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BIOL 4315 Neuroscience Tue Th 8.30-10am - NEURO Lecture 07 Action Potential II Mo Wed version
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00:02 This is Lecture seven of neuroscience. we're first going to talk about membrane
00:08 circuits. Uh If we if you we talked about how channels ion channels
00:16 selected filters and ion channels in this , when you talk about action
00:22 you're talking about voltage gated ion So those channels will open and close
00:28 on the voltage, there's no ligand to these channels to open them or
00:32 them. So it's really the And we know that these channels are
00:39 they're closed, they have very high and if they're open they have low
00:45 . And that means that a lot ions can be conducted through these
00:49 And if you remember arms law E Ir also remember that conductance is the
00:56 of the resistance. Mhm. And if you look at the top
01:02 what you have is a representation of channel in the plasma membrane using membrane
01:09 circuits. So those are the kind a circuit you'd see in electronics.
01:14 Physics department. And this symbol stands resistor. Or if you're in another
01:27 , it stands for conductor And conductance jeep. And quite often these channels
01:34 variable resistance or conductors. And this indicated by an arrow going across the
01:41 symbol, each one of the ions you know, has a separation of
01:46 across plasma membrane and it has its charge. Therefore the separation of charge
01:54 on the inside, positive on the serves as a battery and each of
02:00 islands is going to react to that , depending on the charge, This
02:04 electrical forces. Electoral chemical forces that in this case stands for the battery
02:13 this is the symbol for battery. electrochemical forces. The battery and in
02:22 case it's a battery for potassium. this is a symbol for a
02:27 And obviously if you have plasma membrane will have more than one channel.
02:35 lot of times neurons will have 10-20 voltage gated types of channels. You
02:42 have four subtypes of sodium, five of potassium, some subtypes of
02:47 calcium and so on. It depends the individual cells. Remember the channels
02:53 they will express and the intracellular markers they express, which makes them unique
02:59 their subtypes and their functions. So can see that each one, the
03:05 , the potassium and the chloride will . The channel can be represented as
03:10 resistor with a battery across plasma membrane the charges build up and notice that
03:17 plates of the battery are different for than it is for potassium because like
03:22 said, potassium is built up and charge on the outside of the south
03:28 of the cell where there's negative charge sodium is built up on the outside
03:32 the cell, there's positive charge. if you wanted to know for example
03:38 is the overall potassium conductance, you want to know how much single potassium
03:45 conducts. So if you rewrite ALMS into VM minus C. K,
03:52 is the driving force and will continue about that concept today equals IR V
04:00 IR But here is the difference. difference in voltage with the difference
04:05 when the equilibrium potentials for the ion between the membrane potential, which is
04:10 by several ionic species conductance here, or G is one over R.
04:18 I, current is equal B over . Or current is equal conductance times
04:25 driving force driving force right here. , if you have that for potassium
04:35 conductance and its driving force for an channel, then you have to know
04:42 many potassium channels you may have in piece of the membrane or in the
04:47 . And the densities of channels may themselves. They have dense populations of
04:54 and certain parts of plasma membrane and more sparsely distributed channels. If you
05:03 a total number of channels which is of potassium channels and individual conductance,
05:09 can know the overall conductance of potassium that cell and most of the electro
05:16 recordings when they record activity from they can actually record either from single
05:24 or single channel activity or the whole current activity. The whole self current
05:31 will be the collection of all of channels in the membrane and what they're
05:35 is it is reflected in Vietnam. you're recording single channel activity, you
05:41 recording a single channel activity that will the rules that we know with equilibrium
05:47 , that's own individual batteries. In to that, we also mentioned in
05:55 past that whenever you use electronics and is an a. one on the
06:01 and you stimulate with the current. you inject current into the south and
06:06 will say, why do I have care about injecting current into the cell
06:10 action potential firing properties Because this is the brain operates. You will understand
06:15 in the course that the activity the the numb brain handles activity, the
06:21 the cells produce these different patterns of and later the structure in which it
06:27 imposed in systems like visual system. that leads to varied levels of computation
06:36 is communicated between networks as different frequency as waves or brain waves. So
06:44 is really important. And this is of the basis behind how different membranes
06:50 different channels can produce different responses. ? So this is the electronics.
06:57 you were to inject current into the of the electrode, electrophysiology, readouts
07:03 potentials and plasma numb brain read us you to understand the properties of the
07:10 experimentally record them, manipulate them and predict of what might be happening in
07:18 conditions, not just physiological conditions or of physiological conditions versus normal.
07:27 the response of the cell is an . two and for all of the
07:32 stimulus that is immediate, like a in the electronics on the cell doesn't
07:39 with immediate maximal change in voltage. it takes a few milliseconds to change
07:48 voltage because you have to open up channel. So there's a resistance that's
07:54 the fluxus of currents to be immediately the plasma membrane. The second thing
08:00 the South has capacitive properties. So is the symbol for capacitance. Plasma
08:17 of neurons are very good capacities. future is a very good capacitor is
08:22 it has large surface area because if has a large surface area it can
08:27 a lot of charge. The two of the capacitor, the positive and
08:32 negative plate of the capacitor should be close to each other. You have
08:38 here by possible lipid bi layer of and negative charge and that this discharge
08:45 charge of storage and then discharge and between the plates of positive and negative
08:51 on the two plates of the capacitor fast and neurons are very good because
08:58 of course is because of the resistance the capacitance. It takes time to
09:04 the maximum amount of change in voltage you inject a certain amount of
09:09 And also after you stop this it will take time for it to
09:14 and re polarize also take a few , but it's a few milliseconds.
09:19 it's fast, lots of surface Yes, because you have all of
09:24 processes. Not just so much as not just around south. You have
09:27 of these processes and riddick spines that the surface area and therefore the ability
09:32 store charged across plasma number. Very . Very highly charged capacitors.
09:41 And so you can also see that the injected amount of current these channels
09:47 react with a certain amount of change the voltage. And so this current
09:54 here outward current or inward current which simulating through recording electrode or through an
10:03 physiological electrode. Those changes in current causes certain changes in voltage. I
10:12 for current. V for voltage. shows a Vm numbering potential in millet
10:20 and current in nano amperes by definition inward currents is negative values of of
10:31 and bears. Mhm. And the current by definition has positive values of
10:40 . In this case, nano amperes the value for the current. But
10:45 shows for example that for certain channels relationship between current and voltage or ivy
10:55 or I. V. Plot is . So in this case it's showing
11:00 if you changed outward current. Well say half a banana and pear.
11:09 get the change in membrane potential of mil levels. One nanogram pair,
11:16 get a change in membrane potential in million bowls. And then if you
11:22 the inward current for all. For of a nanogram peer you get five
11:26 of old. Another direction. For you get 10 mil level change in
11:30 other direction. And this is a or atomic as an arms law.
11:36 . I'd plot in reality the cells contain channels that will have linear plots
11:47 the channels that will have complex plots don't look linear. A lot of
11:53 activity. A lot of flux of through the channels is nonlinear dynamics.
12:02 again this is just speaks to how surface area of the historical neuron plays
12:09 the resistance and capacitance of the So if you have Small sparkle neuron
12:18 square is the radius of hysterical You have a small neuron then you
12:25 high resistance of that neuron. The resistance is referred to are in which
12:34 on the membrane resistance divided by four a squared small cells. High
12:47 Okay small uh hose for the water high resistance. You're gonna take your
12:58 pressure to put things through that. that water through the hose for
13:06 The input capacitance is the opposite input is the member in capacity and stands
13:15 pi squared which is the larger the , the larger the surface area,
13:21 larger the capacity, it's just the because you're in verse. Well not
13:28 but they depend inversely on the radius the neuron. So this is numb
13:37 equivalent circuits. And I would say maybe you should draw these. These
13:42 gonna be exam questions for recognizing the and also you may encounter them and
13:51 the subject matter that you may study you'll remember that wow you know what
13:59 neurons can actually be represented as So now this is a circuit for
14:06 potassium and chloride with their own distinct . Extra cellular side the side of
14:11 mix side below you're seeing that you passive, you have chloride that is
14:19 , there's no arrows so there's no of current going on here. But
14:23 and potassium conductance is our active. that would be something representing of the
14:28 potential. You also have active A. K pump and you can
14:33 that this will always work against the gradient actively actively in this case it's
14:41 transport. No not it's active transport a teepee of potassium into the south
14:48 sodium out of the south against the gradient. And finally you have in
14:52 circuit the positive and negatively charged capacitance which is overall capacities of the plasma
15:02 . So you can use these circuits and plug them in and you can
15:09 conductance, is to do these circuits you can make them really complex and
15:13 can scale them up and you can introducing all of the different I.
15:22 . Components, linear, nonlinear and start modeling essentially the selectivity and that
15:32 be done computational and ultimately we're trying build machines like computers that will be
15:41 good computing and processing things as we . They're already much better at computing
15:50 processing things much faster fashion. But kind of walk on their own.
15:59 no plasticity but artificial intelligence people will the opposite uh that there is learning
16:12 , There is plasticity you can observe some model some behavior and it will
16:20 from that behavior and it will self itself. And then you would want
16:26 copy some of the rules that you in the south with ivy plots with
16:30 synaptic transmission to make the computers and as close as possible to, you
16:40 , to humans. So who's buying verse stock yet? It's tanking joking
16:51 course. But you know, that's a lot of, a lot of
16:55 are concerned. It's a lot of that can be modeled and calculated by
17:03 circuits. Comes from understanding some of basic physiology of the plasma membrane and
17:09 of the neuron, no individual neuronal then neuronal circuit conscience. Because these
17:15 very complicated circuits that that are in machines that we're building, recreating a
17:21 with Now during the action potential. that when we calculated the resting membrane
17:32 , we said that the most dominant address it has leaked channel. So
17:40 has the highest permeability. And this permeability for potassium sodium and chloride and
17:48 resting membrane potential and during the action during the action potential, especially during
17:56 rising phase of the action potential. conductance and the premier ability is 20
18:02 higher for sodium than it is to . But as you can see,
18:08 is not flexing much either addressing member potential or during the action potential.
18:14 when we talk about the dynamics of action potential here during the rising overshoot
18:21 phase were mostly talking about um we're talking about these kind of ions like
18:36 and potassium. Obviously sodium influx ng the rising phase and potassium e flux
18:42 during the following phase. Let's go to this diagram here, remind ourselves
18:52 that we've learned in the last lecture a half or two E que e
19:00 and a calcium Standford equilibrium potentials for ions. We calculate using nurse equation
19:09 . M. Stands for the overall of potential. So this blue trace
19:14 the action potential is the overall number potential. Remember which is a combination
19:19 sodium and potassium flux is happening at same time. Okay, so DM
19:28 calculated using Goldman operation. The resting in potential is about minus 65.
19:35 if the cell receives excitatory glutamate it d polarizes, it receives inhibitory
19:42 Inputs that hyper polarizes. If it the threshold value for the action potential
19:47 -45 it generates an all or non it goes through this deep polarization,
19:55 deep polarization, sodium deep polarization sodium positive feedback loop And sodium because it's
20:03 permeable now, more permeable to potassium is trying to drive the overall number
20:09 potential value to the equilibrium potential for . It fails to reach the equilibrium
20:16 for sodium for a couple of Because the more it d polarizes at
20:21 beginning here, this is the green that you can say is a driving
20:26 , which is the difference between equilibrium for sodium here and the number in
20:33 . And when the membrane is hyper , this green line, it's very
20:39 , there's a very large driving force sodium. But when the number of
20:45 is here at the peak of the potential, the difference between the member
20:49 potential and the equilibrium potential for sodium minute. However, now at this
20:58 the difference between the member and potential blue and the reversal or equilibrium potential
21:04 potassium is huge. So that's one why sodium fails to drive the number
21:11 potential to equilibrium value. The second is the actual kinetics and dynamics of
21:17 channels. So, we'll start looking the sodium channel and how it opens
21:21 closes and so it happens that sodium open very quickly, utilization more sodium
21:27 they also closed very quickly. And in order for them to reopen
21:34 , the membrane potential has to re or hyper polarized back to some resting
21:41 potential level Once during the falling phase e flux takes over again as the
21:49 dominant formidable ion. It tries to the number of potential value to equilibrium
21:56 for catastrophe. But they're they're driving for potassium is minute. Of course
22:05 are leaks channels. So the membrane still most permeable to potassium at these
22:11 . But you also have N. . K. Active pumps kick in
22:16 A. T. P. Rebuilding potential by transporting sodium and potassium against
22:22 concentration here against. So if you in this phase here, which is
22:29 absolute refractory phase of the action that means you cannot produce another action
22:35 . If you were to stimulate the and give it the maximum stimulus you
22:39 and help, oh, there's going be even more deep polarization I can
22:42 Instead of 80,140 and another action It's not going to happen because you
22:49 exhaust the sodium channels and they're all now. So even if you
22:53 the south sodium channels are closed and not going to open again during the
22:59 polarization. Then when it crosses this value with the action potential, it
23:06 enters into the relative refractory period. if you were to produce a strong
23:10 of shock onto the cell during the refractory period, it will be able
23:15 produce in that action potential. And on the dynamics and properties of the
23:20 and the channels that are in the membrane. The frequency of these action
23:25 can be slow, it could be and that's why you get different firing
23:31 of these different subtypes of cells that were discussing earlier in the course,
23:36 this is driving force again. And action potential within the concept of the
23:44 force. Oh and so again. is the depiction of what is happening
24:09 the conductance is where you have potassium , G. K. Dominating and
24:15 stronger than sodium at rest. You the sodium conductance that takes over.
24:22 that mean that there's no at all conductance in in this area here in
24:29 rising phase. Is it zero for conductance? No, It's just that
24:37 is so so much greater. It's zero. You saw that there's still
24:41 for both ions. It's not zero it's much much greater for sodium number
24:47 potential here, it's showing this deep . But we now that we have
24:52 sodium coming in and there's some potassium to come out and the more default
24:59 , the bigger is the drive for the driving force falling phase, you
25:05 see now potassium is all dominating and . You have leak channels that are
25:14 here. That so now we are off these two major concepts for the
25:22 remembering equivalent circuits. Okay and the force and I think that I hope
25:31 this makes sense. And if you these action potentials a little bit in
25:38 different light when you actually start understanding from the driving force perspective, and
25:45 just from nerds equation or your involvement . Okay, voltage clamp. And
25:55 do you have to start to understand technique? And it's because as I
26:02 that this black line is the membrane , it's VM. And within that
26:09 shows that it doesn't show that K. Is equal zero. So
26:15 this box, within this rising phase the action potential, what is really
26:19 on is mostly sodium is going in is dominated by a lot but there's
26:24 little bit of potassium leaving at the time. But we can't see it
26:31 we just look at the member of country. So we have to isolate
26:38 sodium individual potassium cards. If we those currents we can then determine the
26:47 of flux is of islands through these these channels and through these individual currents
26:52 how they may be affected and how transpired during different phases of the action
26:59 . So, we employ the technique called the voltage clamp technique. And
27:05 the older days, voltage clamp technique performed by using two electrodes, as
27:11 shown here, the green electrode which the recording electrode and the orange electorate
27:17 is a stimulating electrode in modern day electrophysiology. The sampling rates or the
27:25 of which the electorate's can inject. also a sample a record current is
27:31 fast that you perform these experiments with electorate. However, looking at it
27:38 way the technique right? Looking at this way you have the reference electrode
27:56 you have this axon here this is giant squid axon squid axon. The
28:06 is not like giant. It doesn't ships it's about this size but the
28:14 on It's giant in that spirit about . So when they're older days and
28:21 and will actually look at that's that's cool. What were you able to
28:27 ? You were able to put this on on the dish and would stay
28:32 separated from from the selma but stay for a couple of hours. So
28:37 had a living nerve sitting in the . Now you can do a lot
28:40 things. You can manipulate the extra environment, right? Which would be
28:46 it's being bathed in in the Uh huh. You can inject
28:51 You can report current. You can a lot of things with it.
28:55 you have a reference electorate because if recall the outside of the cell as
29:00 as the inside of the cellar. neutral. The charge and accumulation and
29:07 is across plasma member. So the electorate will be zero saying the outside
29:12 zero. This is the recording electorate you have one internal electorate that managers
29:19 And it's connected to the voltage clamp . It's measuring the VM. And
29:25 connected to a voltage clamp amplifier which member and potential to the desired command
29:31 . And it says here command I said what is command voltage In
29:35 case? Command voltage. It's what decided to be. Find the saving
29:43 40 zero plus 40. You command voltage. You are you are wanting
30:04 voltage at a given member into potential because if you just do cellular recordings
30:14 you put an electorate inside the south you record activity. Okay you're recording
30:19 activity. It will look like this will produce some action potential protests with
30:24 recording membrane voltage. The E. Ir. You can record voltage or
30:39 can record current from current. You calculate voltage and so on. You
30:45 be on either part of this It's a voltage clamp on the command
30:50 . Instead of just recording this Instead of just recording this video,
30:57 actually tells the membrane. I'm not gonna sit here and listen to you
31:02 a radio, you're gonna play me song and I'm gonna listen to
31:05 I can inject the current and still how you respond. I'm actually going
31:10 tune that radio and dial it into different frequency which is your number.
31:17 I'm frequency. But this is just analogy. It's a different station -80
31:22 his 40s at different stations. zero 40 is a different station. Different
31:28 range for the membrane potential. So set this command voltage and you have
31:33 voltage clamp amplifier when the member in Is different from the command voltage.
31:40 let's say you said the command voltage -80. And all of a sudden
31:46 see a deflection 2 -85. What clamp amplifier is going to do?
31:59 going to inject current into an axon the 2nd orange electrode. This is
32:05 feedback arrangement that will cause member in to become the same as command
32:11 So every time you're going to have shift from I know Sadie's gonna clamp
32:15 back 2 -80 and I have a shift to -75. I just don't
32:21 the best and everything that you record that is different from your plan
32:27 Are the currents that are flexing that are now picking up with this feedback
32:35 . The current flowing back into the and thus across its membrane can be
32:40 here. And so you would be these currents that are flowing in and
32:45 currents that will be equal and opposite the ionic currents that are flexing through
32:50 plasma membrane. So now you have wonderful feedback circuit. You want to
32:54 at -80 and see what currency you at -80 and stimulate the cell or
33:01 from it either way. But you clapped now different holding potentials. And
33:08 you look during this deep polarization actually is shown is that you have concurrently
33:16 inward sodium car. And you can that sodium current peaks very early and
33:23 very fast. But at the same during the action potential, you also
33:30 potassium current going outwardly and you can that there's a significant delay with potassium
33:40 . So potassium current really starts engaging sodium currents starts reaching its maximum.
33:46 when the potassium current goes almost through exponential conductance says, okay and now
33:56 you're starting to understand is that the potential represents an overlap of currents vo
34:11 an action potential. And when you currents you will see that there is
34:20 the word sodium current with our potassium . Yeah. And this is happening
34:33 the same time. So if you're recording voltage, you cannot pick up
34:39 currents. You're recording a some off the currents of ionic currents. But
34:45 fact of the matter is the two happening at the same time. And
34:49 when the voltage clamp was invented, and Huxley used this voltage clamp technique
34:57 study the inward and the outward And so you can see that They
35:03 the voltage clamp and they held the , they clamped it at -26.
35:10 as they climbed it in -26 they this short transient inward current. This
35:17 deflection followed by somewhat weak, late persistent, prolonged outward current. He
35:29 the potential at zero. And they that inward current got stronger, but
35:33 did the outward current positive 26. of a sudden they saw a decrease
35:40 inward current, but they saw an in outward That's positive 52, inward
35:48 disappeared. And this is why I you that reversal potential values Are different
35:54 different textbooks. Can be positive 55 56, positive 62 in this experiment
36:01 the Hodgkin and Huxley. The inward , which is the equilibrium potential value
36:07 the inward conductance. It reversed. actually disappeared at positive 52 million
36:15 There's no net inward flocks of sodium it's reached its equilibrium potential value,
36:21 you have huge tremendous drive for And then if you surpass if you
36:29 to even more positive clamping or holding in the membrane beyond the equilibrium potential
36:38 for sodium. You see this little here, maybe not, mm
36:52 You see this little blip here on right, this is sodium currents.
36:59 it's reversed. It's flowing in the direction because you surpassed. They're delivering
37:06 value and that's what equilibrium potential values also known as reversal potential values.
37:12 currents will literally reverse in the opposite . Okay, The number is electro
37:19 force is dependent On not just the gradient with the membrane potential. And
37:26 course these d polarized potentials, you have a tremendous outward driving force.
37:33 , in 1963 Hodgkin and Huxley received prize in physiology and medicine for their
37:40 on the action potential. The experimental , but also the modeling work.
37:45 there's a model, huh, chicken hustling model for the action potentials with
37:50 . And that is I don't know it's part of it. I think
37:57 publicly available, but this is a that allows you to play with different
38:01 , is to recreate action potential. now you can see from that model
38:05 from the number in equivalent circuits. you can build more complex models ah
38:11 recreating different patterns. Not just one potential. But imagine if you had
38:17 model to recreate this in the circuit then you had something like this that
38:21 have to be creative. It's a more complex and it will take a
38:26 more computation and preparation and and maybe a circuit of interconnected self, not
38:33 one neuron doing it on its So before we go into the sodium
38:45 structure which will be about the last to talk about today. Did I
38:51 you the video of the of the the squid recording? No, I
38:57 think I did. It's a really video here. That's why you sometimes
39:01 to browse over into the support and lecture material where you find migrating neuronal
39:09 and micro glial cell dynamics, I'm stop the shared and re shared and
39:16 sure that I share the sound also some way and there might be some
39:27 strange commercial. No, thanks very . The careful airpods, body plans
39:36 habits are so very different from those humans that there might almost be aliens
39:41 another world. So perhaps it's not that it took a long time for
39:47 to discover that there are fundamental similarities the nervous systems of cephalopods and
39:57 Yet it was the recognition of a difference in their nervous system, which
40:01 scientists to undertake research that has led a growing understanding of the mechanisms controlling
40:07 own nervous system. The breakthrough concerned nerves that control the contraction of the
40:13 muscles used in jet propulsion. As archive film shows by simultaneously contracting it's
40:22 muscles. Even a moderately sized squid inject a huge amount of water with
40:27 force. In the mid 19 the british zoologist Professor James Young was
40:38 in a study of the squid's Young observed an array of large tubular
40:45 , each as much as a millimeter diameter, in the squid's mantle as
40:50 structures were never filled with blood. could not have been blood vessels from
40:55 similarity to surrounding nerve fibers. Young they must be single neurons. Giant
41:01 , they're transmitted nerve impulses from the of nervous tissue called the cingulate ganglion
41:07 the mantle muscles using electrodes. He the surrounding nerve fibers and found that
41:18 could only produce large muscle contractions in mantle when the large tubular structures remained
41:29 . So these were indeed giant Scientists quickly appreciated the significance of young's
41:40 for here at last was an large and robust enough to investigate with
41:44 techniques available at the time and one survived for several hours when isolated from
41:49 nucleus, the intracellular contents of the axon could be removed and analyzed,
42:00 to the that's exactly how you would the concentration of ions and talked about
42:06 you would use for non situation concentration islands on the outside versus the inside
42:13 outside is, you know, the spinal fluid and the inside of the
42:20 . I mean the the outside is interstitial fluids around the cell and the
42:26 is the side. Applause. And in the squid, the outside
42:32 is the ocean, which is very high salinity. It's a lot
42:38 salty here and our brain fluids. nonetheless, this is how you would
42:45 . Different ions would literally squeeze it . Discovery that sodium ions were more
42:50 outside the nerve cell and potassium ions concentrated inside by refilling the empty axons
42:59 solutions of precisely known chemical composition. were able to unravel the mechanisms of
43:05 transport across the membrane. The giant are large enough and robust enough for
43:16 electrodes to be inserted through the cell and into the axa plasm. In
43:27 early techniques. A fine glass tube first inserted into the axon and secured
43:32 thread. That's it. Then the was used to introduce a fine wire
43:58 from which the voltage between the inside the outside could be measured. But
44:04 formation of the Nerve Impulse was far rapid for detailed study with any of
44:09 electrical measuring devices of the late It wasn't until the 1950s following the
44:16 improvement of electronic equipment such as the ray Oscilloscope, that major progress was
44:25 . Scientists found that the nerve impulse transmitted as a characteristic wave of electrical
44:32 and that this all or nothing action was generated mainly by transient movements of
44:37 and potassium ions across the nerve Research on the squid giant axon unravel
44:46 mechanisms of the formation and propagation of nerve action potentials. This understanding led
44:53 to the development of drugs that block potential formation and so act as local
44:59 now used routinely as painkillers in dentistry minor surgery. There's also your answer
45:07 you want to know these things, and the changes because a lot of
45:15 channels that we're talking about are also for therapies, various therapies for different
45:25 substances. So we are still on action potential. And we are now
45:33 to understand the second reason that I you earlier why sodium doesn't reach its
45:38 delivering potential value. And that's because the structure and how that structure functions
45:46 the sodium channels. So sodium channels four sub units 1234. Each one
45:54 six trans membrane segments as one through six as for trans membrane segments is
46:04 charged as high polarity. And it dubbed as a voltage sensor. This
46:10 the voltage sensor that will influence the and the closing of this channel.
46:15 within the structure of the three dimensional of the channel itself. Within this
46:23 acid sequences that are positively charged between five and the six. We have
46:29 selectivity for the roderick mackinnon when he potassium channels showed that selectivity four and
46:38 is between five and 6. So subunit will contribute this poor loop and
46:45 poor loop coming together will be selecting the islands to pass through the
46:51 In this case for sodium channel also out that sodium channels both educated sodium
47:01 , they have two gates. Let's . I cannot feel it draw from
47:17 , but I can explain it in following way, resting membrane potential.
47:25 have this voltage sensor positively charged pulpits that is sitting on near side of
47:32 mix side of the membrane that is charged. So this positively charged amino
47:39 residues within sodium channel are attracted to negatively charged inside of the plasma
47:47 keeping the gates closed. So the polarized potentials that hyper polarized voltage.
47:54 sodium channels are closed. What is to open the gates of the sodium
48:00 ? It's the voltage that's going to the gates is nothing binding sodium minds
48:05 bind two channels to go through What is going to happen when there
48:10 a deep polarization from -65 to about 40 Myla balls is you have accumulation
48:20 positive charge on the inside of the membrane and the more positive the plasma
48:26 on the inside becomes. This sensor getting repelled by positive charge entering into
48:34 cellar. And by getting repelled, literally slides up through this three dimensional
48:42 channel structure changes the confirmation of the And now causes the opening of the
48:50 gates. So you will learn that are actually during the deep polarization here
49:00 -60 to -40. If you were look at the sodium channel dynamics,
49:07 will see that as soon as deep engages year, you have multiple sodium
49:13 , you're represented by each trace. you have three channels And you have
49:19 states of being for these channels noted , 2, 3, 4.
49:24 , when you de polarize plasma numb and you record sodium channels because you
49:29 voltage clamp and you can isolate individual currents. You see that these channels
49:36 very fast, but they also close fast. So it's fast opening.
49:45 it's fast inactivation of this channel. the channel is closed. It doesn't
49:52 . You still have this persistent deep . The sodium channels they open transient
50:00 and they closed fast opening and their . And that's why it doesn't reach
50:05 equilibrium potential during the peak of the potential for for sodium here.
50:11 because the channel is closed and the force decreases. So these channels close
50:18 they actually have two gates. The two arms close like this are called
50:25 gates. And this ball and chain out here, it's called inactivation
50:32 So when the channel opens because of voltage because the voltage sensor slides open
50:38 to deep polarization you receive positive D polarized. Now you're starting to
50:43 the channels because the voltage sensor sliding sodium starts coming in. But as
50:49 as sodium Russia's end through the this guy that ball on the swing
50:57 , it doesn't wait and it So the sliding of that voltage sensor
51:04 the channel. But the change in confirmation of that opening gate also causes
51:10 conformational change in the swinging and the of the inactivation gate At that point
51:16 number three the channel is inactivated. in order for the channel to open
51:22 because it's enacted now it's plugged It's not conducting anything in order for
51:28 channel to open again, you actually to deon activate it. Which means
51:33 have to remove Inactivation Gates from the four Deion activated. Okay. and
51:43 do that by releasing this member and from D polarized values back and to
51:49 polarized values. Now when you have polarize the plasma membrane you now have
51:57 voltage sensor that starts sliding back down the plasma membrane has negative charges starts
52:05 back down as a sliding back It pushes out the inactivation gate and
52:11 causes the activation. Get too close the number four position it's closed and
52:17 to open again. You cannot go . It will not happen. You
52:24 to deactivate and hyper polarize. That's during the absolute refractory period you cannot
52:29 on that action potential. I have hyper polarized the plasma number in order
52:35 produce another action potential which is during relative refractory period of the actual
52:42 Great stuff. So when we come we're gonna talk about the patch clamp
52:48 techniques. We already introduced a little about some of the recording techniques and
52:54 actually watch some Simpsons. Um The the Simpsons as they explained some neuroscience
53:05 us. We're gonna talk about brilliant Toshio Narahashi who studied the toxins and
53:15 the definitive functions of vault educated sodium . So we'll talk a little bit
53:22 pharmacology will basically finish talking about the potential. This is gonna be our
53:28 lecture for the material and we will about the back propagating action potential.
53:35 if you go in your lecture supporting , this is the slide that we're
53:43 to discuss next lecture and you can it that much greater resolution with full
53:50 . Explain, I'm just pointing it for you that it's there for
53:54 so that when we go over that , we can fall back or you
53:58 open it up and see it a resolution. So we'll leave it here
54:05 . Remember all of these really important we discussed and and also the sodium
54:15 , I would say the sodium channel and activation and activation would be probably
54:22 The 4th and 5th most important concept we've discussed today. Thank you for
54:27 here. Let's see. I'm gonna the recording here, mm
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