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BIOL 4315 Neuroscience Tue Th 8.30-10am - NEURO Lecture 06 RMP II and Action Potential I
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00:02 this is lecture six of neuroscience and will talk about the resting number and
00:11 about the actual potential as well. in the last lecture we discussed some
00:17 concepts in particular, we talked about arms law, the equals IR.
00:26 so we started talking about what voltage , what current is, what resistance
00:31 . And we looked at those We also talked about how you have
00:38 equal separation of charge and how the of potential addresses -65 million volts.
00:46 that this unequal separation of charge is across plasma membrane. The plasma membrane
00:53 podium channels. And when we talk resting members potential and the action
00:58 we're talking about voltage gated membrane That means that voltage will be controlling
01:05 open or closed these channels are. we looked at how these channels are
01:11 out of the single amino acids into final ordinary even temporary structures in some
01:20 . So for the ions to flow these channels, we discussed that the
01:24 are specific. So each ion has own specific channel. There's both educated
01:30 channel, both educated potassium, both calcium channel and the flux of aisles
01:36 these channels are somewhat depending on the of the ion but also dependent on
01:43 charge that are ion carries in the of hydration by which that ion is
01:49 . So positive cat tiles will enter the innermost lumen of the channel and
01:54 will actually interact with the negatively charged acid residue that's hanging out there.
02:01 will propel that particular ion in this sodium will be coming in if it
02:08 potassium potassium will be leaving the So once these cells flux through the
02:18 , the flux is can be very and you need to have these very
02:23 flux is in order to have very action potentials that get generated. And
02:30 an example of very fast behavior is reflexive behavior. And within that context
02:36 talked about the patella tendon reflex and reflex arch that's involved in it talked
02:44 the three subtypes of cells that are in mediating the reflex arch, the
02:49 , those are root ganglion neurons that excited. The modern murals that are
02:55 excited to and project there if parents the muscle cells and the spinal cord
03:03 neurons that are local and project inhibitory onto the in this case opposing muscle
03:13 neuron. So review this circuit. the cell subtypes that are involved with
03:20 , they release, how we think different cell subtypes. The excited to
03:26 sing multipolar pseudo unipolar. How else you describe these selves? The projection
03:34 the local inter neurons. So keep that information. Then we started talking
03:42 how this unequal distribution of charge will it was just simple chemical gradient,
03:50 would drive all of these ions sodium and sodium chloride that's on the outside
03:55 the cell inside the south. And said well the channels are not open
03:59 is a certain the system by which channels open and closed the Follow certain
04:05 and properties # one and number We also said that while ions are
04:13 . So it's not only about the concentration of that ion and the polarity
04:20 that ion, but it's also about charge that that ion carries. So
04:26 you had a lot of potassium ion the inside intracellular side side of plas
04:34 side here, but you also had a minus and an eye on let's
04:41 , or a negatively charged protein that cross or another ion that doesn't have
04:47 channel open. And then you open channel and you say, okay then
04:50 potassium should flow across the membrane until equal molar concentrations of that attachment.
04:58 that's not the case because as this charge flows across, makes the inside
05:05 negative than the outside, more positive all of the accumulation in neurons is
05:12 the level of the plasma membrane. this positively charged membrane starts rebelling
05:20 So at this stage there is no ionic movement because the chemical force that's
05:30 potassium in one direction is equal and to an electrical force that's repelling potassium
05:40 the opposite direction. So there is fact flux of ions, there is
05:44 net flux into one direction of the in one side of the membrane or
05:51 harder. And that is because cat get retired by analysts and attracted by
06:03 . And again, you can see this charge separation here you have on
06:08 plasma membrane. So, chemistry and gradient drives neurons across plasma membrane if
06:17 channels are open. But the second is voltage or the electrical potential.
06:23 is either attracting or repelling neurons depending their charge and depending on the charge
06:30 the plasma membrane. So, if looked onto this diagram, this is
06:38 extra cellular fluid and this is the assault. And you can see that
06:45 you approach the phosphor lipid bi layer , there is negative charge that's accumulated
06:53 the inside and positive on the But the inside of the cells inside
07:00 the neurons and the extra cellular environment charge neutral. In other words,
07:08 you record the electrical potential and that's it's called, resting membrane potential,
07:14 resting self potential. As you're recording potential at the membrane. What happens
07:24 you recorded the potential and mitochondrial we don't talk about that, But
07:32 charge would be very different actually. , this is if you look on
07:38 inside of the side is all it's , it's charge neutral, it's equal
07:44 and negative charge. So, it's the action here that we talk about
07:47 rest of memory potential and flux is charges during the action potential. They're
07:52 happening at the level of the plasma and that's very important. Uh Now
08:00 is again a situation where potassium will its concentration gradient until it encounters its
08:06 positive build up charge that becomes recurrent its own molecule. So, Smalley
08:16 the concentration change can cause large fluctuations voltage. So that means that if
08:21 change the ion fluctuations across the plasma , you can change the voltage quite
08:28 . Nothing protons exactly, but much greater negative potential. So so that's
08:42 I'm saying, but also at the of the membrane. So and then
08:46 you look in the side is all the inside the cells floating around the
08:51 , its charge neutral. But we're on the order plasma number and possible
08:59 the number and of the south net differences at the membrane. And then
09:06 have this ionic driving force. So ionic driving force is the difference between
09:13 potential, which is e ion and number of potential which is br hang
09:20 with me. We'll discuss that in second. If you know, the
09:24 concentrations we can calculate equilibrium potentials for . So now we're interested to know
09:32 is the potential here at which potassium the equilibrium potential value where the chemical
09:40 electrical forces are equal and opposite to other. What is the value for
09:44 . So, each ion has its value. And by the way when
09:49 talk about electrochemical forces, we're not talking about potassium the same cases for
09:58 , sodium will be coming in from inside and at some point there will
10:03 be a lot more sodium on the because it will get repelled, it
10:07 reach the equilibrium potential for sodium if recall we looked at this diagram and
10:14 said that there is an equal separation charge and that there is a lot
10:18 sodium and chloride on the outside and is a lot of potassium on the
10:24 and so this is the mill imola of these ions on the inside versus
10:29 outside. That's something that I asked from the test actually you have to
10:35 and the other way to represent these is in ratios outside versus inside.
10:42 for potassium for example, it's 1 20 that means there is 20 times
10:47 potassium on the inside, sodium is , which means there is tell
10:55 So do you 10 times more sodium the outside than the inside.
11:00 pointing it out. And then next it you have this E ion and
11:04 can see that it's measured at 37 , which is body physiological temper
11:12 And each one of these ions seems have a different value -80 60 223
11:20 65. What does it mean? how do you derive these values?
11:26 calculate the equilibrium potential which I also reversal potential. And you understand why
11:35 next couple of lectures to calculate the potential. We use the learns equation
11:43 equation which is E ion for equilibrium 23.3 comes R. T. Over
11:54 Log Base 10 logarithms of ionic concentration outside and ionic concentration on the inside
12:03 the side of klasnic. Yes. you're gonna use 2.303. Let's uh
12:11 of the ir what's the units of aisle. So let's walk through this
12:18 . So first of all the ion we know them. So these are
12:23 Malamala concentrations for the ions and we them because in the old days you
12:28 take this axon and you squeeze it and you actually know what's inside the
12:33 . And if you take the let's say from a squid that lived
12:37 a saline ocean would also know what's the cell to sow. E.
12:44 is equilibrium potential. R stands for gas constant. T. Stands for
12:50 temperature. Z. Is the charge the ion. That's the valence of
12:56 ion. Mhm F. Is Faraday's , an electrical constant. And then
13:02 log of the concentrations of the outside the inside. And remember that the
13:08 is the balance of two influences diffusion hmm, its concentration gradient and also
13:17 charge. Okay, so opposite charge we call each other. So the
13:24 , E ion is inversely proportional to charge of the ion. Mhm.
13:31 R and F. Are the constants , the gas constant and the electrical
13:36 . The temperature obviously fluctuates. But using physiological temperature here. This whole
13:44 . T. Z. F. Can get collapsed into 61 54 mila
13:53 . So if you actually go through form the whole formula you derived in
13:59 end you get miller balls here from ef we're not going to go through
14:05 derivation of the formula. I don't you to be responsible for it but
14:08 want you to understand the major components how you actually would calculate the nurse
14:13 . You will not need a calculator the exam but you will be able
14:19 by knowing the formula by knowing the Ives or reversal potentials, you will
14:24 able to answer the questions properly without the calculation of multiplication or or taking
14:32 log of anything. So now if look for potassium ion because it's mono
14:38 ion it gets abbreviated to 6154 million . And then you take the log
14:43 the concentrations For sodium it's also 61 . But now because the concentrations are
14:51 be different inside versus outside the blog gonna give a positive value instead of
14:57 negative value. The chloride because chloride negatively charged. So Z is minus
15:05 here you get minus 61.54 millones and has two plus. So that's why
15:17 calculation of calcium it's 30.77 which is of 61.54 because you're dividing it by
15:28 , You're dividing the same amount that would be getting here. But the
15:32 too. So you get 30.77 Then finally can follow through the formula by
15:39 the equilibrium potential for potassium the 6154 volts and taking a log. And
15:46 is shown here is you're taking a . This is actually the ratios.
15:52 if you recall, you can either this formula use the actual values and
15:58 values and you can put five On outside and 100 on the inside or
16:04 can just use the ratios one and . Either one. It's the
16:09 Huh? We'll give you the same . So once you plug in potassium
16:14 the outside, over potassium on the , take a log of 1/20.
16:19 get negative 1.3 And now you take negative 1.3 and multiplied by the abbreviation
16:26 potassium 61.54. And you get the potential value for potassium of monarchs,
16:35 . Yes, Exactly. So at particular -80 mil of all value.
16:44 where the two poor forces are equal opposite to each other and there will
16:49 flow to the left and to the . It will be flown both directions
16:52 it will never be favoring one direction the other. And as in biology
16:59 , you know, Things don't stay one potential resting number in potential fluctuates
17:06 potentials also fluctuate because there are slight of concentrations inside versus outside. This
17:15 fluctuations local and thermal and temperature. you will have some of the some
17:21 these equilibrium potentials fluctuating. They also change during the development because the concentrations
17:28 violence across plasma number and during the as you go into the adulthood changes
17:35 . So now there is no need us to go through these calculations for
17:39 ion. But instead we have an potential value here shown for potassium which
17:47 -80 for sodium 62, Calcium positive And chlorate about -65. Now you
17:58 see a chloride -65. It's the as resting membrane potential. So,
18:04 I mentioned, everything, especially in has exceptions. And so you have
18:10 textbooks that will say that resting membrane is -65. I just will say
18:17 -70 -75. Some will say equilibrium for Florida's -65, I just will
18:23 -70. And there's actually variations in because if you measure that resting membrane
18:30 in one cell, it's going to slightly higher than the other cell and
18:34 equilibrium could be slightly different between different subtypes because they will have a slightly
18:40 expression of these receptor channels that determine dynamics of the flux of the
18:47 So you have all of these equilibrium values and that is great. What
18:52 we, what are we supposed to with them? So I know that
18:55 equilibrium potential is for potassium is but that doesn't tell me the resting
19:01 potential. So I still need to the resting membrane potential. So neurons
19:07 us to calculate the equilibrium potential for ion and then Goldman cats equation.
19:16 equation here allows us to calculate the membrane potential or the membrane potential,
19:24 just the resting membrane potential, the potential overall. And to do
19:29 it essentially uses the same parameters and from the first equation. So the
19:36 R. T. Z F 23.3 same log of outside versus inside.
19:45 instead of calculating for one ion, now incorporating potassium together with sodium.
19:54 it's also saying that look, channels their openings and closings. That means
20:02 channels are more permissible when they're open an ion and less permeable when they're
20:07 a closed position. So this permeability potassium and there's a permeability for
20:16 Again, you can have very high of something and very high driving force
20:22 the channel is closed. Nothing is through. Okay, the hose has
20:27 turned off shut. So if you that there's going to be flux and
20:32 going to be changes that there's gonna permeability, interesting member in potential the
20:37 is most permissible to potassium. So cell membrane has what we call potassium
20:43 channels and it's constantly leaking potassium the charge outside. That's just the nature
20:51 of neurons. And so if you in The premier ability which is look
20:57 resting the premier ability for potassium is . And permeability for sodium is
21:04 That's exactly what I'm saying is that breasts. These are the rules.
21:09 are the rules that cell membrane is profitable at rest to potassium 40 times
21:14 permeable to potassium and sodium. And you plug in the 40, you
21:20 in now and in this case it's over 100 Mila Mauler. It's the
21:26 as 1/20 if you use the ratios then you have one this is not
21:33 . This is one permeability for sodium the concentration of sodium on the outside
21:40 is very high and sodium on the which is low. And once you
21:46 through this calculation and take a log get -65 million votes. So the
21:57 Between nine Ernst equation and Goldman Equation that nurse equation calculates the equilibrium potential
22:06 one IR and Goldman equation and by way you're welcome to add chloride and
22:17 welcome to add calcium to this I'm not saying this is a homework
22:23 or something. You're welcome to do if you are into this kind of
22:26 because you'll say, well wait a . You showed us These four ions
22:32 , sodium potassium, calcium chloride. actually said that there is the highest
22:39 in concentration gradient for calcium 10,000 more calcium on the outside and on the
22:50 , then you'll say like wait, a second. So does that mean
22:53 islands are not flexing their not Why aren't we using all four ions
22:59 the Goldman equation? And the answer , go ahead and try it.
23:04 you'll see that these elements have very permeability, ease and because of very
23:10 permeability, Ziff you plugged in calcium chloride into this equation. They're outside
23:18 inside concentrations their premier abilities here just counselor flora. The value wouldn't change
23:25 . Now, if you change the rules, then the values could change
23:30 lot. So this is the big in calculating for single ion and calculating
23:38 overall number of potential which is comprised multiple ions but is dominated really by
23:44 and potassium because those ions are most for plasma membrane. It's very important
23:59 you don't have changes in these concentrations ions locally. And the permeability of
24:08 channel is controlled by the sell by membrane and how that channel reacts to
24:13 outside world. But then it's very that those concentrations stick around those values
24:21 we just described the normal physiological condition the reason for it is the
24:28 This is the number of potential on y axis and this is the outside
24:35 ko of potassium and millie mole. You have a normal physiological concentration of
24:46 about 3.5 or five million moller outside cells. But look what happens if
24:54 go from five million mauler to 10 concentration of potassium You d polarized plasma
25:02 by about 20 million balls. What if you just go Another 12,
25:10 million Mohler, you're not about this $-40 million. And what happens at
25:16 level here? You produce an action . So if you increase extra cellular
25:23 concentrations you can de polarize the cells rapidly and cause this very rapid firing
25:30 action potentials that is abnormal. In if you look at a lot of
25:36 models, whether its biochemistry or neurophysiology lot of times the cells get stimulated
25:43 high concentrations of potassium chloride. So a lot of potassium that's being dumped
25:50 the outside of the cell and that number of potential D. Polarizes and
25:55 cell becomes very active. So in different models and the other function that
26:03 served is to slurp up these abnormal increased concentrations of ions such as potassium
26:14 and even neurotransmitters to. And so there was an increase in the extra
26:20 potassium concentration here and remember the astrocytes part of the tripartite synapse. So
26:27 means that there's something going on and neurons are incredibly active. And this
26:33 side that's checking this communication between Now census is a lot of potassium
26:39 on the outside. And that's not because if you accumulate potassium on the
26:44 and it keeps rising, the tissue firing away, it's very excitable and
26:50 becomes toxic to the local circuits. astra sides have these very extensive processes
27:00 their aunt feeds and not only on synapses, is there also a blood
27:04 barrier? But what they do is slur pop and siphon off basically spatially
27:13 the abnormal concentrations that local concentrations increases potassium calcium ions and also neurotransmitters because
27:23 their on extensive processes. It allows to let's say pick up high potassium
27:33 here and very quickly spatially buffered, through its own processes. And in
27:41 the astrocytes are connected to other astrocytes electrical junctions called gap junctions and we'll
27:47 about them later in the course and they can actually pass these ions and
27:53 waves and ionic waves and two other that they're connected to. And in
27:58 way there's a rise if there is peak and something abnormal concentration of Ireland
28:05 will pick it up and we'll spread out through the network and that way
28:09 can balance out the abnormal activity and in local cells and local networks.
28:35 in your textbook you have this atomic of potassium channel and in this textbook
28:44 a story, Dr Roderick Mackinnon and encourage you to read this story because
28:56 we talked about the channel structure, talked about what the channels are comprised
29:03 , talked about amino acids. But know that these are very complicated three
29:10 molecules and ultimately you want to know exact structure. Each protein think about
29:21 protein is a building that you're sitting . And how complicated is this
29:27 How many floors does it have? many classrooms? How many bathrooms?
29:33 many chairs in each classroom? What's in each chair? Different time of
29:38 day? So it's a three dimensional . It's a structure that's also
29:48 So imagine this building would be able contort itself and change the shape into
29:55 different and then go back and change shape and to the same and then
30:00 and change the shape into other Very complex three dimensional structures. In
30:07 end, scientists like roderick Mackinnon and else wanted to know the exact structure
30:13 these channels. And so in your there is a description of how roderick
30:19 derived the structure of potassium channels. it now sounds okay because now these
30:27 of things are done by computer models minutes where 30 years ago took one
30:36 maybe five phds To do that work five or 10 years. And so
30:44 other reason why I point out roderick is from the perspective of career and
30:54 really career is roderick Mackinnon actually is successful medical doctor and in Harvard and
31:05 mhm decides that he wants to study channel structure. So how many successful
31:14 . D. S all of a to say I really want to know
31:17 the structure of the molecule, I care about the therapeutics or something.
31:21 care about the therapeutics that I really about the structure of the molecule.
31:27 he opens and establishes a lab where uses genetic mutations. You use this
31:35 that's called side directed me to And he used this models different
31:43 So he mutates potassium channels and as mutates potassium channels? He's using flies
31:52 he creates shaker flies. So this out of normal shaking ability. So
31:59 what does that mean? Well then interested which part of the channel slide
32:04 near the genesis? That means that are trying to mutate a specific site
32:09 the channel and that tells you whether channel is important, that site is
32:15 or not for that channel because not in this building is that important.
32:22 there are certain things that if you the building will collapse. Huh?
32:27 you want to know what causes the , what causes the closing of this
32:32 ? How do you do this without the channel? There is some pro
32:41 in an animal in a fly we'll a fly. What does that have
32:45 do with human? Well you have similarities Entomology is to have the same
32:52 and in humans having flies or similar functions. So how do you do
32:58 ? You're sitting there, you have tissue, there's a protein and then
33:02 can't see it. You can see sow you cannot see a protium unless
33:09 label approach fluorescent label but that doesn't the atomic structure. So you have
33:17 think of all the tools you have hand genetics. I'm gonna try to
33:21 this side this sequence and bam I 10 sequences and one sequence that I
33:27 mutated and this specific site caused the or opening of the channel which basically
33:34 the animal to produce the shaking That's one way of doing it.
33:40 the nature produces very powerful toxins and that are agonists. And a lot
33:47 times, antagonists antagonists will open or channel activity antagonists or blockers will close
33:54 block channel activity and a lot of in nature produce very powerful toxins and
34:01 toxins bind to different proteins in our . Spider toxins venoms from snakes.
34:12 bacterial toxins and fish clam shells all the stuff there now. So he
34:22 toxins also because toxins are important because will bind to specific sides within the
34:30 . So he is a successful medical using these side directed me to genesis
34:36 techniques, toxins and electrophysiology is studying function and the structure of the potassium
34:47 . So again, the only way really can understand the structure completely is
34:51 either fully see it atomic structure or to derive it, try to calculate
34:58 . And so then you use all the tools at hand, genetics,
35:02 , toxins, electrophysiology, you're recording much current is coming through the channel
35:09 not. Much current is coming through channel after you did a mutation or
35:13 you used the toxin, it still show you the structure. You have
35:17 use biochemistry and the map. There's rules right there is the way the
35:23 to build, there are certain You cannot build everything with these amino
35:29 and their polarities and molecules. So rules by which it's built. And
35:37 roderick Mackinnon then decides that he's gonna an electrophysiology, I mean X ray
35:46 lab. So he essentially people are him you're a medical doctor but you're
35:54 about potassium channel, you did all this electrophysiology. What Roderick Mackinnon wants
36:00 do, he wants to visualize the . He said I want to see
36:02 channel and the only way that you do it in those days in the
36:06 and nineties and still in two thousand's X ray crystallography and it's incredibly difficult
36:13 you have to essentially trap a single inside a crystal. Then you have
36:20 shine an X ray light through that that exposes the structure of that protium
36:26 then use additionally biochemistry and mathematics to the final structure. And there aren't
36:34 many labs and it's a real, skill to be able to do
36:39 So people are like man, you're do another thing like we invent again
36:44 wheel and he's like I want to the structure of this channel. So
36:47 gonna open an extra crystallography lab and , I'm going to visualize this beautiful
36:53 . I'm going to show that this inside the lumen has these poor
36:59 these hairpin loops, robert Mckinnon says selectivity filters that we talked about that
37:06 contain this amino acid residues. He where the molecules are binding to this
37:14 . He can apply a lot of knowledge to human brain and human channels
37:21 there are conserved amino acid sequences. so if you find a sequence that's
37:27 important in the potassium channel and the , that means that sequence is probably
37:32 to be very important in other If they have that same potassium channel
37:37 similar, including humans, this is roderick mackinnon unstoppable. What is he
37:46 by? He is driven by a and the passion to answer the
37:52 he is not driven by a In other words, many people would
37:59 you're an MD, you're good. his passion is to find the answer
38:05 his, what he's looking for is be able to visualize in three dimensions
38:13 fully these beautiful protein channels. That's great lesson because as you start on
38:21 career it can be always move forward never straight because the path is winding
38:32 there are hills and valleys. Sometimes will be on top of the world
38:37 a prize in front of your colleagues next day, you will be down
38:40 trash because you get rejected a grant everybody else is getting one. Ah
38:47 take this as an inspiration, as scientific in the human inspiration of somebody
38:54 is really smart and driven by the is to answer and solve the
39:00 Whatever that is, problem could be disorder. Problem could be hearing issues
39:09 plastic lures for fishing, whatever the is. So these are the
39:17 this is the resting membrane potential and regulation of the science outside and the
39:24 membrane potential is we calculate based on permeability ratios and incorporate other ions.
39:32 today we're going to start talking about action to town shaw which has from
39:37 membrane potential, it reaches a It's an all or non event with
39:42 rising phase that crosses zero mo vault and overshoot. Then there's a falling
39:49 and it crosses the resting membrane potential into more hyper polarized values, into
39:55 what we call the undershoot And there many different ways in recording that action
40:02 . So one method of recording and most common and the best method of
40:08 action potentials. And we're talking about experimental neuroscience. Although some of these
40:14 are used in neurosurgical setups to in hospitals. The best way to record
40:21 put on Charles is with intracellular So you would stabbed that cell or
40:26 certain electorate into the plasma membrane of cell and you would pick up on
40:31 oscilloscope, a very large fluctuation of 100 million volts from minus 62 about
40:38 , 40 over one or two milliseconds time. The other mode and this
40:45 is actually more common than clinical If it is before the neurological surgery
40:51 extra cellular Elektra recordings of action In that case you can either pick
40:58 an action potential from just a single by being lucky and having your electrode
41:04 outside the axon of that single cell you may be depending on the size
41:09 the electrode. If that electro tip much larger, you may be picking
41:14 a composite action potential that is being by two cells or three cells at
41:21 same time. So synchronized activity When you do extra cellular recordings.
41:28 the scale isn't microloans. So when you're inside the cell, the amplitude
41:35 the signal readout that you get is larger and you don't need to have
41:40 amplifiers and you don't have to gain more than 10 or 20 times.
41:45 with extra cellular recordings, because they're micro volts, you need amplifiers that
41:51 give you the gain of about 1000 or so. So these are the
42:00 ways of recording action potentials. But we talk about intracellular recording later and
42:05 course we will talk about the techniques are called wholesale techniques. Huh?
42:14 wholesale techniques are varied. But in the action potential, would you inject
42:21 positive current here? You will de the plasma membrane. If you do
42:26 the plasma member into -45 million you will produce the train of action
42:33 . What is shown here on the is the injected current through the
42:38 So in the older days, you to do these recordings by injecting current
42:41 one electorate and recording current with another . Now the circuits are very fast
42:47 the same electorate can do both inject current and record the current. The
42:52 injection is a square wave. It's . You can see current on from
42:57 computer or sila scope. The current the response of the cell is not
43:03 because the cell has resisted and capacity properties. So there's some certain delay
43:08 the charge build up. And then course the cell responds frequency of action
43:14 . The frequency of action potentials often this. The size or the strength
43:21 the stimulus. So if this injected would be half the size, maybe
43:26 would be half of the frequency of potentials produced. So the frequency of
43:31 potentials can be used as a readout the strength of the stimulus or the
43:37 that is coming in. And you see that if you inject a little
43:42 of current, the cell doesn't respond the square wave like fashion the cell
43:48 time to build up the current across membrane here and then if it doesn't
43:54 the threshold for the action potential, you stop this current that you're injecting
44:01 , the cell number and relaxes back the resting membrane potential, you inject
44:06 current, you get enough of the polarization to reach the threshold and you
44:11 a few action potentials. And then stronger current ends up in producing a
44:17 frequency of action potential ionic driving And for this, what I have
44:31 actually is in your lecture notes, have this presentation. That place is
44:39 together. And if you are, know, for some of you this
44:44 be a lot of information. It's . We're gonna be talking about this
44:48 lecture. We're gonna be talking about lecture after. And we're gonna be
44:52 last lecture. We'll be talking about of voltage gated sodium channels and forward
44:58 back, propagating spikes. So in third lecture, you will feel like
45:01 is very basic information. So, have done the following for you
45:12 I put your resting membrane potential aw million volts right here, this is
45:19 blue line here in the cell membrane fluctuate, fluctuate up and down up
45:55 down every time it goes up. because there is glutamate and there is
46:01 polarization every time it goes down, because there is gaba inhibition and there
46:10 hyper polarization. So when neuron receives excitatory inputs De Polarizes. And let's
46:17 this is -65. And then it polarizes polarizes a little bit hyper polarizes
46:25 polarizes more hyper polarized polarized. The is getting these constant bombardment of
46:31 exciting or inhibitory. But for the part of you were to sink an
46:35 into neuron and that neuron wasn't getting direct input or direct stimulus, that
46:41 would look something like this, they're very active. Now if you injected
46:52 direct stimulus has stimulated this neuron then would produce these trains of action potentials
46:57 we were looking at. So at stage. Uh Thanks. See if
47:11 something. Yeah. Oh yeah, so it's doing this, it's doing
47:26 until it reaches -45. middle of value, which is the threshold for
47:36 potential generation. Okay, even worse worse. The threshold for action potential
47:55 . And if it reaches the threshold it will produce an action potential.
48:01 this action potential reaches the threshold it's the all or non event.
48:08 if it reaches the threshold it cannot go back down again and be polarized
48:13 , it's going to turn on the , it is going to produce action
48:21 . So you have the resting membrane , you have the action potential threshold
48:27 45 million volts. So if the potential, which is VM Measured in
48:33 , reaches -45 mil of all it will produce the spike action
48:39 So the deep polarization is excitatory inputs in and the hyper polarization are they
48:46 their inputs coming in. Once you the threshold of the action potential,
48:52 channels open up and they engage and sodium influx, the sodium is coming
48:58 , sodium is going through the positive cycle. More sodium channels open more
49:04 coming in more deep polarization. More channels open more sodium coming in more
49:10 . More sodium coming in Notice that wrestling member in potential, which is
49:16 -65 was calculated with Goldman equation which into consideration potassium and sodium high on
49:27 you recall, the sodium reversal potential very high. It's positive 55 for
49:33 reversal potential. That's equilibrium potential for that's positive 55 equilibrium potential for Florida
49:39 -90 How come rustling member and potential so close to potassium equilibrium potential because
49:49 cell is most permeable to potassium it's leaking potassium ions And so once
49:55 channels are open with potassium is trying do address the potassium is trying to
50:00 the overall number of potential to its potential value. Once the threshold value
50:08 -45 has reached you open the sodium in this positive feedback cycle. More
50:14 multipolarization, more sodium multi polarization. sodium is trying to do his sodium
50:20 driving the overall number in potential because premier ability for sodium now has increased
50:26 the permeability for sodium for potassium has That 42-1 ratio now is the
50:34 Now the cell membrane is most permissible sodium and what sodium is trying to
50:40 is drive the membrane potential this blue and this action potential is overall membrane
50:46 . Trying to drive this overall membrane to reach the equilibrium potential value for
50:53 . But it doesn't succeed, potassium over potassium now becomes the dominant eye
51:02 during the following phase there's potassium influx on and during the following phase potassium
51:09 trying to do what potassium is trying drive the number of potential value to
51:15 equilibrium potential value of -90. And almost succeeds to do that because we
51:23 that undershoot that we talked about except sodium and potassium pumps which work against
51:30 gradient works slowly Within 10 or so to rebuild this member in Patan shop
51:39 the wrestling member and potential value So when we talk about driving forces
51:48 was in the previous slide that we looking at, I said that the
51:56 force or V. Equals I. . Driving force is V. In
52:04 case it's VM. Which is a potential and E. Ion or equilibrium
52:13 value for a given ion. That the higher difference is the greater difference
52:24 this blue line which is overall numbering and an equilibrium potential forgiven ions.
52:31 greater that separation, the greater is driving force. So at -80 minus
52:39 here, potassium is leaking. It the it has the channels open to
52:45 leak channels. But here the biggest force. The biggest difference is for
52:56 as the influx coming in. So blue line here. I'm sorry,
53:01 green line here would be a driving for sodium when the number and potential
53:06 depressed. So this driving force is here for sodium driving it in.
53:14 guess what happens when it comes closer the equilibrium potential per sodium huge,
53:20 , huge smaller smaller, smaller driving becomes smaller. Driving force for potassium
53:27 larger, larger, larger, larger starts driving potassium e flux and
53:32 okay, so in each case the can think of them as selfish.
53:39 open sodium channel. It's gonna go to get its equilibrium potential. You
53:44 potassium channels gonna try to get its potential the main dominant ions here.
53:56 , absolutely. There's another very good and it's exactly the other reason why
54:03 never reaches its equilibrium potential. It's of the dynamics of the sodium
54:09 And so in the following lecture, going to try to end here around
54:16 today. But in the following when we come back, we will
54:20 at the structure of the sodium channel the structure of the potassium channel.
54:26 a reason why I introduced the How you think about the structure and
54:31 structure also means function or dynamics. channels are very fast opening but they
54:39 close very fast. So you can concentration gradient, you can have a
54:46 force that is huge but there are channel dynamics that are going to close
54:53 channel independently of these forces. And going to say I'm closed. I'm
54:59 , I know that, I know you want to reach equilibrium potential,
55:03 the protein is telling me I'm closed so you'll learn, you'll understand why
55:07 how this protein closes. It has own gates. The sodium gates open
55:13 close quickly. But then one of gates closed. The start equipment.
55:18 just the transient nature of this channel . Close open, close so constantly
55:23 and more sodium channels opening up. up, Opening up and then
55:27 closing, closing, closing, And then once the force reaches for
55:31 , the potassium says uh I got much of a driving force, it's
55:35 time. It tries to take it to the equilibrium potential for potassium?
55:41 question. I love the wild. ? How does how does a violation
55:52 the accent influence the driving force? you have no Axon Myelin Nation,
55:57 have leaky ions, ions will be out through these channels through the
56:08 Um It it's a it's a it's very difficult question because there's so many
56:16 would be happening if you have no elimination, it's just would be leaking
56:20 . Uh The axon will reproduce action of loads of Iran beer and loads
56:25 ranveer have high densities of sodium and channels. But there's nothing if there's
56:30 in between insulating it. The charge just leak out really. And the
56:36 gradients and the driving forces, they're going to be disrupted and will not
56:41 these rules and they follow some pathological . And those could be very
56:47 So, alright, so we'll end today. We'll do two more lectures
56:53 the action potential. So, some these questions that you had today are
56:58 good questions and you'll get some of answers to those questions. Also as
57:03 move in, remember that you have supporting materials and in these lectures supporting
57:13 , you can find some information about things that we talk about when we
57:20 about the back propagation of the action , there is a short discussion and
57:25 article that I included. But you also review and read about to help
57:30 understand the topic at hand. Okay I'm gonna learn the stop the lecture
57:36 . Thank you very much. Please warm and watch out. There's a
57:42 coming into texas and Texans are not good at driving with black eyes on
57:47 road. So be careful please. Thank you for being here and I
57:53 see everyone on Tuesday next
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