simple diffusion, and this is a slow type of a movement across the membrane and it is a more general type of movement. So it's anything that's soluble in lipid can move across this. So this would be some of the steroid hormones, it could be urea. These are molecules which are able to cross the membranes without having a specific transporter. And they will always move down their concentration gradient. And they will move down the concentration gradient until they reach an equilibrium, so that you will have an equal distribution of the materials on either side of the membrane. Fourth, we have non-permeable solutes will cross the membrane by facilitated diffusion. This is going to be fast, it uses transporters, these are those integral membrane proteins, and the process again requires a gradient, it's saturable and it's specific, and that's because it's using a transporter. So this is a much more targeted type of movement of materials across the membranes and into the cells. Five, primary active transport moves a solute against its concentration gradient. And this mechanism requires ATP, so we have to cleave ATP in order to be able to move this material across the membrane. Again, it will show specificity, the sodium-potassium ATPase moves sodium and potassium in an anti-manner, but that it will move protons out of the cells if it's the proton ATPase. But if it's a proton ATPase, it will not be moving sodium and potassium across the membrane. And again, these things will be saturable. We'll have a finite number of these pumps that are going to be on the plasma membrane surfaces. And six, secondary active transport couples the activity of a co-transporter with a pump. So under this condition, we will then have the active extrusion of one of the solutes that's coming in with that co-transporter. And this is the mechanism that's used for trans-cellular transports of solutes across the gastrointestinal tract, epithelium, and across the renal tubule epithelium. So we're moving from a lumenal surface, all the way across the epithelium, to get into the blood space. Okay, so, the next time we come in here then, we're going to consider how we move water across the plasma membranes. So, see you then.