This material is going to be something I'll be referring backto frequently during the next couple of lectures and actuallyperiodically throughout the course, because when we talk aboutthe mechanism of various kinds of physiological processes, whatwe frequently find is that the mechanism, at least at the cellularmolecular level, involves membranes.
How do things gets in and out of cells? How do cells know aboutthings that are going on around them in the environment? That'swhere membranes get involved in these physiological process.
You have probably all heard in an introductory biology class,that membranes are phospholipid bilayers. How many people haveheard that general idea, membranes are phospholipid bilayers?You know, that a phospholipid is an organic molecule that hasa phosphate group which is charged. And it has a couple of longstrings of fatty acids, 18 to 20 or 22 carbon long strings offatty acids. And that the phosphate end of the phospholipid issoluble in water. So we call it "hydrophilic."
It's soluble in water; it likes water. "Hydro" meanswater. "Philic" means liking. And the rest of the molecule,the fatty acid of the molecule, is lipid soluble, it does notdissolve in water, and it is called "hydrophobic." Itfears water or hates water.
And if you take a certain amount of purified phospholipid, andyou put it into a water and sort of shake it up, the stuff willspontaneously arrange itself to a little tiny cell-like structure,little spheres of phospholipids.
But it's not just one phospholipid molecule. What you actuallyfind is that these things have aligned themselves into a doublelayer, a bilayer. That's the phospholipid bilayer arrangement.So that the hydrophobic parts of the 2 layers, or 2 parts of thelayer, the hydrophobic parts are able to get together and excludewater, and the water is on the outside. So what you really haveis this little membrane structure.
The 2 dark lines I have drown here would represent the phosphategroups, the water soluble parts.
On the inside of the cell you have cytoplasm which is an aqueoussolution, a water solution, surrounding the cell. But what youhave separating the inside of the cell from the outside of thecell is a continuous layer of this -- of the phospholipids, ofthe fatty acids. It's like you have a little bubble of fat.
The cell is a microscopic bubble of fat with cytoplasm and nucleiand proteins and all kinds of good stuff on inside, but there'sa continuous layer of lipids surrounding the cell.
Now, that is only half of the story, because only about halfof the mass of the membrane is composed of phospholipids. Theother 50% of the mass of the membrane is composed of proteinsthat are, in fact, floating in this phospholipid bilayer.
So that if we were to make a picture -- in other words, takethat membrane and make a cross-section through the membrane, whatwe would see in addition the phospholipids would be some moleculesof protein. And sometimes those proteins -- you know, proteinsare long strings of amino acids. And amino acids are sort of simpleorganic molecules, but they have charged areas on them.
And some amino acids are lipid soluble, and some amino acidsare not lipid soluble. I draw proteins just as a long string.It's thousands amino acids long. And in some cases it is complexlyfolded into a particular shape. Sometimes it has big parts thatstick out of the cell.
And these proteins are floating in the membrane. They are completelysurrounded by -- on all the way around there, the sides aroundthem, they have these phospholipids, a layer of lipids that completelysurround them.
And so we look at this cell membrane say from the outside orfrom the inside, what we would see is all of these phospholipids,which in some cases are kind of -- they can kind of float around,but in the middle of that would be these proteins.
Proteins that are intrinsic to the membrane. They are containedwithin the membrane. They are called "membrane-bound proteins."
And back in 1972, a come of scientists named Singer and Nicholsonproposed this model of a membrane, which turns out to be true.It's called the "Fluid Mosaic Model" of the membrane.
The fluid part of this term refers to the fact that the lipids,themselves, in many cases are free to move around to some extent.The "mosaic" part refers to the fact that you have amosaic. Many have probably seen a piece of art work that is amosaic. It's made up of a whole bunch of little tiny pieces ofceramic or something like that. And the protein is contained withinthe membrane.
In fact, the proteins are surrounded by particular -- the proteinshave exposed on their outer surface here, of this sort of 3 dimensionalstructure, they will have particular amino acids that lipid solubleand have weak molecular attractions for these what are calledannular lipids surrounding them. Those are the annular lipids,forming an annulus or like a little donut around the proteins.
And in some cases, the proteins go all the way through themembrane like that. In some cases, the proteins may be exposed,maybe, only on the outside of the membrane. And in some casesthe proteins may be exposed only on the inside of the membrane.
You know, that is they have -- they're in contact with cytoplasmof the cell, but they are not in contact with the outside of thefluid that surrounds the cell.
But they are membrane-bound proteins. And they are the key tomany physiological processes, because they have the ability toallow things to get into and out of a cell, among other things,things that could not otherwise get through the membrane.
Now, because the of the phospholipid bilayer, there are somekinds of things that by themselves would not be able to get intoor out of the cell. Anything that is not soluble in lipid couldnot get through the membrane. In other words, in order for somethingto go through the phospholipid part of the membrane -- in otherwords, for a potassium ion, for example, to get through the membrane,it has to actually dissolve in the lipid layer.
And things that are not soluble in lipid would have a hard timegetting into our out of the cell. Things that are soluble in water,by and large, are not soluble in lipids. So that means that allthe different kinds of ions, sodium ions, potassium ions, chlorideions, phosphates, all those different kinds of ions, they couldnot get into or out of a cell by themselves. They would not beable to get through the phospholipid bilayer.
Sugars, amino acids, are charged water soluble molecules ofmoderate size. They can't get across the membrane. Of course,proteins are way too big to get through a membrane. Which is goodbecause when a cell makes a protein, like an enzyme, it doesn'twant the thing escaping from the cell; it wants to stay insidethe cytoplasm and do what the cell made it to do. So they cannotget through the membrane.
So one of the things that membrane-bound protein do is helpthings get into or out of a cell.
STUDENT: You said that ions cannot get through the membrane--
INSTRUCTOR: Because they have charge and they are not solublein lipid. They are soluble in water, which is polar molecule.There's a separation charge between the hydrogen and oxygen. Butions are not soluble in fat. So they cannot get through the membrane.
Anything that has a charge is not going to be fat soluble, andtherefore couldn't get through the membrane.
What we find is that there are 3 major classes of proteins,at least in terms of their function, the kinds of things thatthese membrane-bound proteins do.
And each of these -- one of these classes has 2 subdivisions.And there are terms that are used for proteins that have thesefunctions, and that's what I want to introduce you to right nowis these 3 major classes of functions of 3 major functions.
There is name a that is conventionally used for a protein thathas this function.
The first one, which is something that I haven't set you upfor is catalysis. One of the 3 major functions is catalysis. Whatdo we call a protein whose function is catalysis? It's an enzyme.
Now, 99.9 percent of all the enzymes that you will encounterin a cell are cytoplasmic proteins. They are not membrane-boundproteins. Most of the enzymes in the cell are floating aroundin the cytoplasm of the cell. But there are some very interestingexamples of membrane bound proteins whose function is catalysis,and they cause chemicals reactions to occur. Sometimes they catalyzechemical reactions to occur.
Sometimes they catalyze chemical reactions within the cytoplasm.It might seem like it's totally unnecessary for the protein tobe a membrane-bound protein if it's sitting there exposed on theinside catalyzing a chemical reaction. But as you see towardsthe end in the lecture, immediately before the second midterm,I'll tell you about an example of one of these membrane-boundproteins that catalyzes chemical reaction.
Sometimes they catalyze chemical reactions in the fluids surroundingthe cell, and I will tell you about one of those on Monday.
You may not have ever thought about it you may have always thoughtthat chemical reactions always took place inside the cells. But,in fact, there are very important chemical reactions that takeplace outside of cells.
And one of ways in which cells do that is by having an enzymein the membrane, catalyzing chemical reaction in the fluids surroundingthe cell. And we'll hear about one of those on Monday.
Now, another function of membrane-bound proteins is "recognition."
In other words, a cell may need to know about something thatis present in the fluids surrounding it.
Many of the hormones in the body, for example, are proteins.
And these hormones are big -- they are not necessarily thousands,they may be only 6 or 7 amino acids long, but they are not lipidsoluble. Those hormones need to cause the cell to do something,but they can't get into the cell.
And the way in which they do that is by having a protein exposedon the outside of the cell that has a stereospecific -- you know,a lock and key kind of ability to recognize a particular hormone.And I'll give you an example of one of these. We call these "receptors."
So a protein, a membrane-bound protein, that is called a "receptor"has the function of recognition, it's like a doorbell, or it'slike -- a doorbell is very nonspecific. Maybe it's more like thelittle card reader that you have at the market when you run yourATM card through. That's a little interface between the computerand the outside world.
Well, that's what a receptor protein is. It's an interface betweena cell and the outside world. It thing doesn't have to actuallyget into the cell for the cell to know something important isgoing on out there. But it's very specific. It's the same kindof enzymes substrate specificity that you have already heard aboutin basic biology.
Now, the third function is the one I have already referred toand that is "transport," the movement of things acrossthe membrane. And that has a very specific scientific name it'scalled "carrier-facilitated (mediated) transport."
"Transport" means to move it across the membrane.
"Facilitated" is just a too bid word for aided. Helped.Facilitated.
And "carrier" is a reference to the protein itself.In other words, the translation of this phrase is the movementof something across the membrane which is made possible by a membrane-boundprotein. And there are 2 major classes or two major sub-headingshere that are related to whether this is an energy-consuming processor not.
There are 2 different kinds of proteins that are going to bedoing this. The one that does not require energy input is called"facilitated diffusion."
Now, in a basic biology or chemistry class, somewhere alongthe line you should have heard about "diffusion." Diffusionis a physical process that occurs in a nonliving system as wellin a living system where something simply moves from an area ofhigh concentration to an area of low concentration.
So, for example, if the sugar concentration in your blood ishigher than the sugar concentration in your cell, there wouldbe a tendency for sugar to diffuse into the cell. But sugar isnot soluble in lipid. So you have a membrane-bound protein thatsits there in the cell membrane and says, "Oh, fine, youwant to go in that direction, let me help you."
What you actually have is a molecule sitting in the membranethat can apparently change its shape and kind of ushers the sugarmolecule through, in some cases. The potassium ions are alwayswanting to get out of the cells because potassium is at a higherconcentration inside the cell than outside the cell. But potassiumcan't get through the membrane.
So you have like a little protein in the shape of a donut witha fluid -- a water filled core in the middle of it that at thatallows potassium ions to escape from the cell, and these are called"channels."
So we have a potassium channel or we have a sodium channel orwe have a chloride channel. These are membrane-bound proteinssitting in the cell membrane that are specific for a particularsubstrate and which allow things to go in the direction in whichthey would be diffusing anyway.
It allows things to go from an area of high concentration toarea of low concentration.
It doesn't require energy to do this. It just last to make ahole in the lipid for this thing to move through.
That's the mechanism of carrier-mediated transport that doesnot require energy.
The one that does is called "active transport."
A protein which performs active transport, we call a "pump."
So a pump is taking something and moving it in the oppositedirection from which it would naturally tend to diffuse. It'smoving from an area of low concentration to an area of high concentration.And that requires energy.
This active transporter in most cases going to use up ATP inorder to move things in the direction from low concentration tohigh concentration.
So those 3 major functions are catalysis recognition and carrier-- I'm sorry, change that -- carrier-mediated. I'm sorry. Carrier-mediatedtransport; not carrier-facilitated.
Carrier-mediated transport includes facilitated diffusion andactive transport.
Now, as an example of a situation in which membrane-bound proteinsare essential to the function of a particular physiological process,you are going to be looking at nerve and muscle next week in laband I am going to be talking about this function of nerve andmuscle in the lecture starting on Monday.
And the material I'm going to talk about right now sort of introducesthe basic beginnings of that information on the structure of nerve.But it's a generalization. It's a feature of all living cells.
And that feature is called the "membrane potential."
All living cells have a membrane potential. That is it's anelectrical difference across the membrane, electrical gradient.All cells are slightly more negative on the inside than on theoutside. There is slight separation of charge.
So the cells are a little bit more negative on the inside thanon a outside. And that electrical gradient is a the membrane potential.It's found in all cells. It ranges over a variety of differentvalues.
A nice representative value for vertebrate cells which is trueparticularly of nerve and muscles is that difference is about00.070 volts.
Recognize volts, measurement of an electrical potential. Butit's a lot smaller than voltage. What's the voltage in the wallhere?
120, 115. We're talking about something that is a thousandthof that.
The units that we use to get rid of all those, at lease someof those 0s is millivolts. We would say 70 millivolts.
A millivolt is one one thousandth of a volt.
So 70 millivolts as sort of a representative membrane potential,with the inside being slightly more negative than the outside.And the explanation for the presence of this membrane potentialin any cell, it hinges upon 4 facts.
These 4 facts. And then some things that result from them.
But the you have to start by remembering the 4 facts.
The first one is that the concentration of potassium on theinside is much higher than the concentration of potassium on theoutside of the cell.
So remember a chemist's symbol for concentration is square brackets.The chemical symbol potassium "K." And we'll call thisSub N.
So that potassium concentration on the inside is very much largerthan the potassium concentration on the outside. Sort of graphically,we can make a great big "K+" on inside, and little tiny"K+" on the outside.
That's the first fact.
There is something else that accounts -- that produces thatfact. But we start with that fact, potassium concentration ishigher on the inside than on the outside.
The is second fact is the membrane is permeable to potassium.The membrane is permeable to potassium. Now, potassium is anion. Therefore, we know that the potassium can't be getting throughthe phospholipid bilayer. And that tells us that there has tobe potassium channels.
So this is like a little cross-section of a donut here. There'sthe hole in the middle of the donut. This is a potassium channel.Actually, there are hundreds and hundreds of potassium channelsin the membranes of all cells. That is why the membrane the permeableto potassium, because the cell wants it to be permeable to potassium.
And we know that it wants to be permeable to potassium becausethe cell put these potassium channels there to begin with.
What does that mean? That means that potassium can get out.There is a difference in concentration. There is a channel there.Therefore, there is a possibility of potassium diffusing out ofthe cell. And a little tiny bit of potassium does, but not verymuch because there are 2 more important facts.
The next fact, the third important fact, is that the majorityof the negatively charged ions, the anions, the majority of theanions in the cell are protein.
So I'm going to abbreviate protein, put a little negative chargenext to it to remind you that many of those amino acids, infact, have given up a hydrogen ion and are a negatively charged.Protein is the majority of anions.
So there are lots of negatively charged proteins inside thecell. And they provide most of the negative charge that balancesmost of the positive charge, which is in the form of potassium.
And then the forth fact is that the membrane is not permeableto protein.
So if this potassium, this little arrow next to the potassium,that's the physiologist's way of indicating diffusion, this protein,while there is almost no protein in the fluid surrounding cell,so there is big concentration of gradient, protein cannot getout of the cell because it has -- the membrane is not permeableto protein.
So what happens then is that a little tiny bit of positivelycharged potassium diffuses out of the cell through the potassiumchannels and that causes a slight separation of charge, so theinside of the cell is negative because there is a little bit morenegatively charged protein than positively charged potassium.
And that separation charge creates the membrane potential.
Now, potassium does not continue to leak out. Why?
Because there is an attraction of the positively charged potassiumfor the negative charge that's inside the cell. And that electricalattraction balances the chemical concentration difference. Butthere is this very slight separation of charge that causes theinside of the cell to be slightly negative relative to the outside.
STUDENT: If you describe what happens -- if this is what happens,then why is it that the inside is slightly electro negative. Ifyou have a slightly more number of potassium inside the cell andit continues to be moving, you still have slightly more amountof potassium inside the cell, if diffusion continues to occur.Then why is it that the cell still has much more negative, ornot much, but a little more negative charge on the inside thanon the outside?
INSTRUCTOR: Think about it this way. If you started off witha cell where there was exactly the same number of positive potassiumsas negative proteins, perfectly balanced, the cell would not havemembrane potential.
Now, all of a sudden, you allow diffusion of potassium to occur,and some potassium leaks out of the cell. That's going to makethe inside negative. Then the potassium is going to stop leakingbecause there is a balance. If you think about a potassium ionsitting here, it's what we would call a "dynamic equilibrium."It has a concentration force tending to make it leave.
And it has an electro-static attraction that almost perfectlybalances that. And, therefore, the potassium is sitting therewith forces of equal magnitude pulling on it in opposite directions,and it doesn't go anywhere. That's a dynamic equilibrium, it'snot perfectly balanced.