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BIOL 4315 & 6315 Neuroscience Mon-Wed 1-2.30 PM - NEUROSCIENCE Lecture 06 Resting membrane potential
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00:02 This is neuroscience Lecture six. Last we talked about the complexity of the
00:12 and the lecture before that. We about the complexity of the circuit.
00:17 if you have any lingering questions about the important information to know about
00:22 You may want to review the two lectures, especially in the last lecture
00:29 I said, well these are some the key points you need to know
00:32 it. Okay. That will clarify you need to know about the exam
00:37 you can see that even in review spent considerable amount of time. We
00:43 about the diversity of the inhibitory We then talked about glial cells.
00:50 we discussed different subtypes of glial We discussed the legal tender asides,
00:57 discussed exercise, we discussed micro glia in addition we discussed radio Glia shown
01:06 and we also discussed another type of which is in the peripheral nervous system
01:12 from island nation, the peripheral nerves is Schwann cells. So now the
01:20 of the glial cells what they're responsible . Ah now there is a lot
01:30 class supporting lecture documents in your folder will lead you to some of these
01:37 , some of the articles, some the figures from the articles that we're
01:43 in the course of That's information that will not find in your textbook.
01:48 requires you to open that boulder on blackboard and open an article or click
01:54 link and we'll be potentially adding more the course. And at the end
02:03 the course, when we study the sensory system, we're gonna watch a
02:08 talk for about 20 minutes long. talk. There will be about five
02:11 six exam questions in the ted So we'll have a link to the
02:16 talk and the blackboard. You can on it and watch it and then
02:21 the questions for the exam. My with regard to my elimination, we
02:28 D Myelin Nation and in particular we two types of disorders. Multiple
02:34 shark marriages. We also mentioned encephalomyelitis encephalitis, infection, inflammation in the
02:43 that can lead to the Myelin So please review these as always think
02:49 uh some of the things that we talk about. What is the prevalence
02:54 what is the occurrence of these What is the symptoms, What are
02:59 mechanisms cellular mechanisms we have addressed so not everything because we're just scratching the
03:06 on most of these neurological disorders, brain barrier, the importance of it
03:11 normal function. The importance of More filtering how it can be dysfunctional
03:17 you have infection, inflammation hypoxia and it can present an obstacle if you're
03:24 about no pharmacological drugs that are consumed ingestion through oral ingestion. So all
03:32 these things important things to talk about we said, we're gonna talk about
03:37 resting membrane potential and we spend quite bit of time on this circuit and
03:44 the circuit are actually outlined the most things and do the most important things
03:50 need to know. So the three subtypes that we're talking about the affair
03:54 little ganglion cells more theologically, their unipolar cells excited to release glutamate and
04:01 motor neurons, which are multipolar cells the spinal cord. They exit out
04:06 the ventral part of the project. parents are the skeletal muscles causing the
04:12 ganglion cells can also contact multipolar inhibitor neurons which released glycerine. As an
04:19 . There's a major inhibitor neurotransmitter in spinal cord and can subsequently inhibit or
04:26 , keep the relaxation and the opposing . So please review these cell
04:32 no morphology. The neurotransmitters they release they're excitatory or inhibitory. And
04:43 the subtypes of neurotransmitters, glycerine and motor neurons. It's the acetylcholine.
04:50 when we talk about synaptic transmission, gonna look at the neuro muscular junction
04:54 , so we can understand this very form of synaptic transmission through acetylcholine release
05:02 a major excited to a neurotransmitter or muscles coming from the motor neurons.
05:12 so this is where we ended. you're Lecture four and 5, I
05:20 we ended here and then we can this is kind of a review and
05:27 is a few slides that we're going talk and then it goes into
05:31 I'm just going to switch to 56 we're in six. Lecture six.
05:36 is a little bit of overlapping the with the review. So the cast
05:41 chemicals that we're talking about. And we talk about the resting number and
05:45 , there is this potential difference between outside of the cell and the inside
05:49 the cell and the cast of chemicals is involved. The four major pieces
05:55 ions. So we will be discussing course it's a quiz environment. Water
06:01 hydrogen and oxygen forming water and then have a lot of ions that dissolve
06:11 water or they're surrounded by the waters hydration. So ions are atoms and
06:18 that having that electrical charge, they're by ionic bonds rather than the prevailing
06:24 like H 20. The difference in number of protons and electrons is what
06:30 valence or ionic valence or ionic charge give an eye on some ions mono
06:37 and a plus some of di See a calcium two plus cat ions
06:43 positively charged ions and ions and negatively islands. So, some of the
06:51 information here. Now let me see this long. Yeah, fine.
06:58 I on scandal freely pass through the numbering and there is a separation of
07:04 equal concentrations of these ions and the major species that we're discussing, The
07:09 potassium chloride and calcium. The fifth is shown here is uh an ionic
07:19 . So it's not an ion But as a pump will discuss that
07:24 a second. So in order for ions to pass through the possibility by
07:29 unique channels, each ion in this will have a specific channel. That
07:36 that each channel in fact will select channels to select their, selected for
07:44 items. So this channel is going allow for the sodium two flocks
07:49 So the channel only for potassium fluoride calcium in this course where we learn
07:56 different channels and receptor channels and there different ways that these channels can close
08:08 open. And in the next few we will be discussing predominantly the channels
08:16 are closed and open or gated. other words, by voltage. These
08:24 are voltage gated channels, especially when comes to action potentials. With an
08:32 of some channels that can be always . Like leak channels that are potassium
08:37 and are quite unique in the So The reason why we have this
08:45 up of charge and separation of charge the outside of the cell to the
08:51 of the cell with the inside portion the plasma membrane is negatively charged.
08:56 it says anywhere 60 to -75 million . What does that mean? It
09:03 means that in biology there's slight fluctuations slight variations and wrestling number and potential
09:10 is not one set value and it stay at one set black wine.
09:17 , it's a process that is fluctuating and down around a certain number of
09:22 value. And that number of potential . And that distribution of ions across
09:27 numbering is different in different subtypes of that we're discussing kind of, it
09:32 on their local environment, the extra solution as well as the properties and
09:39 channels and the kinetics of regulation of opening and closing of these channels.
09:44 different subtypes of cells are capable of by regulating these channels by opening them
09:50 clothing and allowing the flux of ions and out. That's a different subtypes
09:54 cells can create what are called the of action potentials to. But we're
10:00 about wrestling number of potential. Let's to understand where that wrestling number of
10:04 comes from. And what is this of ions and outside is So cellular
10:11 I and sodium chloride. And these in parentheses are written in milan molar
10:18 . So approximately 100 45 million molar ion on the outside versus about uh
10:27 million moller or 20 million moller 18 moller of sodium on the inside of
10:33 south Chloride. There's $120 million $7 dollar on the inside With potassium potassium
10:44 is dominating on the inside. It's of them all on the inside And
10:50 3, 3.5 million mall on the of the cells, Calcium has the
10:57 difference in concentration. There is $1.2 0.1 microphone. So millie is 10
11:11 minus three micro is 10 to the six. So this is 10,000 times
11:17 in concentration and there isn't that much free side of solid calcium inside the
11:22 so typically is bound up or is a certain function serving as a secondary
11:28 of being stowed away in the intracellular stores. Finally this is not a
11:35 , this is an A. P. A. This is a
11:38 that requires a teepee and it always sodium and potassium ions against their concentration
11:47 , meaning that it will always drive to the outside. Although there's more
11:52 on the house and always drive potassium the inside of the highest concentration of
11:58 is on the inside of the So it doesn't follow down the concentration
12:02 down the chemical gradient but works against and using A T. P.
12:07 a source of energy. There's a of calcium on the outside about $1.2
12:16 and only about 0.1 will come back that 0.1 micro mole on the
12:22 So these channels. The way they're is that their proteins, they're trans
12:27 proteins that are complex three dimensional It's like a house that has a
12:34 going through the middle of that And so they all have the unique
12:41 And the building blocks of these three structures. Amino assets, amino assets
12:48 be how by peptide bonds and forming polyps peptide chains essentially because, you
12:56 , some of the amino assets are amino assets. That means that you
13:00 to get them from outside intake, intake food sources. Uh we do
13:07 produce these assets, so we rely the food outside in order to have
13:13 in our system. The central ones these primary structures are strings of amino
13:22 can be turned into secondary structures. this case it's a alpha helix like
13:28 can also be made into sort of winding beta sheets that are stacked on
13:34 of each other as a secondary structure to each other as a secondary
13:39 Then multiple of these alpha hell exists one of the alpha helix is could
13:45 used viewed as a trans member in and multiple trans membrane segments will form
13:51 subunit and then channel channels that we're about. They will contain multiple
13:58 So it goes all the way from secondary tertiary to ordinary structure of these
14:05 membrane proteins that are in this case and they're opening and closing of gated
14:14 voltage ion channels are selective in the that they act like molecular seeds.
14:24 they're performing molecular seething and the seating based partly on size but a lot
14:31 it based on the chemical and some the molecular interactions that are taking place
14:36 different ions and their specific channels. at the neuro muscular junction, at
14:45 junction that we're looking for motor neuron the muscle. For example, a
14:50 acetylcholine receptor can conduct as a current is I can conduct 100 million islands
14:59 second. So very high conductance certain . Now N A K A
15:08 P pump in contrast is something that much slower. So ion channels can
15:16 conduct hundreds of thousands or millions hundreds million islands per second. Typically uh
15:24 pumps are slower and they can deliver 100 or so. I on the
15:30 using good energy DP channels are selected in this case this is an example
15:38 a sodium channel. So sodium is by water a lot of times we
15:46 as clouds of hydration or waters of . And as the sodium molecule is
15:54 more and more toward the inner side this lumen. From outside where there's
16:00 lot of sodium trying to push the in, it gets recognized and gets
16:06 of these molecules and then there are amino acid residues. And in particular
16:12 this positively charged sodium is going to a negatively charged amino acid residue right
16:20 the very luminous of this channel which going to have a very short electrostatic
16:29 kind of a binding interaction. And electrostatic forces in divisional divisional forces will
16:37 for the sodium to be propelled on other side of the channel from outside
16:42 come into the inside of the south get sort of the waters of hydration
16:48 then enter into the inside of the . So larger diameter potassium for example
16:56 trapped and sent back out. So ions will try to go through sodium
17:03 . potassium ion will try to go sodium channel and it says that because
17:09 larger diameter but size is not the important thing here. What is really
17:17 And uh to understand is smaller ions actually have stronger traction forces. So
17:25 may have larger waters of hydration around . Number one smaller ones. What
17:31 small, what is large? Really it is? And second of all
17:35 are unique interactions with these. I the acid residues So sodium will have
17:42 special binding side to these amino acid to allow for sodium ions to be
17:49 . The potassium channel will have a charged amino acid residue that will favor
17:55 going through the channel. So it select for specific ions. Okay,
18:01 size is not all that matters but is important and it's important in a
18:06 of different ways. Okay, Arms , does everybody remember that from high
18:12 ? And then maybe again at the level Arms lawdy is equal IR V
18:24 for voltage I stands for current and stands for resistance G. Which is
18:31 conductance is the inverse of resistance. G is equal one over R.
18:38 then you can rewrite that I equals . V. And I think I've
18:43 strip of but one time that doesn't and see be somebody going uh somebody
19:01 have a dry race. Oh I thank you appreciate it.
19:10 so vehicles ir how do we get equals don't forget to grab a.
19:21 . So G. is equal one R. Okay I is equal
19:35 Okay and I is equal G or . G. Okay, everybody sees
19:47 . So that's uh that's international arms uh where the conductance is the inverse
19:56 the resistance and voltage. V is in volts. And the relative scales
20:04 are important for neurons is miller Current is an ampere sent to
20:10 It's milli amperes, nano vampires. PICO amperes depending on whether it's a
20:16 channel single cell or network of cells is conducting the current resistance, neurons
20:23 very high resistance. So it's measured megatons typically in tens or hundreds of
20:32 . Okay, conductance is seaman's. , the relative scales to neurons and
20:38 is about PICO seamen's and nano semen . Just to keep that perspective in
20:47 . So if for example, as mentioned there is no channels in the
20:53 the membrane, the sodium and chloride the outside of the cells will not
20:58 able to come inside of the south just be surrounding the cells as a
21:02 environment. And that's what it It's a saline environment on the outside
21:06 the cells. And if you have channels and you open these channels and
21:13 you would guess is that there's a of sodium concentration here, then there's
21:17 here. Therefore sodium is gonna blow chloride are gonna flow down their concentration
21:26 from high concentration, low concentration until equalizer both sides, they become equally
21:33 the same concentration on both sides. that is if you have a diffusion
21:40 diffusion that follows the concentration gradients from to lower. And that gradient in
21:48 is responsible but only in part for ions across the channels. Now,
21:55 second thing that we have to realize when we're dealing with ions, we're
22:00 with charged molecules. So it is only just how much concentration of that
22:06 , but also as these molecules flocks the membrane, the charge and the
22:13 separation across the membrane changes. So is electrical potential that we have to
22:19 in mind where cat ions such as , such as calcium such as potassium
22:27 be attracted to cat does negative end the battery and it will actually be
22:34 by the anodes positive. So positives and opposites attract and chloride, which
22:41 an ion will be attracted to the end of the battery, which is
22:46 node. So once we block an into the membrane of the cell.
22:53 vault meters Will read out the resting potential of approximately negative 65 million
23:04 Thank you. What's that Resting membrane of -65 mm. Okay, you
23:13 see that there's negative build up negative on the inside, positive on the
23:19 . So separation of this charge across membrane here is what gives rise to
23:26 in electrical potential. The inside voltage the outside voltage. Is the membrane
23:34 abbreviated as VM. Or we'll call the membrane potential. Yeah, remembering
23:42 valley Addressed membrane potential. The rest is the same as internal and it's
23:52 million balls. When we talk about potential, you'll see very fast
23:57 Two different potential. In When we about some of the conventions that you
24:05 current flows direction of net movement of charge. So Catalans move same as
24:12 direction and opposite to current direction. you reduce the separation of charge,
24:20 means that inside of the cell becomes positive. There's less difference. This
24:26 is d polarized if the inside of cell becomes more negative with respect to
24:31 outside it becomes hyper polarized. So and charge separation. Deep polarization of
24:39 in charge separation is hyper polarization. they're in reality neurons high above concentration
24:53 chemical gradient and electrical potentials which is forces of attraction or repulsion. And
25:05 happens in reality is that the separation charge is only present at the level
25:11 number. That means that the inside of plasm around the cell one.
25:17 see the inside of the south is neutral. And so is the outside
25:23 charge neutral except of this separation of rather across plasma membrane, giving it
25:31 resting membrane potential. Certain rules that it the number of potential. So
25:37 this case, for example, we a lot of potassium on the inside
25:41 the cell and you also have a , negatively charged protein or you have
25:49 negatively charged an eye on that doesn't a channel and the channel is not
25:55 for it. So, so this they try to go for potassium.
26:00 selected for potassium but I'm gonna open potassium channel and see what happens.
26:06 , you have negatively charged inside of south. Now, potassium, like
26:10 normal conditions you would, potassium channel open. potassium flows so it will
26:17 from high concentration to the low concentration and you would say, okay,
26:24 it equalizes right becomes equal, Mahler , because as this positive charge flows
26:31 , there will actually be a build of positive charge on this side of
26:37 membrane and the inside is gonna become negative. And this will actually start
26:44 this positive charge build up on the will start repelling as an additional
26:52 This still be this force of chemical saying more concentration, I'm gonna drive
26:58 to this side. On this side force. The charge says no I'm
27:05 you and these forces become equal to other and there is no nut flocks
27:16 potassium and the point at which the force is equal to an opposing direction
27:27 the electrical force. This point is as the equilibrium potential for specific
27:35 So e ionic which stands for equilibrium or equilibrium forgiven ion. Ionic is
27:45 combination of diffusion, a land electrical and when they become equal and opposite
27:53 each other there's still going to be of potassium going here and potassium going
27:59 . But no net flux. That that means that there's gonna be more
28:04 going to this outside versus inside it's be may be equal flux of potassium
28:09 no net movement. So small ionic changes. Smalley on the concentration changes
28:17 cause large voltage fluctuation. So ion or enters it can change the membrane
28:26 significantly. Net ionic differences at the . This is when the other differences
28:34 you have the charge of the And we will be discussing today and
28:40 during the next couple of lectures, concept of ionic driving force. But
28:45 mentioned to you that D. Stands for membrane potential and I said
28:51 E ion stands for equilibrium potential and just said for one ion. So
28:56 is the difference between the two? you'll understand how to calculate equilibrium potential
29:01 membrane potential for now. You should that the difference between member and potential
29:09 equilibrium potential for each ion is giving concept of driving force that will be
29:17 now. How do we calculate ionic potentials? What information do we have
29:25 know in order to calculate equilibrium And we have to know one of
29:31 things we have to know is that the concentrations on the inside versus the
29:37 of the cell. So what I'm you now, it's like there's 100
29:40 on the outside and 20 on the . Somebody at some point measure that
29:48 to squeeze these axons and measure the cellular environments to determine all of these
29:56 concentrations of ions. So uh but we need to calculate it and
30:04 you're gonna say so we're only going calculate it for potassium. It's only
30:07 case for potassium. No, this an example of sodium. Now there
30:13 sodium on the outside channel is This molecule does not have a channel
30:20 flocks. sodium goes down its concentration but it doesn't equally Mohler doesn't become
30:29 same size and concentration because now from inside is built up of positive charge
30:35 the positive on the inside of the number. It starts with balance.
30:39 that sodium equilibrium potential and each ion we're talking about chloride and calcium have
30:47 own equilibrium potential values. Now the that we're talking about. A.
30:54 . P. A. S. . A. K. T.
30:55 . A. S. It doesn't about equilibrium potential. It doesn't care
31:01 concentration greedy and it doesn't care about or attraction. It just says I
31:10 a teepee and my job is to me a T. T. I'm
31:15 bring into protection inside and three sodium three sodium out to protection then give
31:22 more 80 P. I'm gonna do . So it doesn't change the directional
31:29 it's independent of the concentration. Just the availability of sodium and potassium and
31:36 . D. P. As if all to drive the two molecules.
31:42 this is another diagram. It's the that you saw before. But here
31:48 talk you will see a table and stable now will have slightly different
31:56 So when we said okay there's 100 of sodium on the outside and 18
32:02 the inside and then this table says 100 and 50 On the outside and
32:08 on the inside. Why is Because different books were written by different
32:14 . Sometimes different figures in the same were prepared by different people are taken
32:20 different research articles and such. And because there's variability in biology, there's
32:29 really a flat line, there's There are fluctuations. There are local
32:34 of ionic concentrations in the outside of south and the inside of the south
32:40 regulations of these ion channels as they and close. Different glial environment as
32:47 see. Glee is very important in uh ionic concentrations and chemical concentrations in
32:55 brain. So but nonetheless, this another way to look at it.
33:00 can look at a lot of potassium inside 100 versus five or ratio.
33:07 I like ratios because ratios are independent 145 blah blah blah. And there's
33:13 approximate because obviously 1 50 15 is ratio than 1 45 and 18.
33:23 so the point here is that there's lot of sodium chloride on the
33:27 there's 20 more times potassium on the . 10 more times sodium on the
33:34 and there's Calcium 10,000 more times calcium the outside. Some I'll tell you
33:45 ones, Yeah, I'll tell you be the best way to prepare yourselves
33:51 the exam two. Or that's what would do. Or maybe that's how
33:55 even write questions. So if you were to think about chemical gradient,
34:06 ion, it's undoubtedly calcium has the chemical guide. So, do you
34:12 that mean that there's most calcium being constantly crossed by the membrane now?
34:20 that's because in biology these channels are gated. But then for potassium it's
34:27 an exception. Some of the potassium in addition to all this created their
34:32 , which means that they're always open they're always allowing for potassium to come
34:39 inside of the south to the Just the way the neurons are built
34:44 ? Because this is the way neurons built at resting membrane potential, they're
34:50 leaking or using potassium. And as see, resting membrane potential is mostly
34:57 by potassium and then we will explain why. But for now you can
35:02 that the highest concentration gradient, the chemical diffusion force if you may exist
35:09 calcium, but it is not the that is flexing the most instead of
35:13 potassium. And you'll see why. you can see here the E ion
35:19 is equilibrium potential for each ion. means that potassium has its own value
35:25 80 sodium has its own value 62 calcium chloride. They have their
35:33 equilibrium potential values and you will have know this. But I'll show you
35:36 diagram that I want you to study today. Okay, so how do
35:41 calculate equilibrium potential? We use the equation. Nurse equation is E.
35:47 equilibrium potential for ion 2.303. Rtz of ionic concentration on the outside of
35:55 south versus ionic concentration on the inside the south where e ion is ionic
36:03 potential are, here is a gas . T is the absolute temperature the
36:10 were doing is at the 37 which is the physiological temperature Z is
36:18 of the ion at disparities constant, is also constant. So it's electrical
36:25 , log is based on logarithms ion concentration versus iron. Inside concentration.
36:35 let's see if we can make sense this. Remember equilibrium is the balance
36:40 future influences diffusion which pushes out and this concentration of chemical gradient and electricity
36:46 the charge which causes an island to attracted to opposite charges and result by
36:52 charges. Increasing the thermal energy of particle, increases diffusion, hotter things
36:59 faster and will therefore increase the potential achieved at equilibrium. So its temperature
37:05 E ion is proportional to T. the other hand, increasing the electrical
37:11 of each particle or the valence. the charge of each particle will decrease
37:17 potential difference because valence values Z. to increase the value, decrease overall
37:26 of the potential. Now therefore the is inversely proportional to the charge of
37:32 ion surveillance of the island. We not to worry about our and ask
37:37 nurse equation because they are constant. gas and electrical Faraday constant body
37:43 The nurse equation for our four favorite species. So for potassium we have
37:50 . K. Equals 61 2 and million balls. Where does this value
37:56 from? R. F. Constance . Is plus one T. Is
38:08 concentration of potassium on the outside versus and here you can feel free plug
38:17 either the miller moller value or the value doesn't matter under divided by five
38:23 20 divided by one. So you in the out inside outside versus
38:31 This collapses are TCF collapses into 61.54 volts. The values miller volts plus
38:41 the log, sorry, Outside versus . So if you calculate for 1/20
38:47 get negative 1.3 and if you take abbreviation 61.54 million volts and multiplied by
38:56 1.3, you're getting minus 80 million . So this is how you calculate
39:02 potential. And then we can calculate same for sodium and sodium will also
39:10 collapsed and abbreviated into 61.54 because it's same are constant, it's the same
39:19 , it's the same valence, it's same electrical constant. The difference is
39:25 outside versus inside. Now for chloride value 61.54 becomes negative And that's because
39:38 as -1 negatively charged balers -61.54 million . While the fluoride outside versus fluoride
39:51 and for calcium that now he becomes for the same reason because calcium is
39:59 di valent ion, so it's going be two plus here. Therefore everything
40:07 gets divided by two because the other a concept that is constant to abbreviation
40:14 becomes 30.77 million balls log of calcium vs so for each one you have
40:25 own respective equilibrium potential values minus 80 minus 65 million volts in each
40:35 And even in the same textbook may you slightly different values. My exams
40:42 are not built to trick you. it 62 or 60 million balls for
40:49 reversal for sodium and billy graham So what I do instead is I
40:54 give you a diagram in the you have questions and the values in
41:00 diagram that I will base my questions exams. Yes. Can you maybe
41:20 your right? Yeah. What is ? What does it mean? It
41:34 the highest concentration disparity across inside versus . And it's specific to calcium.
41:43 not much a lot. There's not calcium on the inside of the cell
41:51 But the channel has to be So you're thinking right and I'll answer
41:56 question to you in maybe the next minutes. But also remember that
42:02 These are ions that will change member potential chloride, sodium potassium. If
42:10 enters inside the cell, it does more than changes the number of potential
42:16 in fact it changes number of potential a very small value because it's low
42:23 compared to others. But once inside cell it's a secondary messenger. Once
42:33 the cell it can activate chi nations can force for a late that can
42:41 influence activity of other person channels that be long lasting. So it's very
42:47 controlled and it's not watching very So this is the concept of permeability
42:58 the potassium is flexing because potassium channels open. I told you their leaky
43:04 addressed but calcium although it has so pressure, chemical pressure to move
43:11 it's positively charged. It's a lot the chemical you know inside is
43:16 You should move. The channel is open therefore it's not permissible to this
43:25 . And so your question is really because it leads and maybe hang out
43:29 one minute. That may answer the that leads us to Goldman equation.
43:37 Goldman equation is what allows us to the wait a second. I thought
43:42 were calculating you know we were calculating potentials for each ion. So we
43:48 four values, we have one resting . And the difference between learns the
43:58 and Goldman equation is this looks familiar you guys this part 61.54. It's
44:07 same abbreviation from 2.303. R. . Z. F. So you
44:16 the learns equation, you take the on the outside and the inside from
44:22 equation but there's two big differences in Goldman equation. First of all,
44:32 not just using one aisle to calculate number of potential. You're adding potassium
44:43 sodium concentrations. So you're using two and this P. K. Is
44:53 liked by availability studies and an illegal P. K. But its permeability
45:00 potassium. So this term from the did not exist. And the first
45:10 . And nurse equation is just for ion species for the equilibrium potential.
45:18 golden equation is to calculate the membrane . You kind of calculate the number
45:25 potential just looking at sodium or potassium chloride. But why isn't chloride
45:36 Why isn't calcium included in this Right. You told us there's four
45:41 ionic species. Okay. This term tell you a lot at resting membrane
45:51 , the permeability for potassium, It's times higher than for sodium.
46:05 Which means what the resting membrane potential membrane is most permissible for potassium,
46:11 is leaking out of the membrane. ? And this -65 million balls
46:18 Look at this, if you look the equilibrium potential for potassium is -80
46:26 potential value for sodium is positive I would say both islands are
46:33 Should it be somewhere in between the arrests non because potassium is open.
46:39 leaking the sodium channel so virtually Almost impermeable compared to potassium. And
46:51 the resting membrane potential is that this values which are much closer to liberal
46:58 value than it is to equilibrium potential for sodium. Mhm. So this
47:06 how why don't we have chloride and because virtually no permeability of Western member
47:15 potential for fluoride and calcium. And if you plug in their concentrations right
47:24 of chloride outside versus concentration of The inside with permeability? 0.1 or
47:34 to what do you plus here, . So they will be inconsequential.
47:41 chloride plays a small role in resting potential overall in in determining it a
47:48 bit calcium even less. So um chloride plays a really big role
48:02 in in inhibition. Yeah, an of gaba calcium plays a huge role
48:13 neural transmission. So this is where gonna get in a few hours.
48:19 that there is a strategy that neurons use how they distribute these different voltage
48:27 channels in different locations. In other , sub cellular early expression of these
48:35 of these different channels, maybe different initial segment versus soma versus dendrite and
48:45 on. So we'll get into that little bit. But calcium will be
48:49 important for neural transmission. Not as in determining the number of potential,
48:57 it is one of the four major species and we'll talk about it a
49:02 actually in the course. So the are clear I think. And for
49:09 at this stage here I'd like to into You're 5 6. This really
49:16 as well. Maybe it was going take a break in but I'm
49:22 Yeah. So on top we have nurse equation, equilibrium bionic and on
49:31 bottom we have golden equation which is so I quite often get the
49:37 do we need a calculator for the ? No you don't. Do we
49:41 to calculate the equilibrium for controls? we need to derive the formula?
49:48 you don't. But do you need understand the values and know that if
49:54 show you a formula that has a of sodium on the outside versus the
49:58 that that's correct. If I show a formula that has a lot of
50:03 on the outside of course is the and say this is wrestling number and
50:06 . You should have a red So the principle and the concept and
50:11 variables that are important. What is . T. Z. F.
50:16 not the actual calculations because these things require a calculator that's not very
50:26 But you don't need to know the calculations but you do need to understand
50:32 differences between the two formulas, how different terms. Why isn't there a
50:37 in those equations? Right. Or I call this nervous equation, you
50:43 say, I don't think so to . So this is what I expect
50:48 to know. No calculators needed and calculations are needed. Maybe in your
50:54 if you want to or if you to uh you know have a little
51:00 or something. So these outside versus concentrations of ions, they don't change
51:07 . What changes is permeability if they , we'll see an example here.
51:14 happens if extra cellular potassium levels go ? So this is a diagram that
51:23 the paseo and the X. So all of you guys should give
51:28 to read some basic neuroscience grass including some of the number and potentials and
51:34 like that that we'll talk about. until we get the I.
51:38 Curves can be fun. So addressing of potential and the normal regular
51:46 The outside concentration of compassion is about million Right here. So we'll be
51:53 to resting memory at the time This is membrane potential which is a
52:00 fault or D. M. Measured milli volts voltages measured in relative scale
52:08 to points You raise the concentration of to 10. You're already at about
52:18 . He raised it 15-20. Actually the number of potential enough to start
52:26 action potential. So you'll know this . What we call the threshold for
52:31 potential value. So what does that you? That tells you that in
52:37 physiology normally functioning brains these concentrations on outside versus inside there'll be very tightly
52:45 and they'll be pretty pretty pretty constant a certain fluctuating dynamic range. What
52:52 if there's way too much potassium In area of the brain? That means
53:00 all of the cells in that area be polarized and start firing action
53:07 If you have $15 million milliar potassium can start inducing epileptic seizure activity in
53:16 cultures and in many experimental methodologies and . High potassium or high potassium chloride
53:26 used to stimulate the cells have cells something or jolt them so that they
53:33 really really active by chemical E and on. So we don't want that
53:40 . This is experimental conditions. So have increases in potassium concentrations. We
53:45 these beautiful astrocytes to be ourselves. astra sides are gonna essentially slurp up
53:53 the processes that will uptake potassium and at the massive processes. They're very
54:04 process is very far reaching processes. this high concentration of potassium on the
54:10 . Now it's spatially buffered through this which has an extensive spatial uh foot
54:20 . But it also has interconnected networks other astrocytes. So potassium goes
54:26 Astrocytes kick in and they start regulating cellular concentrations. In this case of
54:32 astrocytes will also be regulating extra cellular of glutamate, the major excitatory
54:40 So what this diagram shows is if increased extra cellular potassium concentrations K.
54:52 . The physiological level is 3.5 which us close to resting membrane potential.
54:59 you come to about $12, $20 million, you're in the potentials
55:03 will make these cells very very very . The membrane potential. You will
55:09 a massive depolymerization. Yeah. Sorry just got myself in a heat of
55:20 moment. Yeah it is. It's same 2.303 rtz uh you don't need
55:38 you want to calculate it, you to derive it. Okay, it
55:43 from this. So this is the north equation 2.303 r. t.
55:50 . This is 61.54. You see 61.54. Okay so this 2303 are
56:00 collapses into 61.54. But because of nurse equation, so imagine that you
56:21 calcium. Right? And you're saying added calcium now but it's not
56:28 So it's zero and it is it tricky if you're adding a dive ale
56:33 here but that guy veil and has Source If you're adding chloride minus also
56:40 -65 minute bowls. Right? But don't do that because you're collapsing it
56:48 from unavailing 61 54 in this Because you're only really concerned with the
56:59 of potassium and sodium, it's just membrane is permeable to these ions.
57:04 not it's not permissible to all of ions. All of the times.
57:09 there are certain conditions where it's going be really permeable to calcium and not
57:14 to chloride. And there's going to conditions where it's permissible to chloride through
57:18 means. So but if you just the same abbreviation here and then the
57:26 is the permeability and the fact that have to incorporate sodium and potassium.
57:35 if you added chloride here if you put plus chloride with zero permeability it
57:41 be like adding zero. Yeah but can break break up the formula and
57:48 divided by two and also in the and then add it all together
57:52 But basically see that it's still dominated sodium and potassium. Uh you wouldn't
58:10 it for the resting number and And this is just kind of this
58:14 what it's for. It's for the number and potential. Yeah so good
58:21 . Good good good insights. Maybe perfect answers. But uh do my
58:28 . Okay well now when you talk the best is actually this this guy
58:33 some of the best and I want spend a few minutes talking about him
58:39 this is in your book. You these inserts and let's one page is
58:46 pages called Discovery. This one is atomic structure of potassium. Traveling talks
58:52 Roderick Mackinnon. So Roderick Mackinnon is inspirational figure in your science because of
59:00 discoveries and because of the professional athlete he took he was a medical doctor
59:05 MD. That decided that he wanted pursue the studies of the structure of
59:11 potassium ion channel. So he loved M. D. Career and switched
59:18 basic research on the structure of the channel. We're talking about 80s and
59:26 before artificial intelligence and before the solutions are available in modern day times.
59:33 you have to understand that sometimes in sixties and seventies people just started talking
59:40 these things called the channels And we visualize these channels that we're talking about
59:49 in the 90s. So this is very fresh that we've been able to
59:54 in the last 30 years or So roderick Mackinnon, he wants to
60:00 the structure of the potassium channel and is on a quest. That's why
60:07 like his story. He's not on quest to get an M.
60:11 Or to get a PhD. He on a quest to solve question and
60:18 goal. His drive is to reveal structure of the potassium channel. So
60:25 uses fruit flies to study potassium Fruit flies is a good model
60:34 You don't need animal care and use approval to work with fruit flies multiply
60:42 . You have a short lifespan. don't need big room to store a
60:47 of flies. Just a little test . Uh So they're easy to
60:52 It's an interesting system. We looked the multiple sclerosis, we talked about
60:58 rodent system and the myelin nation which chromosomal genetic mutation. Now these
61:04 if you mutate potassium channel in they start shaking or they basically are
61:11 convulsions. So they were termed the flies. And why would you want
61:19 do genetic mutations also known as side to genesis in order to solve the
61:28 of the channel. Because if you alter a certain code for this
61:35 that means that genetic illegal will alter expression or the three dimensional structure of
61:42 channel. And if you do what else you go to alter?
61:45 gonna change the function of this If you know which sequences you're
61:50 remember this is very complex three dimensional acid sequence. If you know which
61:56 you're targeting by a dramatic code, can finally get to the important sequences
62:02 this channel that allow the opening and of this channel. There's a lot
62:10 these amino acid sequences that are conserved the species. So we are similar
62:16 a lot of animals and organisms that lower order organisms than us genetically.
62:23 . Ology of proteins. So there's lot of things that you can discover
62:29 simple systems like a fruit fly that actually directly applicable into what you would
62:36 in humans because they would have the sequence. And that same sequence may
62:41 located in this hairpin loop, which discovered as a hairpin loop, which
62:48 the poor loop that is formed by one of the sub units and it
62:52 as a selectivity poor he described the of this hairpin loop for the poor
62:59 and the selectivity structure of this So you did a lot of side
63:05 me to genesis. He did electrophysiology if you alter the structure of the
63:13 genetically. It's a big experiment, have to identify the sequence have to
63:18 . You have to have some sort a way of double checking across a
63:25 . And then once you changed this you want to know if its function
63:31 . So then you're gonna record conductance from ions through the channels using
63:41 And he also in addition to the directed me to genesis and went to
63:47 . He also used toxins because different that are found in nature and also
63:54 toxins that are produced by by They have very specific binding sites on
64:03 program. And these channel programs May 20 different targets sides to which 20
64:12 substances combined to them. And another that we haven't discovered it and we
64:17 know that bind to them. So would use toxins because again if toxin
64:25 out to a specific sequence that was to block the channel. And then
64:33 took my side directed me to genesis genetics and I changed that sequence.
64:39 now the toxin count of bind is channel still open. So now you
64:47 multiple ways to start deducing and calculating structure of this town. So he
64:56 all of these techniques again, the toxins that will bind to potassium channels
65:02 fruit flies or and other primitive organisms will bind to potassium channels or conserved
65:10 acid sequences in our own bodies and . So we learned a lot through
65:17 process, bungalow toxin, alpha venoms snakes, black spider, black widow
65:30 . Um Different snakes that can inject with venoms that contain toxins and they
65:41 be very specific frogs, poisonous amazon frogs that they use poison on
65:53 . There's a toxin that can incapacitate . You know, we will learn
65:58 little bit about that actually. It's cure our uh so this is examples
66:04 toxins now, human toxins, you it, we don't even know all
66:09 toxins. We make anything that looks color. It kind of smells
66:15 you know, and it's made in lab could be a potential toxin,
66:18 know, but there's a lot of made toxins. There's a lot of
66:24 toxins coming from nature. But here talking about the toxins that are the
66:28 of animals, spiders and snakes Uh Now he's still not satisfied.
66:40 if you use all of these electrophysiology side directing you to Jenna says
66:46 toxins And you are calculating and you , trying to deduce the structure in
66:53 80's now he wants to see the . So he decides that he's gonna
67:00 yet another field of study called X crystallography and an X ray crystallography,
67:09 trap a single protium inside a Then you pass the X ray lights
67:17 that crystal that has your protein trapped it and you reveal or develop its
67:24 structure. People were telling him you're a mistake here because X ray
67:32 it's not like, especially in the the nineties, I'm going to be
67:36 ray crystallography for you know, I'm put burgers on the grounds, no
67:42 , you need a whole lab, equipment, millions of dollars of
67:50 experience students and post docs, they to work and not even know how
67:56 technique exactly works because it's fairly but he doesn't, he does it
68:02 he reveals the structure precise structure, atomic structure of the potassium channel and
68:10 reveals it through calculations and he reveals through actually envisioning the structure. So
68:17 this quest that's what I like about Mackinnon story, it's his quest to
68:23 the question and as you are entering paths, ending career paths entering
68:34 you just need to keep moving Also there will be step backs but
68:38 doesn't mean that if you have step that that's where you stay. Sometimes
68:44 come back on step backs and propel more by learning from the setbacks or
68:51 or whatever they make, but pathways , it's also never straight. So
68:59 prepared that the road splits into intersections you may be left standing looking at
69:07 family, yourself, your loved your friends and thinking what you should
69:13 , but you should do what what you really are driven to do and
69:19 important is if you can identify that that goal or something that you're passionate
69:27 science and nature mostly, most of biology related sciences, I think that's
69:35 , really important. I think the is secondary if you focus too much
69:41 the degree and you lose sight of you're doing this and what in the
69:48 you want to do and that's not have a nice house, a couple
69:51 cars but doesn't hurt and a lot people that pursue their passions and are
69:59 true to their course. A lot times may get rejected early on.
70:02 , look, Ramona alcohol was being by goals. You're saying, I
70:06 believe in this neuron doctrine that you're about. So but who is more
70:14 Ramona ca hall who's more accomplished in , Ramona alcohol. So in the
70:19 , you know, it's it's it's keeping the goal in mind is the
70:24 important thing I think. And then the degrees, this means the techniques
70:31 means not as end goals. I'm learn side directed me to genesis,
70:36 gonna decide directed me to genesis you know, or something like
70:41 It's not, it's about the Of course you have to be good
70:46 sometimes being really good at something it's really, really, really valuable.
70:52 and you have to switch the careers a new lab in order to become
70:57 , really, really good at something something new and then prove to the
71:01 . Yeah. So you can visualize structure of the potassium channels. So
71:06 the story of rather than kenan Alright we're going to start talking about action
71:13 . But I just looked at my and I guess I'd like to talk
71:17 but when we come back we will about the rising things, the overshoot
71:22 falling phase, the undershoot. And gonna understand all of these things about
71:28 action potential. I will start explaining you the different dynamics of action potential
71:35 the driving forces behind different ions as play into the action potential dynamics.
71:41 you very much and I will see all on
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