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00:00 action. So we're back on this . This is an inspirational story,

00:06 . Everyone to learn how Thio basically Stop it Something but pursue something not

00:15 it. Getting a degree, not it. Making some project. But

00:22 getting driven. Thio solve more complicated to get Thio more details about what

00:32 in nature and things like that. Roderick MacKinnon All right, before we

00:37 into into the action potential lecture wanna out that I have a couple of

00:44 , walk you through and let me this should switch now because what I

00:50 to finish, actually talking about resting and potential is that what we're building

00:56 an understanding that membrane is like a . The plasma membrane is like a

01:07 that you have an extra cellular aside you have these channels and these channels

01:15 like conductors. So here, for , you have on top potassium channels

01:21 they are for G K, which for potassium conductors, or it's a

01:29 . So this symbol here is a symbol. Yeah, this symbol

01:39 I'll draw for you and everyone should this. This is the physics language

01:46 the membrane circuit. Yeah, this the symbol for resistor. It's on

02:04 slide to okay, then you have symbol for battery. Okay, this

02:25 a symbol for battery. Okay, , G there is because G is

02:41 inverse of the resistance. So each the ions essentially has arisen is serves

02:47 a resistor channel. If it's the resistance is slow and ions cross

02:55 the channel. If the resistance is , the channels air closed and then

03:01 have a battery and the battery is electrochemical driving force again. Electrochemical driving

03:09 for each ion can be represented by M minus equilibrium potential forgiven ion So

03:18 potential minus equilibrium. Potential forgiven. driving force equals I. R.

03:24 just basically rewrite arms law. But we incorporated equilibrium potential for potassium.

03:34 conduct intense. Okay can be calculated each one of the ions. And

03:42 we look on the plasma membrane, it's not just potassium channels that you

03:47 on top, but you have potassium and chloride channels, and each

03:54 of these have their own conductor and actually a resistor conductor and it za

04:03 conductor, meaning that Sometimes the channel open and the conduct Ince's high and

04:08 the channel is closed in the Ince's low and each one of them

04:13 their own respective batteries, with the and the negative end shown here accordingly

04:19 sodium, potassium and chloride ions. huh. So to calculate the overall

04:27 ins forgiven High on, for for potassium ion depends on the number

04:35 potassium channels and conductors. Foran, potassium channel all right, and the

04:45 Grady int and potential difference is illustrated top here because we have a current

04:53 potassium, I is equal the are in this case, I is

05:04 D. M. The current for is equal conductors for potassium times,

05:13 membrane potential minus the conductors for potassium , the equilibrium potential or, in

05:21 words, conducting for potassium times its force. So the total current from

05:29 is conducting for individual potassium channel Its driving force and the driving force

05:36 the difference between the membrane potential and equilibrium potential for potassium and below the

05:44 . Ince's the total off the individual channels times the total number of channels

05:50 are present true. So now another important subject to discuss when we discuss

05:59 membrane, this capacitance. It's the that plasma membranes are very good

06:06 There's certain qualities to be a good . To be a good capacitor,

06:12 need to have a lot of surface where you can store charge to be

06:19 good capacitor. You should have the plates of the capacitor very close to

06:27 other. And such is the case plasma membrane. Yeah, yeah,

06:41 is the symbol for resistor. This a symbol for the battery, and

06:49 was a symbol for capacitor in the , which shows a storage of positive

06:55 and the storage of negative charge. what? That's exactly what happens for

07:00 membrane. It stores a lot of negative charge on the on the outside

07:07 the inside of the membrane and a of the positive charge on the outside

07:12 the membrane. So it's very good . Also, the capacitor plates is

07:18 fossil lipid bi layer, so the plates are very close to each other

07:23 then discharge. There's a lot of because there's a lot of surface

07:27 There's a lot of them drives them experience creating surface area for store storage

07:33 the charge. But the discharge is quick across the to place because the

07:39 is very short. Uh huh. these are all of the features of

07:44 good capacitor. Plasma membrane is a good capacitor. This is on the

07:50 . What you have is an injection the awkward corner inward. Current in

07:56 one would have shown is that if just placed on electrode in a solution

08:01 there was no resistance, there was plasma membrane across. Then you would

08:06 the square wise like response. You , these squares that are stacked on

08:10 of each other showed current outward or n word and the measure of the

08:16 and nano ampere 0.5 nanogram pairs. if you inject that current into the

08:23 just like we were looking at that off the car and through the electrodes

08:28 the neurons, you will not get square box like response. You will

08:34 a response as in a two, you can see that there is a

08:38 up of charge of the plasma This is the charging up of the

08:45 . Okay. And then is you the stimulation, which is this this

08:52 end here on these curves. Then is a slow decline, and that

08:58 because the discharge takes some time But that time we're talking here is

09:05 . And that's why the plasma number a good capacitor is it takes a

09:09 milliseconds to fully charge them up. this rise in this, uh,

09:15 shape of the curve which is really off voltage across plasma membrane. As

09:21 inject the square wave current from your equipment into the cell, the cell's

09:29 and capacity to properties shape it into response that you've seen 82 It takes

09:35 to charge up negative charge. And when you release it, it takes

09:39 for it to come back to resting and potential of minus 60 on the

09:45 . What you have is you have ivy curve. This on the right

09:51 B is called an ivy curve. this is is there is voltage on

09:59 X axis in Milan balls and on Y axis. You have current in

10:06 AM Paris, and this is called linear or Ahm IQ ivy curve

10:14 I stands for current, the for . So Ivy Curve. This is

10:21 linear curve, which means that for same amount of current that gets passed

10:26 the cell, let's say 15 positive on Pierce changes the cell from minus

10:35 to minus 55. Positive one and Paris Changes is 2 50 positive to

10:42 it thio minus 40 over here. , so if you inject negative current

10:53 one Nana am Perry's she had changed minus 60 to minus 70 minus point

10:59 him from minus 70 to minus So this is a linear or comic

11:04 curve of the off off a particular . But in reality, all of

11:10 channels have different shapes. Curves that call rectifying curves that will discuss,

11:19 , let's see that we'll discuss in next lecture, Actually, but now

11:24 talk about the capacitance a little All right, you have the are

11:29 here, which stands for the internal or resistance in terms inside of the

11:36 . The RN depends on the resting density. How many channels how densely

11:43 is that membrane with channels, it on the membrane surface area. That

11:49 the small neurons will have very high and low conduct INTs. Large neurons

11:57 have low resistance or lower resistance. when you're calculating the the resistance off

12:09 inside of the South, you have take into consideration the resistance of the

12:15 . Okay, this is where resistance of the membrane over four pi a

12:23 where a stands for radius of hysterical . Yeah, so the larger the

12:35 , the larger the a, the that are in. Yeah, the

12:43 the sell, the smaller the inside of the cell for capacitance capacitance on

12:53 opposite side. It's very different for . Actually, with you have described

13:02 the right is First of all, change in voltage can also be

13:07 Measured in the change in Q Q for charge. Another term Q stands

13:16 charge oversee, which is our which stands for capacitor. In other

13:24 , to change the Walters, you Thio Cross to have to have the

13:29 to be added or removed from one the other plate of the capacity

13:36 And so if we look at the of the capacitor now, it's very

13:41 because the the input the capacitance input the South depends on the capacitance of

13:48 membrane times, the radius of the neural. That means the larger the

13:57 of the spherical neuron. The larger the capacitance. Mhm. That's the

14:05 from the resistance. Mhm resistance. larger the A, the smaller the

14:14 capacitance, the larger the A, larger the capacitance mawr surface area.

14:20 store the charge, you can draw a number and equivalent circuit here,

14:27 is also here. This is what mean by membrane equivalent circuits. This

14:33 a membrane equivalent circuit where you represent membrane as if it was an electrical

14:41 physics circuit. So you put your cellular side but one side of the

14:51 . Extra salary on the other On the side of Plas mix

14:54 you have resistors. A year for eye on battery is here for each

15:00 on, and there's nothing here. really passive flocks here. If you

15:06 at the circuit, there's not much going on. Now let's look at

15:10 circuit below. This shows passive and Fluxus. What I mean by that

15:18 that there's actual flux here. First all, there's an added component here

15:23 the plasma membrane that makes this representation realistic. And this added component is

15:30 M, which stands for numbering capacitance on the side of Plas mix side

15:37 of negative charge and on the extra aside, accumulation of the positive charge

15:44 is here You have a plump here pump using energy. What is the

15:50 doing? Look at what the pump doing. Current i n a.

15:55 . Slowing to the outside of the , there's lots of sodium on the

15:59 , but remember, the pump is against concentration radiant, pushing sodium

16:06 pushing potassium inside the south. Then have again the conduct INTs and the

16:13 for each G. K for potassium folklore, a G n A for

16:21 , and you have the direction of current flow here, too, so

16:23 can see potassium ions so moving from , because there's a lot of potassium

16:28 the inside to the outside, while sodium ions also positive charge of moving

16:34 outside, where there's a lot of chloride to the inside of the

16:41 So So this is membrane equivalent and this is the last one that

16:50 wanna make about resting member and because before we talk about the

16:55 potential is this is the permeability ratio potassium over sodium over chloride. The

17:06 line shows the permeability ratio uh, , very high sodium, very low

17:15 , very low. This is resting of potential that's driven by potassium is

17:22 by potassium conducting. Remember, it's times higher addressing member and potential for

17:28 . The second line shows a very ratio of permeability. Now you have

17:35 times MAWR ratio 20 times mawr, for sodium versus potassium and the permeability

17:43 chloride doesn't change. This illustrates action . This illustrates that during the action

17:52 , the permeability ratio for potassium during rising face of the action potential remains

17:58 one, while the permeability for sodium increases. And it doesn't really change

18:05 chloride that month. So the last here again is a Goldman equation,

18:12 it's also Goldman, Hodgkin and Cats . You can pull again chloride concentration

18:19 you want to also see if chloride change much of the number of potential

18:25 you have the values for permeability, for chloride here. Uh huh.

18:32 the point is, that permeability ratio very much change for individual ions,

18:39 on the state of a neuron. during the action potential, the permeability

18:43 sodium is gonna skyrocket. And that going to very much change the membrane

18:49 . Because imagine having a VM where for sodium is 0.4 here for P

18:58 the VM on permeability for sodium actually 0.4 becomes 20 in this p value

19:06 . All right, good deal. now we're done with the resting member

19:11 potential. Let's try to understand how whole action for temps troll happens.

19:19 by the way, I know that some of you, it's not very

19:22 material. But for some of you are more biology frog, muscle minded

19:31 and neuron firing minded, uh, , you know, chemistry people.

19:37 might be a little bit more so we'll review some of these concepts

19:43 . The basic things that we know action potential. Now we know a

19:47 . We're coming from resting membrane During the rising phase of the

19:51 potential crosses zero mila vault line when crosses the zero move offline. The

19:57 of the action potential is referred to overshoot. And once it reaches about

20:04 positive middle of all value, it returns started returning back through this falling

20:10 of action potential. And it goes low resting member of potential, the

20:16 resting member of potential. Because potassium now driving the science down Thio negative

20:22 , overall number and potential, and experience an undershoot which goes below resting

20:28 of potential and takes some number of to recover. So this process again

20:33 just a matter off one too few in neuron in the heart action potential

20:42 are quite different action potential so much . And primary focus here in this

20:48 is actually neuron election potential. So confuse if you knew something about cardiac

20:54 from previous courses. All right, gonna stop sharing for a second,

21:01 , uh, I'm gonna see if can switch Thio a different.

21:16 see, this is in your supplemental course, electro materials. That's

21:30 uh, fascinating video off how this started happening. Our understanding off the

21:39 dynamics off the action potential. it's pushed them. Of course,

21:50 from another world. So perhaps it's surprising that it took a long time

21:55 scientists to discover that there are fundamental between the nervous systems of careful parts

22:01 vertebrates. Yet it was the recognition a useful difference in their nervous

22:10 which enabled scientists to undertake research that led to a growing understanding of the

22:16 controlling our own nervous system. The concerned the nerves that control the contraction

22:22 the mental muscles used in jet As this archive film shows by simultaneously

22:31 it's mental muscles. Even a moderately squid can inject a huge amount of

22:36 with great force clear. In the 19 thirties, British zoologist professor

22:46 Z Young was engaged in a study the squid's anatomy. Young observed an

22:53 of large tubular structures, each as as a millimeter in diameter in the

22:58 metal. As these structures were never with blood, they could not have

23:02 blood vessels. From their similarity to nerve fighters, Young thought they must

23:08 single neurons, giant axons. They're nerve impulses from a concentration of nervous

23:14 called Estella ganglion to the mantle Using electrodes, he stimulated the surrounding

23:26 fighters and found that he could only large muscle contractions in the metal when

23:31 large tubular structures remained intact. So were indeed giant accents. Scientists quickly

23:47 the significance of Young's finding. For . At last was an ax on

23:51 and robust enough to investigate. With techniques available at the time and one

23:56 survived for several hours when isolated from nucleus, the interest cellular contents of

24:06 giant axon could be removed and leading to the discovery that sodium irons

24:11 more concentrated outside the nerve cell and ions more concentrated inside by refilling the

24:21 axons with solutions have precisely known chemical . Experimenters were able to unravel the

24:27 of iron transport across membranes, the axons, the large enough and robust

24:38 for fine electrodes to be inserted through cell membrane and into the Axa

24:49 In these early techniques, a fine tube was first inserted into the ax

24:54 and secured with threatened, then the was used to introduce a fine wire

25:20 from which the voltage between the inside the outside could be measured. But

25:26 formation of the nerve impulse was far rapid for detailed study with any of

25:31 electrical measuring devices of the late 19 . It wasn't until the 19

25:37 following the wartime improvement of electronic equipment as the capital Greatest telescope, that

25:43 progress was made. Scientists found that nerve impulse was transmitted as a characteristic

25:52 of electrical potential that this all or action potential was generated mainly by transient

25:59 of sodium and potassium ions across the membrane. Research on the squid's giant

26:07 on unravel the mechanisms of the formation propagation of the nerve action potential.

26:13 understanding led directly to the development of that block action, potential formation and

26:20 actors local anesthetics now used routinely as in dentistry and minor surgery.

26:35 that movie that we just watched on John Faxon physiology and is very revealing

26:43 , essentially saying that not until 19 you even had the Silla scopes and

26:50 to capture these action potentials. So development of the technology the electron ICS

26:57 World War Two have actually contributed to advancement of the electric physiological science.

27:04 in fact, it's interesting that some the electrophysiology circuits and connections air similar

27:11 some of the submarine wiring that you in the military is still in

27:18 This is voltage plan, but so gonna have to understand a little bit

27:22 how old this clamp works in order understand how you measure this potential across

27:28 membrane. But let's discuss a couple things 1st. 1st of all,

27:35 the rising phase of the action potential already discussed. You have very high

27:41 to sodium, so you have the influx, so sodium is going in

27:47 influx during the rising phase of action . Do you remember what the equilibrium

27:54 for sodium Waas? Wow, if don't, we can always go back

27:59 few slides and remember it, but za positive value right in the

28:09 so positive value equilibrium potential for sodium positive. 62 mil evolves,

28:17 So what is happening here? What happening here is that during this rising

28:23 , there is a high permeability for and very high driving force. The

28:29 potential for sodium is positive. 55 60. That means sodium is gonna

28:36 driven inside until it tries to reach equilibrium potential. But it doesn't quite

28:42 equilibrium potential in the top of the potentials approximately plus 35 plus 30 million

28:50 , and it starts reversing back. starts going into the falling phase.

28:56 that's because as the membrane potential becomes and more positive, there is less

29:03 less dry for sodium to go inside less less sodium channels from the ability

29:11 off the decrease drive. Because sodium during the rising phase of the action

29:17 is actually a positive feedback mechanism, sodium or deep polarization, more deep

29:24 . More sodium channels open more sodium open more sodium or deep polarization.

29:29 deep polarization. More sodium channels open sodium, so it should be going

29:35 the way until it reaches equilibrium. for sodium here, the peak of

29:39 action potential in the membrane potential. it does not because driving force reduces

29:45 sodium and at the same time as member and becomes mawr positive, more

29:50 , polarized the driving force for potassium minus 80 minus 90. That means

29:57 all of a sudden the roles and driving force a switch, and the

30:01 force for potassium becomes greater trying to potassium now. Okay, Driving potassium

30:09 the potassium concentration sodium is going Potassium is going out. There is

30:16 flux of potassium or e flux in of sodium during rising phase and e

30:23 , or leaving of the potassium during falling face. To reshuffle the positive

30:29 negative charge across plasma membrane and It becomes the most permissible ion during

30:35 falling phase of the action potential, it is so powerful that it tries

30:41 draw. It is a Librium potential minus 80 minus 90 and remember that

30:47 the membrane is most memorable for so it almost succeeds to drive it

30:52 the Librium potential. During this undershoot , and then with the help of

30:57 N a k a purpose pump, have the slow recovery of the plasma

31:03 into the previous resting membrane potential value about minus 65 million balls. So

31:09 the next lecture, what we'll do I'll actually show you how I draw

31:14 of these, uh, action potentials some of the the illustrations that I

31:21 on my own notes that helped me keep track and understand all of the

31:26 potential dynamics. So at this I'm going thio shock if there is

31:36 questions, So where do we find fines? They are all on the

31:46 . 50 fuel amounts? Yes. again, the question is about the

31:52 potential value, and that might be variation between slides. And that's because

31:57 very between South. So it's very . Calculations is very between textbooks,

32:03 it's all within the ballpark. Is caused by 62 Millers? It caused

32:08 later increased probability to potassium. so I'm not sure. I guess

32:18 question was a little bit while so I'm not sure within what

32:21 if you want to repeat it. I think one of the important take

32:26 message is this. Permeability for potassium very high, addressed on that permeability

32:32 very high for sodium during the rising of action potential, and then

32:36 it becomes very high for potassium during falling phase of the action potential.

32:42 if you just keep similar concentrations of and sodium on the inside versus the

32:49 and you change the permeability for these , you will see how the number

32:53 potential changes accord anyway. Okay, determines how soon one action potential can

33:03 a lotta in regards to the falling ? Uh, not exactly.

33:09 there is a absolute and relative refractory . So during the falling phase of

33:18 action potential, you cannot generate another potential. Another important feature that was

33:24 in the video is this action potential all or non event. Once you

33:28 generating it, it goes all the to the spike. It has to

33:31 back in order to generate the next potential. But that period, the

33:37 refractory period when it cannot generate action , is followed by a relative refractory

33:43 . That's when the plasma membrane is re balanced from this undershoot back into

33:48 resting member and potential value. And that period of the stimulus is strong

33:53 this refractory period, relatively factory you can generate another action potential.

34:00 , lot of it depends how fast can generate or How short is this

34:05 period depends very much on the channel and individual cells. And as you

34:12 , we talked about inhibitory Interneuron from fact that they can actually produce up

34:17 600 actual potentials. A second criminal Torrey Sauce really cannot go that

34:24 You can drive them at maybe 40 60 spikes per second or action potentials

34:30 second. That is because they have much longer refractory period to, and

34:35 depends on the channel composition and So how do we prepare, for

34:43 , reading power ports to your commanders read a book? A Swell.

34:47 suggest that I think at the beginning the course, also Thio. Best

34:52 to do this is Thio. Attend lectures, check your lecture notes,

35:00 notes and also, um, view Electra videos that are on video

35:11 Okay, so if you do that attend the review and review the material

35:21 the exam, so the best is you review everything. If you look

35:27 the but the the still of If you review, let's see if

35:37 review everything on the syllabus for all the eight lectures September 20 By September

35:50 will have midterm exam review session. if you look at the materials you're

35:58 the let's just review the videos, have any questions? Bring your questions

36:03 their exam review session, and then should be in a really good

36:09 so Okay, great. This, ah. Wednesday, I will continue

36:21 about that action potential on. pretty much. Trying to catch up

36:26 the rest of the material over the couple of lecture says is listed on

36:31 syllabus. So thank you very Have a great afternoon that will see

36:36 on Wednesday. Take care.

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