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BIOL 4315 Neuroscience Tue Th 4-5.30pm - NEUROSCIENCE Lecture 06 Resting Membrane Potential and Action Potential 1
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00:00 Welcome back. Today is February two . And it's our 6th lecture where
00:14 are noted on the syllabus to talk the actual potential. And last lecture
00:20 just began talking about the neuronal number a trust. So we'll see how
00:25 lecture goes. If we cover the membrane potential and then move into neuronal
00:31 potential or if we'll begin the action on the uh subsequent week.
00:43 so this is from last lecture that discussed and here we discussed the patellar
00:56 or knee jerk or stretch reflex. talked about it as one of the
01:01 basic reflexes and I asked you to the different components of the circuit.
01:08 the dorsal root ganglion cells that are for the sensor information and are a
01:15 , their morphology, the neurotransmitters to uh the inhibitor into neurons of the
01:22 cord. Their morphology neurotransmitters, their and the motor neurons that innovate the
01:31 that cause in this case skeletal muscle . Okay, so all those three
01:38 subtypes will be on the exam as questions. So, if you didn't
01:44 good notes last week, it's uh should review the lecture as I mentioned
01:53 I, what I write on the doesn't always show up very well on
01:59 video. So it is best to notes in class and from the board
02:08 preparing yourselves for the upcoming test, is in about two weeks or
02:15 Okay, so today we're moving into about the resting membrane potential. Oh
02:22 the resting membrane potential happens because we an equal separation of charge across plasma
02:32 . And we have a quiz environment the south and outside of the south
02:40 is oxygen has extra electrons and has charge, hydrogen has net positive
02:51 They both held by cavalry in bonds other polar molecules. In this case
02:56 talking about ions. They will dissolve water and atoms or molecules that have
03:03 net electrical charge or ions. As know, they form ionic bonds.
03:09 70 plus is an ion chloride minus an ion and they form ionic
03:15 The difference in the number of protons electrons results in the valence C.
03:23 charged for that particular ion. So a plus one is a mono valent
03:32 calcium two plus is a dive ailing . You have cat ions. Cat
03:40 will carry the positive charge and and will carry the negative charge on the
03:48 . And so all of the molecules you're seeing here will be floating around
03:52 the sacred solution and then you have chloride uh surrounded here by water molecules
04:00 lot of times, we're referring to as clouds of hydration of waters of
04:05 surrounding these individual, ironically bond molecules individual ions. So, as we
04:14 from the very beginning, plasma membrane of the possible effect by later and
04:20 possible olympic bilateral is not permeable to ions. So for ions to cross
04:28 from inside to outside from outside to of the south, you need ionic
04:35 . So these are receptor channels that embedded in the plasma membrane. And
04:43 receptor ionic channels we will be discussing the next couple of hours are ion
04:52 camels. So you will have a for sodium, potassium chloride and
05:02 And these are the four major ionic that we will be discussing. So
05:08 abundance of sodium chloride on the outside the south. It's a saline like
05:14 . And what this figure shows is there is 100 and 45. This
05:21 an mila moller of sodium on the of the cell and about 18 million
05:28 of sodium on the inside of the , there's a lot of chloride under
05:34 or so million moller on the outside only about seven million moller of chloride
05:40 the inside of the South. potassium is dominating on the inside of
05:47 South has 135 million moller inside in intracellular cytoplasmic delusion and It has only
05:58 uh it has only 3.5 or so . Miller on the outside for potassium
06:05 for calcium if you look at the concentration gradient, the highest disparity in
06:12 concentration gradient and the separation of it is for calcium, there is 1.2
06:22 moller of calcium on the outside of cells. And there is 0.1 micro
06:32 . So millie 10 to the negative micro is 10 to the negative
06:39 So this is the highest disparity in concentration gradient chemical gradient for calcium and
06:47 other important component in the plasma membrane neurons and important and uh regulating and
06:58 a lot of times acted action potential o wrestling member potential, R N
07:04 K A T P A C S A K pumps. And those pumps
07:10 always be working against concentration gradient. if there is a lot of sodium
07:15 the outside against concentration gradient will be put more sodium on the outside And
07:21 concentration gradient would be to put more on the inside of the south and
07:27 do that. They utilize a lot 80 p energy to do that.
07:35 these protein channels that we will be are built from the basic blocks which
07:44 amino assets and as you know, is a variety of amino assets.
07:50 are those that are essential amino assets that are amino assets that you have
07:58 obtain from the outside world. So have to rely on the food
08:05 The dietary intake of the essential amino . But what the amino acids will
08:13 is they will form peptide bonds and will form these peptide chains of amino
08:21 . And so these peptide chains of acids is the primary structure the protein
08:29 essentially will become the trans membrane protein . This primary structure of immuno assets
08:41 twist itself into a helix. It's alpha helix and this is an example
08:49 a secondary structure coiling of the polyp into an alpha helix. There are
08:58 secondary structures of these uh secondary structures the proteins that are not always
09:08 that can also be sheeted so sort of like sheets and they're often
09:13 products, beta sheets, the tertiary would be several of these alpha hell
09:21 coming together quite often. Each one these is a trans membrane segment and
09:28 of these tertiary uh protein components will a sub unit and finally you will
09:40 multiple sub units forming a receptor or ion channel in this case and they
09:50 be receptor ion channels that have to a signal chemical signal. And their
09:57 channels that we'll be discussing in the couple of lectures that are gated by
10:02 . So there are different ways in you can open the channel in the
10:07 and we will be talking about resting potential and action potential, specifically about
10:13 channels that are gated by voltage. means that it's the voltage. The
10:17 of voltage across plasma membrane that is to either cause the opening of the
10:24 of these channels. So ion channels selective iron channels will not allow indiscriminately
10:40 all of the ions inside or the just pass through the channel there have
10:48 specific structure. And you can view channels as being capable of sieving through
10:56 select. So there's a selectivity to for specific ion and it also depends
11:04 the structure and the chemical interactions were that island with the internal structure of
11:09 channel. Some of the channels are fast. And for example uh single
11:21 receptor channel can conduct 100 million ions second. So some of the channels
11:30 conduct ions whether the receptor channels of gated channels and conduct hundreds of thousands
11:37 hundreds of millions of ions per This is in contrast to the pumps
11:43 I've discussed that use A T. . The A. T.
11:46 A. That worked against the concentration . There are much slower and exchange
11:53 the charge between inside and the outside the cell. Exchange of the ion
11:57 and potassium only about 100 or so a second. So channels are selective
12:05 filters And in this example what you're at is the sodium specific or sodium
12:13 ion channel. And here is the molecule in red and that sodium molecule
12:20 enveloped with water and the sodium molecule in and enters into the innermost lumen
12:29 this channel here where it progressively gets off the water surrounding that ion and
12:38 briefly interacts with the negatively charged residue has a sodium binding site. And
12:48 very brief interaction here on the road microseconds. Then also allows for this
12:56 by electrostatic and diffusion all forces of sodium now from the outside to come
13:03 the inside of the cell. and this is the case for many
13:09 ions. So potassium will be surrounded waters and potassium will also interact with
13:19 negatively charged amino acid residue but a different location, slightly different residue that
13:26 more suitable war interactions with the potassium , calcium selective channels will also have
13:35 uh selectivity chloride channels. It's an ion that's negatively charged. So there
13:42 would have a positively charged amino acid inside the inner channel lumen that would
13:49 and have this interaction with the chloride charged ion. So in this
13:56 sodium is stripped off the waters by acid residues and enters inside with larger
14:03 potassium is trapped and sent back So size is important too. And
14:11 this case we're talking about larger So that means does that mean that
14:16 smaller diameter ions can go through the that pass larger diameter ions. And
14:22 answer is no, they're selective and of an ion does not necessarily mean
14:29 size of the waters of hydration. ions can have uh bigger attractive forces
14:37 building these larger clouds of water around . So, it has to do
14:41 several factors with the size selectivity interaction amino acid residue for this channel to
14:51 selected and specifically selected for sodium or over calcium. Okay, so today
15:01 will be discussing some of the things will require for us to remind ourselves
15:06 some of the basics of physics and particular arms law which we all learned
15:14 high school. The equals IR V for voltage I for current. And
15:24 for resistance voltage typically is measured involves and am cares resistance and alls now
15:35 is the inverse of resistance. So is the conductance as one over r
15:40 universal resistance are and that is measured Seamans. What are some of the
15:47 scales for neurons, neurons? The that we're gonna be talking about across
15:52 membrane and the voltage that is generated action potential firing is measured in milli
16:00 . So we will not be talking volts, we'll be talking about volt
16:05 , measuring milli volts of activity for . The relevant scales for neurons for
16:12 in a single cell or current. uh uh that you're recording from a
16:21 is in PICO amperes and nano Resistance of neurons is in mega
16:33 So they have very high resistance from of mega homes to hundreds of mega
16:39 conductance is in PICO Seaman's or nano . Alright, so these are just
16:48 put in the perspective the relative the scales by which neurons operate at and
16:57 voltage, the current resistance. So the scale that one again, like
17:06 like so they have, I believe was also, it's not necessarily that
17:19 low but these are the relative the scales that you are looking at neurons
17:32 amperes, it's million pairs nano amperes even sometimes a million pairs at the
17:41 level and more of like at the cell level. But uh yeah and
17:50 conductance and tens to hundreds of mega , the 1000 mega is 1000 tens
18:04 hundreds of thousands of homes. So uh ionic movement across plasma membrane,
18:13 there is no channels, there's no movement. If we were just to
18:17 at it simply based on the concentration or the diffusion forces. If you
18:24 a lot of sodium here and a of chloride then this sodium and the
18:30 ions would slow down their concentration gradients there's going to be equal concentration or
18:40 moller concentration of sodium on both and chloride on both sides. Inside
18:47 the outside and the inside of the . The way you look at
18:50 But that's not the case. That's what happens. Because apart from chemical
18:58 , we also have electrical interactions between between ions. And so we know
19:06 cat ions are attracted to cat So positively charged ion is attracted to
19:14 negative end of this, in this of the battery and an ion is
19:19 to anna and you have an electrical . So apart from the chemical
19:28 you have electrical potential, you have which is a minority of miller volts
19:33 plasma membrane and this voltage will be the channels and opening and closing the
19:39 . Therefore driving ions through channels and current from inside to outside and outside
19:47 inside of the sound. So again have the separation of charge with the
19:53 of the plasma membrane is negatively 100 among the 65 million balls compared
20:01 the outside of the south separation of across the membrane. So the separation
20:08 charge is what gives rise to this in electrical potential, which is our
20:15 membrane potential inside versus outside At the , it's about -65 loan laws.
20:24 you are thinking about current flow and conventional understanding of current flow, direction
20:31 net movement of positive charge. So ions move opposite because they're negatively charged
20:37 direction. Cantons move same as current . The neurons are hyper polarized at
20:47 million volts the inside and loss or in that charge separation. So neurons
20:53 more positive on the inside, it's polarization, an increase in the charge
20:59 . The inside of the neurons accumulating and more negative charge, it's hyper
21:05 . So, these are some of basic concepts that we should all be
21:11 with. And because we have both , we have the chemical gradient and
21:19 gradient ions have equilibrium potential and equilibrium is a potential where diffusion elite forces
21:32 are chemical gradient forces and electrical forces is the charge and interaction of the
21:40 positive and negative and so on where of these forces are equal to each
21:46 and actually opposing in direction. So happens is you have potassium ions
21:54 A lot of potassium ions on the of the south and you have a
22:00 charged program that doesn't have a channel across through plasma membrane. So this
22:08 , if you introduce the channel will down its concentration gradient, will flow
22:15 its concentration gradient. And you will , well if it was only chemical
22:19 then there's going to be equal amounts potassium on both sides. Except that
22:23 happens is as this potassium which is lot of potassium and it's illustrated here
22:29 this very large K Plus letter over very small K plus letter here,
22:36 K plus large amount of potassium will down outside of the cell from the
22:42 until there's gonna be enough of the charge that's accumulated on the outside of
22:47 South. I guess what happens, positive charge, which is potassium itself
22:55 repellents to potassium which is positively So at that point, what happens
23:03 that point is you have the chemical . One thing to drive more potassium
23:10 this side into this side, but electrical charge saying I'm repelling you,
23:16 electrical forces are repelling you and at point they basically become equal enforced to
23:24 other. These two arrows, not concentrations, but the two forces become
23:31 to each other. And at that there's no net ionic movement of
23:36 It either inside or outside of the , it doesn't mean that there's no
23:40 of potassium, but for each potassium in one there's gonna be one going
23:45 to and to out, it's going be staying at this equilibrium potential.
23:52 the other thing to note is if look at the neuronal plasma membranes,
23:57 charge separation and the build up of and this unequal distribution of ions is
24:03 and the charge is concentrated at the of the plasma membrane. The internal
24:10 . The inside of the cell is neutral. And so is the external
24:16 surrounding that cell as well. So and on the concentration changes can actually
24:24 pretty significant voltage fluctuations as these items the plasma membrane. It will affect
24:31 membrane potential and it will affect activity neurons. Net ionic differences at the
24:41 . There's a concept of a driving that will be starting to learn about
24:48 . And we'll come back and we'll learning about it again. Next election
24:52 we talk about action potential. And actually be explaining a lot about action
24:57 based on the driving force concept. driving forces VM stands for membrane potential
25:05 the cell and e ion stands for potential for an island and the difference
25:15 the potential of the number of the and this other value for each ion
25:21 determine the size of the driving Hang on to this thought if the
25:27 concentrations are known, we can calculate ionic. So let's let's calculate this
25:33 on because we already kind of said if we have the volt meter and
25:39 drop an electrode in we know the at rest minus 65 syllables.
25:47 And we also said that this VM actually a consequence of an equal distribution
25:56 multiple ionic species, not just So, the charge on the membrane
26:02 doesn't reflect just changes in sodium or , it reflects changes sodium potassium
26:08 calcium all for ionic species. so now we know dM -65 address
26:23 we don't know the equilibrium potentials for other. So let's calculate the equilibrium
26:31 . So we can understand how it affect the driving forms. Now,
26:37 I illustrated earlier with the potassium going inside to outside and reaching the equilibrium
26:44 . It's also the case for It's also the case for chloride.
26:50 also the case for calcium. Each of the ions in other words have
26:55 own equilibrium potential which is dependent on concentration gradient. In this case there's
27:01 lot of sodium on the outside of south and also the electrical potential.
27:07 changes that the flux of this ion going to build up on the inside
27:11 the south. So each one of ions will have their own equilibrium potentials
27:17 this case the movement of the outside will get counteracted with the charge positively
27:24 build up here, repelling more of positive charge coming in in the previous
27:29 was positive charge leaving. So the is not as important, but it's
27:36 where you have a lot of what on, the concentration of which I
27:41 . So we already discussed the fact you have a lot of sodium on
27:46 outside and a lot of chloride on outside. And so this actually table
27:51 all of this information together. You 100 $50 million. And you'll
27:57 well wait a second, this has million But this is $150 million.
28:03 even your book will give you several values, several different measurements and Malamala
28:10 across the books. Between the there might be slight differences In some
28:16 . The resting membrane potential will be as -17 million -65 and others
28:23 Why is that? Because there's actually variations. We talked about individual subtypes
28:29 cells expressing different subsets of molecules and functionally distinct and different and part of
28:36 substance of molecules that are different that express these ionic channels that we're talking
28:43 . So now it is slight discrepancies I will tell you what you have
28:49 know for the test because I have diagram for you prepared and an action
28:53 that has all of the values that want you to know. That I
28:57 ask you on the task. It's gonna be a trick questions of minus
29:01 45 1 48 1 51 52. . So I'll tell you the point
29:07 here that there is 10 times more sodium on the outside versus the
29:12 So you can look at it as pure mormon moller uh number measurement or
29:20 can look at it as the So there's 10 times more sodium on
29:26 outside versus inside, there's 20 times potassium on the inside versus outside.
29:33 11.5 times more chloride on the outside inside. And this is why I
29:40 that calcium has the highest Chemical right? It has 10,000 times more
29:52 on the outside versus the inside. , this is this is a this
29:57 a this is addressed and in general ionic concentrations are not gonna fluctuate that
30:06 . They're gonna get constantly rebuilt to uh but we will talk about the
30:14 is how the conductance has changed during action potential. And in general what's
30:19 in for us and I'm kind of you asked them is when we talk
30:24 driving forces, you realize that driving for potassium flocks that rest is very
30:31 but potassium dominates. And the cells rest are using potassium slowly from inside
30:39 the cells to outside of the And these are leak channels and these
30:44 channels contribute a lot to the most the most permeable channels in the plasma
30:50 during resting membrane potential. So maybe question will get answered a little bit
30:56 over the next hour. Hopes if , please come back to it because
31:03 ion has its own concentration inside versus . Each ion has its own equilibrium
31:11 value. Okay. And how do derive the equilibrium potential values? And
31:17 is just an illustration that you have T. P. Tom and the
31:22 that a T. P pump for three ions, it brings outside sodium
31:27 that brings two ions on the inside the cell, bias towards keeping more
31:33 on the extra cellular side here. to calculate equilibrium potentials for each
31:40 we use the lens equation and nursed is he, which is ion which
31:48 equilibrium potential for each ion. And ion has its own calculation for the
31:54 of potential. And the important uh and variables. And this calculation is
32:06 which is gas constant T. Which absolute temperature. And in this case
32:12 temperature is the physiological body temperature. we're using 37 C mhm Z.
32:24 the charge of the ion. So minus one, calcium two plus sodium
32:34 F. Is Faraday's constant log is on logarithms. Ion outside is ionic
32:46 on the outside of the neuron and inside is ionic concentration on the inside
32:54 the neuron. Remember that we had in the molar concentrations and we also
33:00 these in ratios. So in the you can plug in either or values
33:06 the ratio values it will it won't matter. So the noticed equation can
33:13 derived from the basic principles of physical . Let's see if we can make
33:17 sensitive. Remember that equilibrium is the of two influences diffusion which pushes an
33:25 balance concentration gradients, chemical and electricity causes an island to be attracted to
33:30 charges and repelled by the life increasing the thermal energy of each
33:36 increases diffusion and will therefore increase the difference city achieve the equilibrium.
33:43 E ion is proportional to T On the other hand increasing the electrical
33:48 of each particle will decrease the potential needed to Dallas diffusion. Therefore,
33:55 E ion is inversely proportional to the . Value. We need not to
34:02 about the R. F. Because are the constant values for the gas
34:07 third a pounce and this is a degrees that we're calculating this. So
34:14 take this calculation that was the formula . R. T. D.
34:21 . Log ion outside versus inside and can actually plug in in this case
34:27 potassium plus one, 37° are after and we can collapse this 2.303.
34:37 up into 61.54. Then you have . The value here is a million
34:48 times the log off. In this , potassium on the outside versus inside
34:54 same abbreviation and collapse here. Or or chloride. This carries a
35:05 Okay, because this is a minus in the Z value. So you'll
35:09 minus and for calcium it's a positive it's 30.77 because you're dividing it by
35:18 , calcium two plus. Mhm. what you derive then is these abbreviations
35:27 you do the calculation in this you plug in the ratios there is
35:32 more of potassium on the inside concentration on the outside of the cell we
35:38 the log of 1/20 negative 1.3. you multiply 61.454, abbreviation for
35:48 K. Times negative 1.3. And is the equilibrium potential for potassium minus
35:55 million balls. Note that there is government earth equation for permeability of ionic
36:03 . Okay. Therefore calculating the value e ionic equilibrium potential does not require
36:11 of the selectivity or the permeability of membrane for the ion. So we
36:15 need to know all of these values and the concentration outside on the inside
36:21 order to derive the equilibrium potentials for ions. And so this table contains
36:27 potential for potassium. This is for . The value is positive 62 million
36:35 for calcium positive 123 melon balls. for chloride approximately minus 65 million
36:42 So each one of the ions when plug in their respective abbreviations here,
36:49 collapse of this portion of the formula their concentrations you obtain the calculations for
36:58 ion. So each ion has its equilibrium potential. But this is not
37:04 in Patan tra. This is a equilibrium for one high on and the
37:12 potential has several players around the membrane are eager to cross in and out
37:18 the channels that can influence overall potential the plasma membrane. Therefore, after
37:24 calculate learns equation you also have to the membrane potential and what this shows
37:31 that to calculate the DM. Which for the membrane potential, you still
37:38 the same artie's er log outside versus . So this portion is taken from
37:47 nurse equation, this same abbreviation uh . In this case we're looking at
37:57 and sodium. Okay, Mill evolves but in this case it's not equilibrium
38:04 for one ion but it's VM. now you're incorporating the concentration of potassium
38:11 versus inside plus the concentration of sodium the outside versus inside. And not
38:18 that you're also introducing permeability term. is not P. K.
38:25 like an analytical chemistry or neuro This is p for permeability for potassium
38:34 for sodium value. That also indicates if the concentrations and this maybe gets
38:43 your question earlier that you asked how ionic concentrations change. You can see
38:48 if the concentration stay the same but change the permeability, you can greatly
38:56 the change in the number of the . So the there is a dynamic
39:02 of these shifts of ions on the of the outside but they're pretty tightly
39:08 and controlled not to shift outside of boundaries if you shift potassium on the
39:15 from 3.5 to 12, minimal or start generating seizure activity in the
39:22 But you can change the number of a lot by changing the premier ability
39:28 ions permeability is what whether that I as flossing for the channel or
39:35 So the channels are all open for and all sodium is flux in the
39:41 is dominant for sodium and you will that it draws the number and potential
39:48 the sodium values and sodium equilibrium And if the permeability values the highest
39:55 , it will draw the membrane potential to the potassium equilibrium potential values.
40:02 therefore you can see here that if run through this calculation again, this
40:07 permeability in this case at rest, is P value here. P.
40:13 . Is the highest for potassium. 40 tons higher for potassium sodium.
40:20 just the way neurons are built to these leaky channels and these leaky channels
40:25 using potassium outside and the potential is negative on the inside of the plasma
40:32 . And so you plug in the permeability. You go back to
40:37 in the ratios of the concentration island versus inside and you now can calculate
40:46 overall BM number and potential value which minus 65. And it's neither equilibrium
40:55 value for sodium which is positive Nor is the equilibrium potential value for
41:05 which is -80. But because it , it's dominated from the ability by
41:12 that the value of wrestling number of of -65. When you take into
41:17 these two ions. Right. do you know, Having a very
41:22 plus 62 potassium -80. The resting of potential is at -65. So
41:30 dominated by the permeability to potassium. the action potential gets generated is gonna
41:37 into positive values. And that's because ratio uh concentration may stay the same
41:46 the ions more or less. There be small flocks is but the permeability
41:52 going to be dominated by sodium during action potential, especially during the rising
42:00 of the action potential. Yeah. again, we'll come back and talk
42:08 this throughout the lecture. But this concludes our resting number in potential lecture
42:18 going to start talking about the action . And we will start talking about
42:24 of the things we already discussed I'll put them in the perspective in
42:28 the equilibrium potentials. The uh action , wrestling number in potential values and
42:36 . Okay, so let's jump into next lecture. We're learning a lot
42:43 good stuff. Just uh situate yourself law. Uh audience channels, selectivity
42:53 the channels, pumps which are slower. You have equilibrium potential.
43:02 have driving force that will discuss. have four ion species that are dominating
43:11 in the plasma membrane. But it out that when you calculate the membrane
43:17 , when you're calculating the membrane you are mostly relying on potassium and
43:26 . So maybe one of the, should have asked the question, How
43:30 this doesn't include calcium and chlorine. said there's four ions that are
43:37 They're right. It's because there's virtually credibility for chloride and uh resting membrane
43:47 . Therefore, if the permeability is , the whole value here is zero
43:56 . So, so now this is differences that we already discussed between the
44:04 equation on top and the Goldman equation the bottom. Again, the uh
44:12 equation is to calculate individual ionic potentials potential values for individual ions. And
44:24 equation is V. M. Calculation is membrane potential. And it's different
44:31 nurse equation because it doesn't calculate the based on one eye on but in
44:39 case on two ions you can chloride permeability value. Also if you want
44:45 hear three islands, four islands. for the most part here, wrestling
44:51 of potential is dictated by potassium and and the permeability. Uh for the
44:59 . How open are the channels to for the conductance of sodium versus
45:06 This is an example of where you want for these ion concentrations to change
45:14 and that there's a tight control of ion concentrations. Mhm After the first
45:23 , I always get this commentary. never talked about this. So talking
45:29 this and this is how the membrane value. M. D. Now
45:36 guys need to read the figures right access no votes number value. And
45:42 is potassium concentration on the outside in middle of. What does that
45:52 That shows that if our regular outside concentration normal is about 3.5 million Moeller
46:02 here, which would be close to wrestling member of value here. If
46:09 shift the outside potassium concentration from 3.5 10 to 2015 million moller you're shifting
46:19 by about 2030 40 million volts. that doesn't happen. So if you
46:28 a lot of potassium build up on outside of the cells, the cell
46:32 of professionals will be polarized and they reach the threshold for action potential.
46:37 will start firing action potentials. So happens is that doesn't happen. So
46:45 we talked about and what this illustrates how memory potential is dependent on the
46:50 concentration of potassium is that if you increase outside concentration of potassium you will
46:56 a significant deep polarization and the number compassion to prevent that we call upon
47:03 friends the glial cells in this case astra sides that spatially buffer these increases
47:11 potassium concentrations. So there's a lot activity between the south that will be
47:16 up of potassium on the outside. astro side is gonna start slurping up
47:20 locally increased potassium concentration, distributing through own very broad spatially distributed network and
47:31 astrocytes are interconnected with other astra Therefore if there is a local increase
47:38 potassium concentration here this very quickly gets buffered and distributed through the a specific
47:45 to make sure that those concentrations are in check on the outside on on
47:52 inside there's other ways that this is controlled. But this is an example
47:58 if you do have abnormal potassium increases will have deep polarization and firing of
48:04 potentials. And in fact in many techniques to activate cells even in biochemistry
48:13 there will be applications of potassium So high concentrations of potassium or potassium
48:19 that will activate the cells to really degree without doing electrical stimulation or other
48:28 . So yeah. Yeah yeah. there you will see that exercise play
48:41 very important role in maintaining the balance ions and the surrounding neuronal tissues and
48:48 synapses of potassium. They'll be also similar things with calcium. This rises
48:55 calcium extra cellular abnormal there will also buffering calcium spatially. So they're involved
49:03 regulation of the ionic concentrations. And you'll learn later in the course they're
49:09 in regulation of glutamate as well. major excited to a neurotransmitter and because
49:15 have such extensive spatially such extensive processes connections so if there is a local
49:22 in something that's very quickly gets diluted to speak or spatially buffered is another
49:30 so that the concentration is maintained throughout network and about the same million
49:38 Okay so potassium channel structure. We're talk about potassium channels and we're gonna
49:43 about action potentials. But Roderick this is from your book the path
49:50 discovery the atomic structure of potassium Talks specifically about uh dr Roderick Mackinnon
49:59 his career and his passion and his to determine the precise structure of potassium
50:08 . So there's a lot of things are in that path of discovery and
50:13 you to read it. But he's very interesting man and scientists he got
50:17 M. D. And he was in Harvard and then he decided that
50:22 wants to pursue the quest and his was the structure of the potassium
50:29 So hungry for that. He gets a lab at the university and starts
50:36 basic research with flies and he uses mutations. So he uses a technique
50:45 is called side directing you to genesis what he's doing essentially he's trying to
50:52 different genes and see what genes are for the changes and this protein structure
51:02 will also influence the activity on the of ions whether this protein is opening
51:07 closing properly this protein channel. So flies that he was working on our
51:14 flies and this is a model where have a genetic mutation and and the
51:20 channel and the flies have almost epileptic activity called shaker flies. The reason
51:28 you would want to use systems like like shake or flies or flies in
51:33 is because fruit flies are abundant. don't have to get International Animal Care
51:41 Committee to improve your protocols to work flies, they were produced very easily
51:48 have short lifespan. Is very well genetics and the fruit flies. So
51:54 what he's using as a model. also using electrophysiology, he's using electrophysiology
52:01 he's using toxins. So he's recording through this potassium channel, the potassium
52:07 flowing, there's a change in the and then he's using toxins and toxins
52:14 bind to specific parts of this protein . Usually protein channels are targets for
52:22 substances to bind them whether they're endogenous that are produced by our own bodies
52:28 exogenous chemicals, natural poisons, spider toxins, venoms and so
52:37 And it's very important because if you something in the channel structure and the
52:44 function genetically, you can also use toxins and these toxins will bind to
52:51 parts of the channel. And then can mutate specific parts of the
52:54 Now you can say can the toxins bind to that channel and say no
53:00 this mutation toxin doesn't bind, cannot to that channel anymore. So what
53:04 you just done? You have found site where the toxin binds and there
53:11 be multiple sites on this protein one will bind here. It's a three
53:16 structure and molecules chemicals have certain structural to them and for them to interact
53:24 the proteins and with the channels. they're binding to something, they have
53:28 find the correct location. But there be multiple different chemicals that are interacting
53:36 the channel. So he used he used genetics and electrophysiology to determine
53:42 parts of the channel are important for flux of the potassium through it.
53:47 based on all of this information, was trying to deduce uh biochemical and
53:56 the structure what that channel would look . And at that point you decided
54:03 take up another career and become an ray crystallography for X ray crystallography is
54:11 technique where you can capture a single channel inside the crystal. And as
54:18 captured inside the crystal, you passed X rays through that crystal and you
54:27 reveal the channel structure. So already leaving his successful and D career his
54:35 were saying you're crazy, you're gonna now X ray crystallography lab. This
54:41 like you know completely different field. if you are in biology or or
54:48 electrophysiology or sciences about chemistry is still at that point in particular In the
54:56 . And so it's a it's a difficult technique to master. You know
55:00 you have like several PhD students trying trap a protein and trying to describe
55:06 structure. It seems that now these artificial intelligence is really, really good
55:15 much, much faster at solving these instructions. But in the 80s and
55:19 you had the limited amount of science you had and the amount of artificial
55:25 that we have now is based on it didn't come from. Air artificial
55:32 comes from reading all of these papers how all of these channel structures were
55:38 . So, using the toxins using genetic mutations, I directed me to
55:44 in particular, he discovers important parts this channel structure. He discovers the
55:51 parts of toxins mind and he discovers hairpin loop, the poor loop here
55:57 is responsible for channel selectivity. So describes all of these things using X
56:05 , you can finally illustrate the beautiful of the potassium channel using X ray
56:11 . So this is a very long and of course we will say why
56:18 this isn't a fly but we have amino acid sequences. Some of these
56:25 sequences to which our spider toxin binds the shaker fly exist in human potassium
56:30 . Therefore the same spider toxin would the same effect or similar effect in
56:37 in the human potassium channel. Uh reason why I like roderick Mackinnon story
56:45 lot is because he is on a to solve the structure of the channel
56:54 wants to and then visualize that channel X ray crystallography. So he's not
56:59 a quest to get an M. . Or to get a PhD or
57:04 get a faculty position. He's on quest to solve the problem and it
57:11 stop him to shift from M. . Into essentially basic research work and
57:18 ends up having a page or two to him in the textbook because of
57:25 he did, not only his discoveries potentially of how he did it
57:31 So as you're thinking of your future I always tell you that you always
57:38 to look forward but the pathway is straight and in fact quite often you
57:45 even have setbacks where you're not moving , it doesn't mean that you cannot
57:50 forward and then a lot of times come in life and there's crossroads,
57:56 know, personal crossroads. Professional crossroads you have to make these decisions.
58:03 I think that a lot of times you keep an eye on the prize
58:08 what you would really like to accomplish this earth, and it doesn't matter
58:13 you didn't accomplishment this semester, if didn't accomplish it that year, or
58:20 you didn't accomplish it with your degree you got, and you think that
58:24 it's not the right place where I be, I wanna explore. There's
58:27 opportunities to do that and to take different pathway, a different approach,
58:35 it's important to have a goal. important to have a pro problem that
58:40 are interested in, that you're passionate , and there are multiple ways and
58:47 that you can get and trying to to a solution to that problem.
58:53 it could be motivated for personal because you have Alzheimer's in the family
58:59 you have motivated about something else because professional reasons or just you have a
59:06 interest in something. So, this a really good story, I
59:10 to read recommended, okay, action , we have the rising phase that
59:17 the falling phase that undershoot and this the resting membrane potential. So we've
59:23 dwelling in this world here and this number of potential before the action takes
59:28 before the action potential is generally. over the next two or three lectures
59:35 will be discussing the action potential. there are multiple ways that you can
59:40 action potentials. Most of the things we're gonna talk about in the scores
59:44 with the intracellular recorders or when the are recording from individual neurons from the
59:52 patches of the plasma member of individual and these intracellular recordings. And when
59:59 do it for selling recordings, the , oscilloscopes will show you fluctuation during
60:05 action potential of approximately 100 million balls the duration of a couple of
60:12 But there are also techniques by which can bring these micro electorates onto the
60:21 of the neurons. And if you're on the outside of the axon initial
60:26 of the neuron where the action potential generated, you'd have to use much
60:32 amplification and you would only notice the that are on the order of tens
60:40 hundreds micro balls rather than mila But there are techniques, experimental techniques
60:48 also um neurosurgical techniques we'll discuss later of course that allow you to record
60:56 potentials from the outside of the So you have to have really good
61:02 technology for that. You have to really fast circuits and filters that are
61:08 in but you can record action potentials the outside of the cell. So
61:11 just gonna be really small. You're have to amplify that sufficiently to pick
61:15 up from the noise. So you will provide about 1000 times.
61:31 for intracellular recordings, you barely have provide new amplified 10 times. What
61:39 it? Because the resistance because of only law and the resistance on the
61:47 of the south is much smaller than the inside of the south. So
61:51 pulls I are the same amount of resistance, small is small, r
62:00 large, the same amount of current large. So this uh uh it's
62:10 resistance and also preservation of direct charge here on the outside of what you
62:14 when they say direct charge from the , here's the charge is leaking,
62:20 up a fraction of this actually potential has it's everywhere around. It's no
62:27 just a longer location in the salary film. Alright, so generating action
62:36 . We have to stimulate the And we talked about how cells can
62:41 respond to different uh to the same in different patterns and frequencies of action
62:48 . So you can inject some current this is the electrical circuit stimulation through
62:55 electorate and everything that you see in electrical circuits. And you'll read if
62:59 read any neuroscience papers, it will be a little bit of electrophysiology component
63:04 almost all of them. Or a of the electrophysiology neurophysiology component with a
63:10 of neuroscience papers because this is really function and the communication between the south
63:16 we can monitor inside and responses of cells. So if you inject a
63:22 current into the cell is what we the square wave like pulse because square
63:28 ? Because electronic switch on and on response of the cell is not completely
63:33 because the cell has resisted and capacitive . So the charge build up here
63:39 not immediate. This switch here on immediate and this change in the potential
63:46 take a few milliseconds because charge needs cross across possible membrane across the resistance
63:53 the capacity. And we'll talk about and they have uh missed an important
64:00 and they have to come back to talking about resistance and capacitors.
64:05 I think we're gonna talk about it . And of course later in this
64:11 . So if you inject enough current you can inject large enough input into
64:17 cell, the cell will reach a threshold. That's called threshold for action
64:23 will respond in a certain pattern of actions ecologies. And in many cells
64:30 first response is not going to be maximum number of frequencies of action
64:34 So if you give it even a current or stronger input is received by
64:40 south. The south can produce more and at some point it may reach
64:47 highest frequency of firing that it can period but in heart what this tells
64:54 is the size of an input in is reflected by the frequency and or
65:03 number of the action potentials that are . Low stimulus, five action potentials
65:10 stimulus more actual production. So in basic terms, the strength of the
65:18 means higher deep polarization. Or the of the stimulus means higher number of
65:25 frequency of the action potentials. ionic driving for us, do I
65:33 to get into the ionic driving force ? Maybe I should, but I'm
65:40 start here by telling you that what have addressed, which is here.
65:46 value minus 80 million balls. And is not the value I'd like for
65:50 to follow. But this is minus million value here. And what you
65:56 is a resting membrane potential. potassium dominating the potassium conductance is are dominating
66:02 the sodium conductance is during the rising of the action potential. So at
66:10 potassium is leaking during the rising phase the action potential. The conductance is
66:17 are dominating the membrane. Are driven sodium and sodium is trying to drive
66:23 number of potential to its positive equilibrium value during the following phase of the
66:29 potential. It switches again, sodium close and potassium channels become the most
66:36 channels in causing the re polarization and dominating again. The potassium channels at
66:44 membrane potentials. So you have the in in potassium dominating sodium dominating rising
66:52 and then potassium in the following phase resting membrane potential again. So what
67:00 the driving force? The driving force , is the difference between the membrane
67:08 and equilibrium potential for each ion We it equilibrium potential is for one eye
67:14 the membrane potential reflects 2. 3 species plus permeability for these ionic
67:22 So, this is the difference And in this case, what we're
67:27 at is we have E. At minus 80 Equilibrium potential for potassium
67:36 potential for sodium positive 62. And channels are closed. The conductance for
67:43 is zero. The overall current is . So, you can calculate overall
67:51 v equals ir I G is the of our right D equals R Jeez
68:03 over hard. Huh? So by equal G. And instead of V
68:23 D. M. Which is membrane minus E. In this case
68:32 K. Which is equilibrium potential for . And if there is zero difference
68:43 , there's zero conductors or zero the current is zero. Huh?
68:51 sees that. So, this is formula right here that I turned V
68:56 ir Okay, because of. All , so, this is pretty,
69:16 simple. So, this is the force. This component is the driving
69:21 . The driving force is the And then we have the conductors.
69:26 if the channels are all closed, no conductors. No nothing ions cannot
69:32 across the channels. There's no ionic across this situation now. And this
69:38 the resting membrane potential which is dominated potassium leaking potassium channels are over potassium
69:45 collapsing. So guess what? There the same equilibrium potentials. Silk now
69:51 conductors with potassium G K, potassium greater than zero. Therefore the IK
69:57 going to be greater than zero. here, this is a situation where
70:07 measuring from zero potassium, its velocity it reaches a minus 80 million volt
70:14 minus 80 mil, evolve value between -80 and EK -80 is equal to
70:27 ? -80 -80. So do you have conductance here? Yes, I
70:37 flexing. Do you have the driving At this potential of -80? No
70:46 . Therefore the overall current zero. there's not enough movement of potassium either
70:52 the inside or outside. It's still , there's still conductance, The driving
70:57 is zero. So again, the force is the difference between the number
71:01 potential and deliberate potential. If we at this here is the driving force
71:06 zero Mila balls. Is it a driving force for potassium? At zero
71:11 Vm is zero and E K doesn't UK is minus 80 0 minus minus
71:20 80. Zero bolts build number and -80 membrane potential -80 -80. So
71:38 zero the further away you are the is this difference between D.
71:45 And E. K. Liberal The greater is the driving forms.
71:52 if there is no difference between member potential and liberal potential, there's no
71:57 force for that. So these are components of the actual potential. We
72:07 into the voltage clamp. But before get into the voltage clamp and all
72:12 this good stuff. I have a diagram for you in the lecture notes
72:17 that is called action potential and everything need to know for the test.
72:28 as far as values and as far understanding these concepts, I'm gonna run
72:34 through this really quickly today because I'm out of time and I'm gonna let
72:41 think about it for okay. And we're gonna come back and we're gonna
72:49 a cool video on the action Also forgot to show you to you
72:54 . We're gonna run through this But all of the things on this
72:59 you should be able to understand now if not next week. For
73:06 First of all Vm in miller vote and potential value measured by both
73:13 Clocking a lecture on the cell. you measure the changes in the number
73:16 the country, right? That membrane can be zero can be minus
73:21 It can be plus 40. Can Linus E. It's not static.
73:27 resting number and potential of minus 65 70 million balls in this case.
73:32 RMP is resting minus potential is minus syllables. This is the value I
73:37 you to know for the exam, wrestling member and potential is never static
73:43 biology. If you see a it's not good news. Number of
73:48 fluctuates a little but they're small thermodynamic , small changes in permeability of channels
73:55 up and closing up. It's fluctuating 65 -65. If it gets negative
74:02 , gather inputs and hyper polarize is it gets positive inputs and deep
74:09 So this is resting membrane potential. resting membrane potential. This is $0
74:16 . And these are equilibrium potentials, put -90 people further away, chloride
74:26 sodium positive 55 for the book says 62 and in some places it says
74:32 55 and calcium positive 120. These equilibrium potential values. So we talked
74:41 the fact that driving force is really . If you look at the driving
74:49 for sodium which has a deliberate potential and positive 55 and the number of
74:55 is at -70. This is a difference, huge driving force for sodium
75:03 E. N. A. And membrane which is sitting here D.
75:09 . So sodium has big driving force as soon as there is enough deep
75:17 sodium channels will open up. Open . Open up. It's gonna be
75:21 influx of sodium and sodium will try drive this number and potential into its
75:27 equilibrium potential value because it's now most i onto the membrane And it is
75:34 to drive into the positive values with channels. Close driving force for sodium
75:42 because now the number of potential is and the driving force is small.
75:47 guess what? The driving force now huge for potassium miles. Where the
75:53 of potential is here. sodium ions it's a positive feedback loop but we'll
75:59 about the kinetics of sodium channel sodium close potassium channels open and potassium A
76:07 the member and potential to its own potential value. It doesn't quite succeed
76:14 it goes below the resting number of and the N. A.
76:18 C. P. A. S and house rebuild this number of potential
76:23 its fluctuating resting number of potential So positive excitatory inputs come in barrages
76:32 L. D. Polarizes negative Come in this cell number and potential
76:37 polarized. So I'm gonna leave it today and when we come back we're
76:42 review all of this one more I wanted to mention that there is
76:46 umbrella here. There is a car here. Uh There is uh pods
76:55 . There is uh one other pot , there is another red pot
77:01 Uh Please let me know if they're . Otherwise I'll see you next
77:06 Have a good
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