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00:01 | Okay, so this is neuroscience lecture and last lecture. We talked about |
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00:08 | neuronal membrane potential oppressed, arresting membrane , and we discussed several very important |
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00:19 | that air summarized on the slide here front of you. So on the |
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00:25 | left, what we reminded ourselves is arms law, which is V equals |
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00:36 | voltage, be I current. Our and G is equal. The inverse |
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00:45 | resistance and G is conduct INTs. we said that across plasma membrane, |
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00:52 | have separation off charge where there is lot off negative charge accumulated on the |
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00:59 | of the cytoplasm and positive charge accumulated the outside of the number. So |
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01:05 | of the charge exchange that happens fast flow across plasma membrane that happens, |
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01:15 | across the plasma membrane. And we about the fact that the inside of |
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01:20 | Sella's well as surrounding environment outside or away from the plasma membrane they charge |
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01:29 | environments. There is equal amount of and positive charge, but the separation |
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01:35 | charge across plasma number it's creates a of about minus 65 million volts, |
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01:42 | that the inside of the cell is million volts negatively charged compared to the |
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01:50 | of the cell. We talked about there are building blocks and the cells |
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01:56 | all of the proteins. And these blocks are illustrated here on the |
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02:03 | here in the middle, amino assets polit peptide bonds, forming secondary tertiary |
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02:11 | . Ordinary structures informing what we call proteins or trans membrane proteins. |
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02:21 | that will conduct the ions of interest us on this, conductors of ions |
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02:27 | a very fast but a very selective . And so we talked about. |
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02:32 | reason why we need fast things is there is quite a bit that |
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02:38 | that needs to be done reflexively. we talked about a very simple Patel |
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02:46 | reflects. We discuss the types of involved in the circuit after and sensory |
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02:54 | root ganglion through the you know, AF parents that are excited Torrey onto |
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02:59 | multipolar motor neuron south that are excited onto the muscle south. And we |
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03:04 | that single synapse una synoptic circuit activation the quadriceps muscle spindle through the appearance |
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03:15 | through the motor neuron e ference from spinal cord proper back into the extensive |
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03:22 | is one synapse process. However, also discussed the fact that you would |
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03:29 | Thio for this reflex and for the of the lower leg during the patella |
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03:35 | reflex test for the proper movement that leg you would want the relaxation of |
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03:40 | opposing hamstring flexor muscle. And that through the process off bifurcation of the |
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03:48 | affair in In the spinal Cord, one contacts the motor neuron, one |
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03:56 | of the contacts of motor neuron and motor neuron and the other part splits |
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04:05 | contacts that inhibitory Interneuron is here, in black and the proper spinal cord |
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04:11 | inhibitory Interneuron is that in turn, that motor neurons and inhibition of motor |
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04:18 | allows for the relics ation of the muscle and therefore the proper reflexive movement |
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04:25 | the leg during the patella tendon We talked about the fact that through |
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04:31 | channels that are selective, you have flow of a lot off ions and |
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04:38 | ions air surrounded by waters of and they get stripped of these water |
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04:45 | as well as they interact with. mean acid residues typically and uh, |
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04:52 | the sodium and for the potassium, would be negatively charged amino acid |
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04:57 | Um, for the on ions would a positively charged them. You |
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05:02 | acid residue that it will interact with ion inside the inner channel. Luminant |
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05:09 | essentially allow for the propulsion off the , in this case of sodium from |
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05:14 | of salted inside of itself. But channels will select for sodium. These |
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05:19 | will select the potassium. They'll they'll their selective ions that they only passed |
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05:25 | . But at the same time, discuss that there are channels and we'll |
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05:29 | into them a little later, such gloom it receptor channels that ah, |
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05:33 | of the passage of multiple clients. for the purposes of discussing the arresting |
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05:39 | potential on the action potential generation, going to talk about sodium and potassium |
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05:48 | channels that are actually voted voltage gated losses you will learn. So that |
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05:54 | that these channels, the opening of channels in the flow of the ions |
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05:58 | be influenced by several things. And of those things is a change of |
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06:02 | . Across plasma membrane and other things a neurotransmitter, a chemical ligand binding |
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06:08 | the channel on opening off that podium channel. Now on the right here |
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06:14 | the bottom is a t p a showing that, uh, it acts |
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06:21 | concentration radiant by consuming energy. And is a much slower process than the |
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06:26 | INTs off fast conduct its of ions these channels. We further talked about |
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06:32 | fact that we have diffusion radiance, we also have electrical attraction forces and |
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06:42 | port forces. So we discussed for example, each ion is not |
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06:51 | Lee flowing across plasma membrane down its radiant. But in fact, it |
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06:58 | also once in this case, we potassium once. If you have a |
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07:03 | channel over here and you have a of that potassium channel, there's a |
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07:08 | of potassium on the inside of the illustrated by K plus large red |
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07:13 | and that potassium will flow across uh, membrane across the channel. |
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07:19 | you would think that it would flow there's equal amount of potassium on both |
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07:26 | . On the inside of the cell well on the outside of the |
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07:29 | But that is not the case, , as the charge flows, is |
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07:33 | positive charge flows across plasma membrane again very close to the plasma membrane. |
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07:41 | this positive charge accumulating close to the membrane results now into in the in |
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07:48 | electrical force in the electrical force that a rip all repulsing that sand positive |
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07:56 | and therefore you reach the equilibrium potential equilibrium. Potential is where you have |
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08:04 | diffusion all or the Grady in the ingredient forces driving ion across this direction |
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08:13 | gets counteracted by electrical forces driving the in the opposite direction and is illustrated |
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08:20 | of the bottom right. What you is at some point these forces are |
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08:27 | to each other and that there's no ion flow. But there's also no |
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08:34 | Grady int that neutrality in the sense there's still a lot more potassium that |
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08:40 | on the inside of South. so each one of these ions has |
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08:48 | certain, uh, concentration radiant. it also has an electrical force of |
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08:57 | , and these forces, determined based the concentration, radiant and based on |
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09:02 | channels that are open, will determine Librium potential for individual ions and each |
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09:09 | ion will have its own driving What? I mean by that year |
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09:14 | number three, I only driving forces M minus e. Ion. That |
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09:21 | for D. M stands for membrane , and e ion stands for equilibrium |
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09:28 | for at that particular ion equals a force, meaning the greater the difference |
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09:36 | the overall membrane potential and you'll like, What does he mean? |
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09:39 | ? We're talking about this one eye , but you learn that the membrane |
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09:44 | is not determined. Just attacked by . VM represents the species of ions |
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09:51 | we already discussed primarily sodium and potassium part chloride, a small part god |
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09:59 | . Okay, so VM actually represents number of ions where E ion represents |
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10:05 | a single ion such as potassium. now we have to learn how to |
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10:11 | these ionic reversal potentials. And that's we ended up talking about. Way |
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10:17 | about potassium, who said the same stands for sodium, so there is |
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10:22 | lot of sodium on the outside, you open the channel. Sodium will |
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10:25 | on the inside of the cell, as soon as this positive charge accumulates |
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10:29 | the inside of the plasma membrane that actually start pushing back on the positive |
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10:35 | coming from the outside of the cell will reach equilibrium potential. Ah, |
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10:41 | how do we calculate the equilibrium And we talked about the fact that |
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10:45 | know the concentrations off ions. We the concentrations off ions inside plasma |
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10:53 | potassium, sodium, calcium chloride. know the concentration on the outside. |
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11:00 | know the concentration on the inside for of these four islands. We can |
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11:05 | simplify this concentration into the ratio of outside vs inside. So, for |
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11:12 | , in the stable for potassium, have five million Mueller on the inside |
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11:17 | and note that the table that that graph below shows three million Mueller right |
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11:22 | here, where we're talking about the of the plasma membrane in parenthesis that |
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11:27 | list three mil Imola. So there a disparity. There's a disparity in |
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11:32 | textbooks. There is a disparity in south. There is a disparity in |
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11:36 | exact numbers and during the tasks, will not be tricked into a question |
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11:43 | the exact number. But rather the are correct calculated calculation or correct ratio |
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11:52 | these specific ions on the inside versus outside. So for potassium, you |
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11:56 | a lot of potassium on the 100 million Moeller, and you have |
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12:01 | very little potassium on the outside of South. 3 to 5 million |
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12:06 | Let's say 3.5 to $5 million about to 20 ratio Outside, vs |
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12:13 | and look at the sodium is just opposite. There is a lot more |
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12:16 | times more sodium on the outside than is on the inside of the |
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12:22 | Note that we said that for there's greatest disparity in the concentration |
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12:28 | 10,000 times more calcium on the outside the south compared to the inside of |
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12:33 | south, giving calcium probably one of highest concentration ingredient driving forces to cross |
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12:44 | the outside into the inside of the , we discuss how tightly regulated it |
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12:48 | on the inside of the south, you don't have that much of the |
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12:52 | floating side of solid calcium bouncing around nothing. Chloride again ratio is a |
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12:58 | more chloride. 11 times more chloride the outside is compared to the inside |
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13:03 | yourself and now in this table, also in the diagram below you have |
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13:08 | equilibrium potentials for each ion. So on and you have e n a |
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13:14 | 56 million volts BK minus +102 chloride 76. Now notice also that the |
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13:22 | minus 80 in the table for potassium match the numbers of potassium shown that |
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13:29 | diagram minus 102. And that's the why I cannot ask you What is |
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13:34 | Russell potential for potassium? Is it 85 minus 80 minus 90 minus one |
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13:40 | two. It would be unfair of to do that because the actual text |
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13:45 | and different South's because of different concentrations different cells are slightly different reversal, |
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13:52 | or equilibrium ionic potential values because they slightly different concentrations of violence. Uh |
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14:01 | . So again, you have to that they do have each, |
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14:06 | reversal potentials. You have to remember values approximately of these reversal potentials or |
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14:13 | equilibrium potentials. I use reversal potentials ionic equilibrium potentials interchangeably. Uh, |
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14:21 | have to remember those values, but , minus 65 minus 70 for |
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14:28 | let's say calcium plus 120 approximately for plus 50 plus 62 for potassium minus |
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14:38 | minus 19 maybe even minus 100. you see, there is enough disparity |
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14:43 | you to know that potassium ical liberal minus 80 is below chloride, which |
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14:49 | minus 65. Okay, and that's point. And if I ask you |
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14:53 | , is to make that particular point that is important for what we're about |
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14:57 | talk about in this lecture nerds equation the equation that you used to calculate |
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15:04 | reversal potential that you used to calculate Ionic equilibrium potential nerves equation is the |
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15:12 | E For an individual, ion is 2.303 R T over ZF. Log |
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15:24 | ion concentration on the outside of the over ion concentration on the inside of |
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15:31 | south, where the ion is our potential or our equilibrium potential. R |
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15:39 | for gas. Constant mhm t is temperature, and that's why in the |
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15:47 | slide, you saw 37 Celsius because a physiological body temperature, so temperature |
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15:54 | important in calculating biology reversal potential Z for the violence. Charge off the |
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16:02 | or the violence f iss, or electrical constant in this case and |
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16:09 | based on longer rhythm. I on outside the South. I am out |
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16:19 | , and ion concentration on the inside the South. Yeah. So this |
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16:25 | the formula that now you can plug a sodium ion where you have ion |
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16:31 | , concentration on iron, inside concentration you have some constants that they don't |
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16:40 | . Okay, Yeah, temperature was with your calculating in a physiological |
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16:50 | And you have different concentrations of of course, and you have different |
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16:54 | for these ions e plus one versus plus and so on. So what |
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17:02 | says is the nurse equation can be from the basic principle of physical |
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17:08 | Let's see if we can make sense it. Remember that equilibrium just that |
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17:15 | talked about for the last few Equilibrium is the balance of two |
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17:22 | Diffusion. That's the concentration, chemical, radiant and electricity which opposite |
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17:31 | attract and same charges to repel each . Increasing the thermal energy of each |
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17:37 | increases diffusion and will therefore increase the , Uh, potential difference achieved that |
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17:47 | . That's equilibrium foran eye on is to teeth. There's there's more movement |
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17:56 | warmer temperature. The hotter temperature on it had increasing. The electrical charge |
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18:01 | each particle will decrease the potential difference to balance the fusion. Therefore, |
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18:11 | equilibrium of this island is inversely proportional the charge off the ion bail and |
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18:20 | . We need not worry about r F in the nurse equation because they're |
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18:26 | . So we go back to the temperature 37.7 star 37 C. Everybody |
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18:34 | checking their their temperature these days because coded. So you should know 36.6 |
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18:43 | degrees centigrade is normal physiological body temperature humans. The nurse equation for these |
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18:51 | isles that we already know these air main, most important players for us |
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18:59 | , sodium chloride and calcium. Now is we're gonna scroll back up and |
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19:09 | gonna walk through the calculations for different . So if you take 2.303 our |
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19:24 | , you simplify it to 61 54 get Mila balls. We're not gonna |
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19:34 | through all of the details, but is a simplification of 61 54 million |
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19:38 | . If you plug in, positive valin c f r t the |
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19:45 | temperature. Physiological. Remember, we're at it both. Okay, So |
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19:55 | TCF 2303 you can collapse into 61 million volts. Log of potassium outside |
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20:04 | inside. The same goes for sodium 54 million volts. Log sodium and |
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20:12 | vs. Inside. The sign for 54 million volts. Changes to negative |
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20:20 | balls because you're plugging in chloride and has negative minus one violence. And |
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20:33 | rtz f this the you remain the Constance for our for gas constant and |
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20:43 | Faraday Electrical constant the same temperature. when you calculate for calcium, the |
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20:51 | is two plus So that same instead being 61 54 mil of also abbreviation |
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21:00 | 30.77 It's half of that, Artie, divided by two time. |
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21:08 | divided by two times Faraday's constant. therefore, in order to calculate the |
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21:15 | potential for a certain type of the body temperature, we need to |
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21:20 | the only concentration on either side of membrane. So we know that, |
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21:26 | you should wonder how we know But it started out by people squeezing |
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21:32 | ions from large Axiron such as, , such as a giant squid |
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21:41 | But here I look at the, when I was just my windows so |
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21:44 | don't look at me as much, look at the formula instead. Look |
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21:50 | the RTZ f and look at the outside vs inside. Now you'll |
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21:57 | like, wait a second. Where the concentration now, if you |
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22:01 | I told you that in this formula can actually plug in either the actual |
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22:07 | of these ions. Okay? Or can plug in the ratio off. |
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22:16 | concentrations are side versus and says the thing if you put five over 10 |
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22:24 | 100 versus 1/20. Okay, so this calculation, below in the following |
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22:30 | is what is being used are the . So we know that there is |
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22:35 | lot more potassium 20 times more potassium the inside of the cell versus the |
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22:41 | of self log 1/1 20 gives us 1.3. Therefore deliberate on potential or |
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22:52 | reversal potential for potassium equal 61 54 volts times negative 1.3 equals minus 80 |
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23:01 | volts. Notice. So now you . Now you can understand where this |
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23:10 | comes from, where these calculations for potential comes for sodium, for |
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23:19 | for Florida and calcium. You can this new Ernst equation and learns equation |
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23:25 | for single ion, and you can in these ratios of ions outside vs |
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23:32 | , and you will get similar if not the same numbers that are |
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23:37 | in the slide above. Okay, this is how we calculate individual ion |
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23:44 | potential. But notice that there's no in the nurse equation for permeability or |
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23:52 | conduct INTs. So while it is into consideration the chemical and electrical |
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24:04 | it is not taking into consideration a important point for the membrane and for |
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24:11 | islands across the membrane. Is Is membrane permeable? Does that mean? |
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24:19 | these channels for these specific islands thus calculating the value equilibrium potential Forgiven |
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24:28 | does not require knowledge of the selectivity the permeability of the membrane for the |
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24:34 | . You'll see what does that That means and implies a different aisles |
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24:39 | different permeability across plasma membrane. The ions are favored by the membrane to |
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24:48 | , whether it's inside or outside, on the conditions and the charge that |
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24:52 | across plasma membrane, there is an potential for each island, the intracellular |
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24:58 | extra salary with fluid. The equilibrium for each ion is a membrane potential |
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25:04 | would just balance the aisles concentration radiant that no net ionic current would flow |
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25:10 | the membrane were permissible to that So now we have to move onto |
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25:18 | next equation, which is the Goldman . Mhm and Goldman. Equation is |
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25:26 | from the Ernst equation because in Goldman , if you notice if the membrane |
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25:33 | a really learn were permissible, only potassium, the resting membrane potential, |
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25:38 | equal the equilibrium potential for potassium. agree. If you have all of |
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25:48 | ions on two sides of the you have sodium chloride, potassium, |
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25:53 | , But the membrane is only permissible potassium. There's only potassium channels that |
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25:58 | open and Onley along for potassium to through. So guess what happens that |
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26:03 | membrane potential overall numbering potential independently off other ionic species present around the |
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26:11 | The overall number of potential is purely by potassium ion. It's dominated by |
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26:18 | , and such is the case in . That's a great exam question. |
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26:25 | member and potential of glial cells such Astra size is dominated by potash in |
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26:30 | they're mostly permissible to potassium, at the rest. Okay, but |
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26:36 | does not. The measured resting member potential okay of a typical neuron is |
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26:45 | minus 65 million balls. So if point here is that if the cell |
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26:54 | only permissible to potassium, then the member and potential should be minus 80 |
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27:00 | be minus 90 or whatever. The of delivering potential minus 100 is given |
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27:04 | potassium, but the resting number and is closer to minus 65 tu minus |
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27:11 | . Why is that? Because there other no other ionic species that these |
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27:18 | are allowing thio flow through the plasma that they're permeable to. So this |
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27:25 | permeability. This discrepancy is explained because neuron address or not exclusively permissible to |
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27:31 | . There's also some sodium from the stated another way. The relative permeability |
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27:37 | the resting neuronal membrane is quite high potassium and low to sodium, addressed |
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27:45 | could be restated at resting. Number potential There is mawr flocks of potassium |
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27:53 | sodium. Now what Goldman equation does below, it's essentially very similar to |
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28:03 | Equation, but instead of taking into concentration off just a single ion, |
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28:12 | actually calculates and combines. The concentrations potassium and sodium is the two most |
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28:20 | ions to most important aisles and influence most off the overall number of |
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28:28 | And it also introduces the permeability P K stands for permeability, for |
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28:39 | from the ability for sodium. And what's interesting is how do you get |
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28:46 | ? Overall, VM, This VM membrane potential not to confuse with E |
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28:54 | or E ion gm. This is . In previous formula unearned situation, |
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29:04 | were calculating equilibrium potential forgiven ion. Goldman equation calculates the membrane potential takes |
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29:15 | consideration more than one island and also permeability. What this is showing is |
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29:24 | rest. The cell membrane is 40 more permissible to potassium than it is |
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29:31 | sodium, 40 times more permissible to than it is to sodium. And |
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29:37 | you now, in this case, of the ratios off concentration of potassium |
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29:44 | mysteries inside. Actually, it's really Mueller values that have plugged in once |
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29:49 | calculate that taking into consideration the high for potassium over sodium through the same |
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29:59 | 54 mil of all slog is the abbreviation from nonce equation carries over |
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30:06 | But now it's permeability of two different . The log off that, |
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30:12 | number, which gives you in mind 65 million balls. Eso. This |
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30:19 | how, if you take two ions I. So do you mind a |
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30:23 | in there relative concentration on the outside inside and the permeability? And by |
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30:29 | way, this permeability changes during the potential during the rising phase of the |
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30:36 | potential. In the peak of the potential, the cell membrane is hugely |
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30:41 | by sodium, and it's mostly permissible sodium miles. And that reverses again |
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30:46 | the action potential goes back into the phase to return to the resting membrane |
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30:52 | , where potassium once again becomes the dominant ion blowing across plasma membrane. |
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31:00 | these are the two equations that you to know for the exam. You |
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31:04 | not need calculators, thio calculate, , anything using either nerves to Goldman |
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31:12 | . But you should be able to easily recognize the relative ratios of ions |
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31:19 | relative concentrations of P ions, the ions sodium, potassium chloride, calcium |
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31:26 | well as their who Librium potential and so understand and be able to |
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31:34 | the formulas. Be able thio, identify that. No, this wouldn't |
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31:37 | a correct calculation rather than actually go the calculation yourself using a calculator so |
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31:43 | will not need to do that. you do need to know these formulas |
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31:47 | didn't do need to know what different mean in these formulas on Do you |
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31:55 | to be able to recognize the correct , the correct equilibrium potentials in the |
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32:00 | calculation for the number and potential use equation for this exam for the first |
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32:09 | . Okay, so we have E , which is nursed equation above individual |
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32:21 | , and then we have 61.54 million log is the same abbreviation from Nervous |
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32:28 | , and we have Goldman equation you know. So now remember, |
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32:38 | talked about how important it is. see, if you have different if |
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32:44 | all of a sudden have a lot potassium. That means you change this |
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32:49 | of the potassium on the outside versus inside of the cell and the diagram |
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32:56 | the left shows actually that if you potassium on the outside of the |
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33:03 | you're gonna increase the drive of that . The sellers already addressed Permira ball |
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33:08 | potassium, but now you increase its from 1 to 3 million. |
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33:13 | five million Mueller to 10. Mila on the outside. Look what happens |
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33:19 | the member and potential member and potential resting membrane potential of minus 80 slides |
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33:26 | to about minus 60 minus 55 million with 10 Miller Moeller Potassium concentration |
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33:37 | So this is this is quite If you increase the potassium concentration to |
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33:43 | million Mahler here you are now looking about minus 40 million volts. The |
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33:50 | for action potential generation, as you learn later in this lecture, is |
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33:54 | minus 45 million balls. So this that if there is a local increase |
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34:03 | extra cellular potassium concentrations, the cells of the chemical Grady, include deep |
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34:12 | sufficiently enough to start producing action and that indeed is the case. |
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34:18 | high potassium concentrations using potassium chloride concentrations a very common way to stimulate different |
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34:26 | of cells. To make different types cells, especially electrically charged, sells |
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34:31 | active, and it replicates models of activity and high potassium concentration. Also |
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34:39 | an epileptic model off epileptic activity, when you have too much way too |
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34:47 | of the potassium on the outside of South, the activity is not only |
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34:54 | , not only firing action potentials, it can synchronize to produce abnormal epileptic |
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35:00 | seizures. Uh, so this is introducing another disease very slowly. Epilepsy |
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35:08 | way to replicate epilepsy in the model to use high potassium model for |
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35:16 | It's one of the models for and one of the expressions of |
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35:22 | etc. Are epileptic seizures. They've in many different shapes and forms, |
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35:30 | loss of consciousness to retaining consciousness from jerks to almost unnoticeable changes in motor |
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35:41 | , but very strong changes in emotional and agonizes. Uh, epileptic activity |
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35:50 | the brain would be determined using electrons follow Graeme. We discussed that few |
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35:55 | back where we said that to record activity from the brain. You need |
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36:01 | to follow ground, which records activity the outside of the skull through a |
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36:06 | like structure that has electrodes that pick activity from the surface of the cerebral |
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36:16 | on the right. You have astro here and this Astra side. It |
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36:20 | that if you have at the bottom increases in the potassium concentration on the |
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36:25 | of the south, this Astra side actually slurp it up. Slurp it |
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36:32 | . And as you can see, has a very vast dendritic tree that |
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36:38 | these processes going off and spreading. zig Leo processes is spreading all over |
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36:45 | they're actually spreading this potassium concentration through vast network as well as through the |
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36:52 | of Astra sites that are interconnected with Astra sites. It would be passing |
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36:57 | along to other Astra sites, and Astra sites will be passing it along |
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37:01 | other distal networks, thereby preventing preventing sustained rises and extra cellular ionic concentrations |
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37:11 | just potassium or calcium for sustained rises neurotransmitters. Because, as we discussed |
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37:18 | , also play a significant role in transmission. A swell. So this |
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37:26 | a very interesting story and the stories lead us to understand the science. |
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37:34 | , a lot of it has to with a progression off technologies and science |
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37:39 | general. And this is a story Roderick MacKinnon. Very interesting story. |
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37:46 | you wanna look into it on a level, uh, he is one |
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37:54 | an inspiring near scientists because he was driven by the quest to answer a |
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38:03 | or solve the problem. And this a really good reason to think about |
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38:12 | anything. Really. It's a good Thio even think about every day if |
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38:21 | solving something. If you're driven by a problem, I think you will |
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38:31 | reach your success. If you're not by getting a degree to check it |
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38:40 | for the books, you don't really what to do with that degree. |
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38:47 | that is okay, actually, and is quite okay for undergraduate students. |
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38:53 | not know what they want to do their degree, especially in these very |
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39:00 | times, so But it's important now think about what are the problems in |
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39:09 | world. What are the problems in , what air them knows. How |
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39:16 | I find a solution to a How, How? What is my |
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39:25 | for this solution? And for many , is different. Callings for Roderick |
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39:33 | was an M D medical doctor and successful career in Harvard. There's a |
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39:41 | practitioner, but driven by the quest trying to understand there's a medical doctor |
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39:50 | trying to understand. What do the look like? We describe that you |
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39:56 | these Call it topped I chains of acids being folded secondary tertiary co. |
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40:02 | structures placed essentially into sub units and forming the channels. What does it |
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40:08 | like? How do we solve the ? Can we see a channel? |
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40:14 | talked about that We can have electron and you can visualize synapses. There's |
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40:22 | nanometers across 0.9 point five nanometers in . That does not show you a |
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40:32 | structure that shows you there's a channel . It shows you the receptors there |
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40:39 | you their nuclear transmitter vesicles, but does not show those who receptor or |
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40:46 | channel structures. So how do you that structure when you cannot visualize |
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40:54 | And what Roderick MacKinnon used is he genetic mutations. You would mutate As |
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41:01 | know, you're looking at the Here is an actual, beautiful structure |
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41:06 | he described of the potassium channel. when you're looking at all of these |
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41:11 | rings and all of these different connections , that looks like a very complex |
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41:17 | game. Uh, you realize Wait second. This is actually very |
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41:23 | three dimensional model off a neuron off channel of the potassium channel. And |
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41:32 | , you see that red dot inside , there is an ion crossing through |
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41:38 | channel and all this complex structures amino and these amino acids are coded by |
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41:46 | . And so, if you dio directed muted genesis, that means that |
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41:54 | want to mutate a specific site and use genetic mutations. And he used |
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42:00 | flies that air called shaker flies that a mutation and the mutation was in |
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42:05 | potassium channel. And so that was of the first discoveries. Realizing that |
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42:11 | a second. If you impair both potassium channel, it leads to shaker |
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42:18 | . Shaker flies. Essentially, you think of it as model of convulsions |
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42:22 | tremors. Okay, so now he of the structures with genetic mutations you |
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42:35 | you could, you could you could because you would mutate a certain part |
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42:41 | the channel and it will tell you that part of the channel is responsible |
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42:47 | . But in addition, Thio uh, the mutations he was using |
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42:54 | . So he was monitoring activity of channels. How does one mutation over |
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42:59 | ? It causes the changes in activity this channel, and he was using |
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43:06 | . So there are a lot of toxins in nature and some of these |
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43:11 | actually buying two voltage gated potassium So by doing the mutations by recording |
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43:19 | physiological activity through these channels, the and the flow of potassium through these |
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43:26 | by using toxins which binds toxins will find a very specific binding site on |
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43:35 | beautiful channel. And by targeting a site, it would change the function |
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43:40 | the channel. It would change the of the potassium through this inner |
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43:44 | the channel. So to do Roderick MacKinnon exited out of his active |
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43:56 | medical doctor career and pursued essentially this heavy research scientific work. And it |
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44:08 | based on gene mutation, electrophysiology, toxins and trying to solve the structure |
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44:18 | the channel and he was successful at . But he wasn't satisfied. You |
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44:25 | why? Because he wanted to see channel. He wanted to see the |
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44:32 | . It wasn't enough because this structure you solved, you sold it through |
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44:40 | knowing the genetic code through knowing the of amino acids through knowing the folding |
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44:48 | these amino acids through doing the mutations doing the toxin analysis through recording electrical |
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44:55 | . That does not show you the that helps you derive the structure of |
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45:02 | channel. He was hungry. Thio the channel. So he decides to |
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45:11 | a new career off extra crystallography and extra crystallography, which is a very |
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45:21 | technique where you essentially trap individual trapped these individual protein channels within a |
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45:29 | little crystal. And then you pass ray light through that crystal, and |
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45:38 | the fraction of that light through the and bending of the light through that |
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45:44 | by the pro dam otherwise known bending by the crystal. But now interference |
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45:51 | the protein will actually help you visualize structure of these channels. So from |
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46:00 | D to the lab to do the electric physiological recordings and studies on Shaker |
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46:08 | on potassium channels. Thio predict the off the potassium channels to all the |
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46:20 | . Now where you have visualized potassium using X ray crystallography. And believe |
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46:27 | , if you read his personal people along the way laughed at him |
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46:32 | said, Wait a second. Aren't satisfied as an MD here and |
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46:37 | No. I want to be doing studies here to decide, you |
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46:41 | to do really understand and thio to the, uh, structure of the |
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46:47 | channel. Okay. Also, I'm do electrophysiology, and I'm going to |
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46:53 | all of these mutations. Okay? job. Now, I'm not satisfied |
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46:58 | I want to see the channel. really, really say I want to |
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47:02 | the structure fully? He's looking for . His quest. His solution is |
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47:07 | . Find out. What does this channel look like? How does it |
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47:12 | ? What are the important parts of channel? Whether the important parts of |
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47:16 | channel genetically what are the important parts the channel with interacting with nature in |
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47:21 | toxins? I want to solve this . I want to understand This is |
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47:27 | puzzle off life, and he doesn't jumping from two different locations, three |
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47:34 | locations, three different labs, different , switching from M D, mostly |
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47:42 | researcher. And so, um, , it's the quest. It's a |
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47:50 | . It's a solution for nature's a for a problem. Uh, people |
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47:57 | to see right as you know. , for example, Yuan Mosque |
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48:05 | uh, you know, to go Mars so he can see security, |
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48:14 | see what is happening there. so that's the quest that he is |
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48:25 | on. A lot of people are his quest because of that, |
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48:32 | |
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