| 00:00 | computer. This is the six neuroscience meeting we're discussing, member and potential |
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| 00:09 | or resting member and potential. We Lecture seven and lecture eight. Then |
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| 00:17 | have Exam one review session, and you have your first midterm exam. |
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| 00:26 | cost that accounts for one third of grade, and it will include the |
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| 00:32 | that we covered in class that is the lecture slides as well as the |
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| 00:39 | . So the best way to probably for the exam if you have you |
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| 00:45 | asked, is to attend the take notes during the lecturers. Ask |
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| 00:55 | questions you may have. I encourage to do over chat or use your |
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| 01:00 | to ask a question. And finally yourself for the exam review session those |
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| 01:10 | specifically designed, so that because of online format, we could refresh together |
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| 01:19 | of the material for each section before exams. So, please, |
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| 01:29 | the best way to prepare really is . Um, have all of your |
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| 01:37 | ready for the review session. Ask questions so that you really don't have |
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| 01:43 | mystery about any of the material. it on the videos. It's available |
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| 01:49 | video points. Make sure you test you can have access to the |
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| 01:54 | And if you are attending the lectures want to review videos right before the |
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| 01:59 | , please do that before the final session before the exam review session so |
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| 02:05 | you have no technical were just in the videos and logging in with your |
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| 02:11 | , not accounts going back to the that we covered last lecture. It |
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| 02:17 | pretty vast amount of material, and will review some of it on the |
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| 02:25 | . We talked about arms law, equals IR. We talked about the |
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| 02:29 | that the is voltage membrane voltage Current current ions flowing through the channels |
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| 02:38 | is the resistance resistance of the membrane on how open the channels are, |
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| 02:45 | permeable this membrane is to certain And we talked about the fact that |
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| 02:50 | , which is conducting this, is inverse of the resistance. We discussed |
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| 02:55 | fact that because of the separation of across plasma membrane, you have accumulation |
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| 03:02 | negatively charged ions, a negative charge the inside cytoplasmic side of the neurons |
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| 03:08 | accumulation of the positively charged ions in on the outside off the neuron in |
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| 03:17 | extra cellular space. And as we the inside of the side of plasmas |
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| 03:24 | further away from the membrane, there's neutrality in the solution. So the |
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| 03:31 | separation and changes in charge really happened across the plasma membrane. And if |
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| 03:37 | have an electrode is connected to a meter, you will see a difference |
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| 03:42 | minus 65 million volts and voltage, represents the fact that it's negative 65 |
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| 03:49 | bowls as it relates and compares to outside of the cell, which is |
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| 03:56 | . So the inside of the plasma is negatively charged, minus 65 million |
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| 04:01 | . This is our resting membrane That resting membrane potential is created by |
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| 04:08 | separation of charge. We talked about acids is being the main building blocks |
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| 04:14 | , create polit peptide chains and create Torshin or co ordinary structures and building |
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| 04:22 | receptor channels and ion channels. And on the ion channels that we're |
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| 04:29 | the silent channels are very important for ions and to exchange and changes in |
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| 04:35 | fast changes in the voltage across plasma happens because the channels open that are |
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| 04:42 | of these amino acids and allow the of the ions. We discussed that |
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| 04:48 | passage off the ions through the Ionic . In this case, we're discussing |
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| 04:54 | sodium channel, and as it relates the action potential, we will be |
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| 05:00 | voltage gated channels. So these air ion channels that are gated by |
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| 05:05 | You will learn there are several ways which we gave these protein channels. |
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| 05:10 | of them are gated by changes in voltage dependent channels, others segregated by |
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| 05:18 | . So they're ligand, gated channels chemicals, likens like neurotransmitters binding to |
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| 05:23 | receptors and opening up the channels. talked about the fact that these channels |
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| 05:29 | selective for certain ions and what we action potential dynamics in this lecture. |
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| 05:37 | the following two lectures, we will talking about both educated and selective sodium |
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| 05:43 | and both educated potassium channels and and and summary. The dynamics of this |
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| 05:53 | of the sodium through the channel is that sodium ion, also not only |
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| 06:01 | by water, sort of hydration but also interacting with amino acid residues in |
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| 06:07 | innermost limit of this channel, sodium the negative amino acid residue. Potassium |
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| 06:13 | the negative and negative violence with the amino acid residue which house propel this |
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| 06:19 | . And again these channels air not just based simply on the size |
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| 06:24 | on the clouds of hydration as well then you know, acid residue interactions |
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| 06:29 | specific ions. So the flow of channels of aisles through these channels is |
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| 06:36 | fast the order of millions of ions per per second and the flow through |
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| 06:45 | pumps. And remember that these channels mostly act down this electrochemical Grady int |
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| 06:51 | the chemical, radiant, the concentration electrical radiant build up off the charge |
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| 06:56 | electrical interactions of that ion with the on the either side of the |
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| 07:02 | But these pumps will actually transport potassium mines to potassium ions to the |
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| 07:09 | of the cell and three potassium miles the extra cellular fluid. Using ATP |
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| 07:15 | transporting them against the concentration radiant. , so regardless and just uses |
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| 07:23 | it's much slower. We need the flow of ion so that we can |
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| 07:28 | very fast decisions. And some of decisions made by neurons are reflective decisions |
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| 07:37 | means that your body reacted before your agrees to the reaction. That's a |
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| 07:46 | . And we discuss this within the of patella tendon reflex. As you |
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| 07:52 | , I told you to start outlining south types that were discussing in this |
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| 07:59 | . So we talked about that after stimulus of the patella tendon, you |
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| 08:04 | have ah, activation of the muscle and the apparent dorsal root ganglion pseudo |
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| 08:11 | polar neuron, which will then activate motor neuron. And through this |
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| 08:16 | synaptic connection, the motor Noura, , will essentially activate the contraction of |
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| 08:24 | of extensive muscle, and the muscles contract moving the leg forward after the |
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| 08:31 | with Violet. This is unit unit Synaptic link, Really the sensory neuron |
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| 08:38 | in going to motor e Farrant and the command of the contraction. So |
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| 08:43 | the neurotransmitters that these cells release recall morphology, how they're defined, morphological |
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| 08:50 | and also the fact that for any contraction for extensive muscle contraction, you |
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| 08:55 | have toe have relaxation of the posing , flex their muscle in this |
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| 09:00 | and this relaxation happens because the sensory neurons, they're going to the spinal |
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| 09:06 | proper. They bifurcate and one contacts motor neuron that activists extensive muscle on |
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| 09:12 | other. Uh, bifurcated synapse of sensory neuron will activate inhibitory, Interneuron |
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| 09:22 | inhibitory Internet and activation will in turn the flex, our motor neuron and |
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| 09:30 | inhibition off the flexor motor neuron will the flexor muscle, the hamstring flexor |
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| 09:37 | to allow for proper extension of the during this patella tendon reflex. So |
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| 09:45 | the types of cells, the neurotransmitters are involved, their morphology is that |
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| 09:51 | air all great exam questions. So we then talked about the flow |
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| 09:59 | ions, and we talked about the that ions will diffuse down their concentration |
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| 10:06 | int. But we also talked about equilibrium potential and this ionic equilibrium |
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| 10:14 | And we said that if you place lot of potassium like there's inside of |
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| 10:18 | Sao and you have Cem, ionic or negatively charged a even proteins |
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| 10:27 | the inside of the cell that camera . So you have potassium channels that |
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| 10:30 | open. This potassium will start flowing . This concentration, Grady and chemical |
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| 10:36 | . So big K plus represents a of potassium on the inside of the |
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| 10:40 | in little K plus on the right little potassium, and so potassium will |
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| 10:45 | down this concentration radiant but notice See the potassium never reaches concentration |
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| 10:54 | That means there's not even a month potassium charge because as potassium flows into |
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| 10:59 | outside of the cell outside of accumulate positive charge across on the plasma |
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| 11:05 | , which will start rebelling this So this is where the electrical forces |
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| 11:14 | electrical force of this positive charge is mawr. Positive charge Potassium coming out |
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| 11:22 | the cell, and it's Equalling to concentration Grady into the force of the |
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| 11:29 | radiant that it's still trying to Potassium thio equalize the concentration of potassium |
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| 11:34 | both sides, So this is the a point at which you reach an |
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| 11:42 | potential for potassium equilibrium potential. I will use entertain interchangeably as reversal |
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| 11:51 | and you'll understand that in the next why it's also called reversal potential Forgiven |
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| 11:58 | . But one thing that we have understand that off course, this is |
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| 12:02 | specific to one eye on, so if you have a lot of sodium |
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| 12:07 | the outside of the cell, and being driven down. This concentration radiant |
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| 12:11 | the inside of the cell and see happens is accumulation of positive charge on |
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| 12:16 | inside of the plasma number and now repelling the incoming positive sodium charge, |
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| 12:23 | an equilibrium potential for sodium, at point, electrical force opposing the flow |
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| 12:29 | the positive charge is equal to the Grady in force, driving it into |
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| 12:36 | the outside of the subtle from the the outside to the inside of the |
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| 12:41 | . So when we look at this last time we discussed several important |
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| 12:46 | First of all, that you have four most important ionic species that were |
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| 12:52 | when we're discussing resting membrane potential or potential for that matter. So |
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| 12:59 | sodium, calcium and chloride. We that we know the concentrations of the |
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| 13:06 | on the outside versus the inside of cells. And so, for |
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| 13:10 | you have on the outside about five . Mueller noticed that this number five |
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| 13:14 | different from the number right below which shows three for potassium. So |
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| 13:20 | one is it on the exam? not gonna try thio. Get |
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| 13:24 | Is it three years of 3.5 or or five. What happens is the |
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| 13:29 | extra cellular environment will have small variations Milan Mueller concentrations of potassium from about |
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| 13:37 | million Moeller on the outside to about million Moeller. So that Z, |
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| 13:44 | just the normal thing that happens and different environments depending. And there's also |
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| 13:52 | for neurons that contain a lot of . On the outside of such as |
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| 13:56 | case in the hair cells in the air will discuss that when we discuss |
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| 14:03 | hearing system at the very end of corpse. So the point here is |
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| 14:07 | there's very little potassium on the and there's a lot of potassium on |
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| 14:12 | inside, and you can translate this mole or a Mile five on the |
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| 14:18 | 100 million Mueller on the inside to ratio 1 to 20. So there's |
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| 14:23 | more times off potassium on the inside the cell, and each one of |
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| 14:29 | ions now has e ion, which for equilibrium potential for that ion. |
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| 14:34 | each ionic species has its own potential value, potassium. It's minus |
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| 14:41 | . But here in the diagram, will see it's minus 102 so that |
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| 14:45 | deliberate potential will differ. Differ, on the concentration difference for that ion |
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| 14:52 | on the test. I'm not gonna Thio confuse you with that, and |
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| 14:56 | questions will be very clear. By way, I'm seeing a note that |
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| 15:02 | Internet connection is unstable. Um, I'm seeing. See, you're good |
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| 15:17 | , thank you. Appreciate it. I did get a note that the |
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| 15:21 | connection is unstable. So what may ? And it's happened in in many |
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| 15:28 | . If we get disconnected, let's reconnected the same zoom like in case |
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| 15:33 | happens in case we lose the Internet . Now each one of these ions |
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| 15:39 | its own equilibrium. Potential value, you can see that for sodium there |
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| 15:44 | 10 times more sodium on the outside the southern. The inside of the |
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| 15:48 | also noticed that for calcium, there the greatest disparity of calcium concentration. |
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| 15:54 | means that there is a lot of 10,000 times more calcium on the outside |
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| 15:59 | the south, compared to the inside the South and for chloride is about |
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| 16:04 | times more on the outside than it on the inside. So again, |
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| 16:09 | this back into the perspective that these concentrations of all of the ions that |
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| 16:14 | important for us the ratios of these and their equilibrium, potential values way |
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| 16:21 | to these liberal potential values. this is how we get to |
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| 16:26 | We're gonna walk through the nerds which is one of the most important |
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| 16:31 | in neuroscience and the equation that is to calculate the equilibrium potential forgiven |
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| 16:39 | Now, what you have in Ernst is E ion, which stands for |
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| 16:46 | or Ionic equilibrium potential. 232.303 are over ZF Log off ion concentration on |
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| 16:57 | outside of the cell over. I'm on the inside of the south, |
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| 17:02 | R is the gas constant and T the absolute temperature, and so you |
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| 17:08 | you have may have noticed in the diagram that shows here that equilibrium potential |
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| 17:14 | calculated 37 C, which is your body temperature. Important as temperature checks |
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| 17:21 | going on now, 36.6 37 37.2 about normal physiological body temperature and center |
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| 17:31 | . And so you do that calculation this is one of the terms. |
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| 17:35 | the temperature gas constant? This constant may change. See is a charge |
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| 17:41 | the ion other violence for mono Vaillant plus one minus one for dive aliens |
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| 17:48 | one oh, plus two Sorry for two plus, for example. |
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| 17:54 | now f stands for Faraday, Constant Faraday. Constant also is a |
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| 18:00 | It doesn't change. Log is based logarithms I on on the outside versus |
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| 18:05 | on the inside The nerves equation can derived from the basic principles of physical |
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| 18:13 | would see if we can make some of that. I actually want to |
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| 18:16 | through this so that we can all through this. You don't have to |
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| 18:20 | this equation. You have to understand equation and answer questions, not calculate |
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| 18:25 | your calculator. You will not need calculator during exam, but you will |
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| 18:30 | to know the proximate ratios off the and also the reversal potentials Identify with |
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| 18:37 | certain calculation is correct. Forgiven So let's see if we can make |
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| 18:45 | of it. Remember that equilibrium is balance of two influences. This is |
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| 18:49 | equilibrium is the diffusion. It's the Grady in by the chemistry that's pushing |
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| 18:55 | down its concentration. Grady in the , which causes an ion to be |
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| 19:00 | to positive charges and repelled by life . Next sentence. Increasing the thermal |
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| 19:07 | of each particle increases diffusion and will increase the potential difference. Achieved a |
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| 19:14 | . Um, a thermal energy of particle increases diffusion. There's more. |
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| 19:19 | is you increase the temperature. That's . Potential of ion is proportional thio |
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| 19:25 | meaning that if you look at this , if you increase the temperature, |
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| 19:29 | will see an increase proportionate increase in ion reversal or equilibrium potential. Now |
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| 19:38 | on the other hand, increasing the charge of the particle will decrease the |
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| 19:43 | difference needed to balance diffusion. equilibrium potential for ion is inversely proportional |
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| 19:52 | the charge of the ions e, so it's proportional to the temperature. |
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| 20:00 | it's inversely proportional to the violence which in denominator Z. We need not |
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| 20:07 | worry about our NAFTA nurse equation because constants. Their values don't change the |
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| 20:13 | temperature, which we assume is this it's the same 37 C. The |
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| 20:18 | equation for these important ions, our four of our potassium sodium alright and |
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| 20:25 | . I am simplifies to this. can take 2.303 are TCF and collapse |
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| 20:32 | to 61 54 for potassium miles, C temperature z valence plus one and |
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| 20:42 | have 61 54 long potassium outside versus Inside. For sodium you have 61 |
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| 20:51 | log sodium outside vs inside. Notice forklore I calculating equilibrium potential. This |
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| 20:59 | now becomes minus 1 65.54 million And that's because you're plugging in negative |
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| 21:08 | into the valence into the Z here for calcium, this abbreviation becomes 30.77 |
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| 21:15 | is half of 61 54. It's of this because you're plugging in Z |
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| 21:22 | value. Okay, so you're dividing by two. Basic And so this |
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| 21:26 | for calcium Nichola groom potential. Now walk through the calculation for the |
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| 21:32 | a deliberate potential. So in order calculate the equilibrium potential for a certain |
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| 21:37 | of island and body temperature, all need to know the younger concentrations and |
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| 21:41 | side of the membrane. For example we use here is for |
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| 21:46 | On. We discussed that there is times more potassium. You can help |
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| 21:50 | 100 million Mueller on the inside and million on the outside, or you |
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| 21:54 | put their concentration ratios. Therefore, should know approximately their concentration ratios and |
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| 22:02 | there Miller Molar concentrations as well for exam. And so what you have |
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| 22:07 | you have logged 1/20 equals minus Now it's 61 54 times minus 1.3 |
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| 22:15 | deliver. The potential for percussion is 80 million volts. Notice that there's |
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| 22:20 | terms and learns equation for permeability of conductors. Okay, that's calculating the |
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| 22:27 | off the Colombian potential for island does require knowledge of selectivity or the permeability |
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| 22:34 | the membrane. For the ion, is an equilibrium potential for each ion |
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| 22:41 | the inter cellular and extra cellular So you have to know for approximate |
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| 22:47 | and how to calculate those four approximate but not do the actual calculation. |
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| 22:55 | . A ca liberal potential for ion a member in potential that we just |
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| 23:00 | the ions. Country concentration, radiant that no, not ionic aren't flow |
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| 23:07 | flow if the number and were permissible that one eye on right, so |
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| 23:12 | num brain were permissible to just potassium . The membrane equilibrium or membrane potential |
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| 23:20 | be very close to the potassium equilibrium , but it is not. It's |
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| 23:26 | 15 million volts off minus 65 million for arresting member and potential, and |
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| 23:31 | calculations for delivery in potential is for individual ion. You have equilibrium potential |
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| 23:37 | potassium equilibrium, potential facility, for chloride and calcium ions. But |
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| 23:43 | does not allow you to calculate the number in potential. So the second |
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| 23:50 | important equation is the Goldman equation. we already discussed, what's very important |
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| 23:59 | the permeability. How permissible is the to given ion? In this |
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| 24:06 | there's selective permeability to potassium addressed. means that the membrane is slowly losing |
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| 24:13 | leaking out Potassium ions. It's highly to potassium addressed. I'm not permissible |
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| 24:21 | so do you. Now let's read about the Goldman equation. If the |
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| 24:27 | rain off a real neuron were only two potassium as I just mentioned |
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| 24:33 | resting membrane potential would be equal. equilibrium potential off potassium. Don't confuse |
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| 24:40 | two V M stands for membrane E ion stands for equilibrium. Potential |
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| 24:48 | ion. And if you look in like glial cells, glial cells or |
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| 24:57 | permeability toe one ion potassium ion addressed glial resting membrane potential is much |
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| 25:06 | The neuron arresting number of potential. a great exam question. Re arresting |
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| 25:11 | in potential. Essentially, it is Colombian potential for potassium, about minus |
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| 25:16 | minus 90 mil evolves, but neuronal membrane potential is about minus 65 million |
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| 25:24 | , which indicates that the membrane is herbal thio, other ions. And |
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| 25:29 | this case, even if the fact the membrane is dominated by permeability to |
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| 25:35 | , there's small permeability to sodium stated way. The relative permeability of the |
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| 25:44 | neuronal membrane is quite high to potassium low to sodium. Now, if |
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| 25:52 | relative for me abilities are known, is possible to calculate the membrane potential |
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| 25:59 | equilibrium by using the Goldman equation. what you notice in the golden equation |
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| 26:06 | essentially the same abbreviation that you saw the nursed equation minus 61 or plus |
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| 26:17 | +54 Right now, we're gonna use ions. It tells you that to |
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| 26:24 | number in potential, you have to more than one ion that is flowing |
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| 26:30 | plasma membrane, and you have to into account the Sturm of permeability. |
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| 26:35 | PK here stands for permeability for potassium and a stands for permeability for |
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| 26:42 | But the rest of it is the from nuns. Equation are TCF log |
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| 26:48 | 2.303 are TCF log of concentration of , plus sodium times the permeability. |
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| 26:59 | what we now is if we look the right here at rest, there |
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| 27:05 | 40 times the member in this 40 more permeable to potassium than it is |
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| 27:12 | sodium. So in this case and calculation, the actual minimal of concentrations |
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| 27:18 | used five mil imola versus 100 million . That's why I said you should |
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| 27:23 | both because the nurse equation we used ratio, which is the same, |
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| 27:30 | using this 105 million Moeller 20 to . And once you do this |
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| 27:40 | okay, you calculate the permeability off 40 times more than it is to |
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| 27:46 | 40 to 1. The value is 65 million balls, and that is |
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| 27:53 | value off the membrane potential. And membrane is permeable and is differential impermeable |
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| 28:04 | different ions addressed. It's dominated by to potassium. A lot of potassium |
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| 28:11 | leaking out of the cell. You think of lot of potassium on the |
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| 28:14 | of the cell, and the channels open and it's slowly leaking out. |
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| 28:18 | , but not much sodium, is in a little bit enough to offset |
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| 28:24 | membrane potential from the liberal potential for . That's so what are the values |
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| 28:32 | for for these, uh, reversal or Librium potentials? And again, |
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| 28:39 | yourself these air the two most important , the one on top is |
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| 28:44 | Potential for each ion for an individual and the one at the bottom is |
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| 28:52 | equation for calculating member and potential, takes the same abbreviation of 2303 are |
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| 29:00 | , which is 61 54 million were positively charged cat ions and incorporates |
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| 29:08 | than one ionic species and incorporates permeability for these different ionic species. |
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| 29:17 | why is this important. This is again. We talked about the fact |
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| 29:22 | if you have local changes in these , sir, violence either on the |
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| 29:27 | , for potassium on the inside of , it can really change the dynamics |
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| 29:32 | change a lot about cell activity. this case, we're going to discuss |
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| 29:37 | happens if you have increases in the in the potassium K plus in the |
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| 29:44 | concentration on the extra cellular space on outside of the South. So the |
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| 29:50 | on the left shows that if you a membrane potential, which is your |
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| 29:56 | potential, and the X axis shows off potassium on the outside of the |
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| 30:05 | . And we know that normal concentration potassium on the outside of the cell |
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| 30:10 | about 3.5 thio five million Moeller placing resting membrane potential around minus 70 million |
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| 30:19 | here, OK, at about five Mueller, about 70 million bowls. |
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| 30:25 | if we raise the concentration to $10 on the outside, it dipaula rises |
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| 30:30 | about minus 50 million malls, and you raise it to about $12 million |
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| 30:36 | now de polarize it to about minus minus 40 million volts. And that's |
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| 30:42 | potential in which you can actually start action potentials. And the take home |
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| 30:47 | from this graph is that if you extra cellular potassium concentrations even by a |
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| 30:53 | million Mueller, you can change the potential value by a few to tens |
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| 30:59 | million volts. And that is because can go to this equation and now |
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| 31:05 | the concentration of the potassium from three five million Moeller to 10 or 15 |
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| 31:11 | . Moeller. And you can see this membrane potential value overall numbering potential |
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| 31:18 | also going to change. And this where ostracized are very important. As |
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| 31:23 | discussed, Astra sites are several very functions. One of those functions wants |
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| 31:30 | make sure that there are no significant in extra cellular ionic concentrations locally or |
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| 31:40 | chemical increases like neurotransmitter calcium increases and Astra sides do, they will slurp |
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| 31:46 | this increase potassium on the outside of cells and because of their very widely |
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| 31:52 | Astra acidic processes, it will spread through these trees through its processes, |
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| 31:59 | out with local potassium concentration and spreading over far distances and spreading it through |
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| 32:06 | interconnected networks through other Astra sites, preventing for this potassium concentration to be |
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| 32:15 | increase. And and we know that is important because if we had this |
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| 32:20 | persistently, you would then deep polarized membranes. And these neurons that air |
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| 32:26 | polarized will now be very active will firing a lot of action potentials. |
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| 32:31 | high potassium is actually one of the that is being used to stimulate |
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| 32:38 | High potassium or high potassium chloride. lot of crimes is an experimental model |
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| 32:43 | which you induce high activity in cellular networks. High potassium also is a |
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| 32:53 | off epilepsy and epileptic seizures, and discuss this actually even later today. |
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| 33:01 | this is another neurological disorder that you add to your list that is, |
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| 33:08 | , epilepsy, the symptoms of A very, very varied. But |
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| 33:13 | lot of times epilepsy gets diagnosed. a person has repeated seizures, seizures |
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| 33:21 | in many different shapes and forms. of them can resolve in a loss |
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| 33:26 | consciousness and persist for minutes. Others very short and don't result in loss |
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| 33:33 | consciousness could just be manifested in the off contractions, muscular contractions, |
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| 33:41 | UH, it's called tonic and chronic and typically in in Apple FC Thio |
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| 33:49 | diagnosed with seizure activity. There's recordings we discussed at the beginning of the |
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| 33:55 | . They're called electrons to follow ground on the outside of the brain that |
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| 34:00 | allow to the cup activity from synchronized inside of the skull. And if |
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| 34:09 | is synchronized, where it is producing synchronous activity, the patient will be |
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| 34:16 | with epilepsy or with the least seizure , and you have to have repetitive |
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| 34:23 | activity in order to be diagnosed with . Epilepsy is also neurodegenerative disorder. |
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| 34:30 | so if you have abnormal signaling of neurons and abnormal flow off sodium and |
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| 34:37 | and potassium ions, who will have of the neurons through excited toxicity through |
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| 34:45 | toxicity and through calcium toxicity both and high Potassium model raising a potassium on |
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| 34:52 | outside of neuronal networks is also one the models for epilepsy, which replicates |
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| 34:59 | activity in neuronal networks. And so is something for you to keep in |
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| 35:03 | . We will come back and talk epilepsy throughout this course, and this |
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| 35:08 | of ah activity by ostracized is really . Thio spatial buffering in this case |
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| 35:14 | potassium spatial buffering to prevent local and rise is an ionic concentrations in this |
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| 35:22 | and the extra cellular potassium concentration. channels and people that inspire us in |
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| 35:31 | and how you pursue different questions in . I often in this section talk |
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| 35:37 | , uh, Roderick MacKinnon, but only about what he discovered and experiments |
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| 35:45 | he did, but also the kind person that he waas. And for |
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| 35:50 | , he is an inspirational person and neuroscientist. And in general, I |
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| 35:57 | like people that are on the quest change something in the society to |
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| 36:05 | to discover new things in science, change the way we think about |
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| 36:10 | to reveal things that have not seen seen before and solving problems, solving |
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| 36:21 | , making our lives easier, making degenerative disorders, uh, better treatable |
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| 36:31 | . And Roderick MacKinnon is an interesting in this respect, because he started |
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| 36:37 | career is a medical doctors and M . And he had a successful |
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| 36:43 | including working in Harvard Medical School. his brain was always intrigued by the |
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| 36:53 | by the underlying function off neurons and particular he was very much interested in |
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| 37:01 | channels. So he decided as a doctor that he would pursue electric physiological |
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| 37:10 | career and use genetic genetically modified genetically channels in these flies fruit flies. |
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| 37:24 | he is going to solve the structure this potassium channel and to solve the |
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| 37:31 | of the potassium channel, you have predict a lot of it. ISS |
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| 37:37 | predictions and then he employed several different , so he recorded electric physiological activity |
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| 37:45 | these channels. He did side directed Genesis, which means he mutated because |
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| 37:53 | gene mutation, you mutated certain parts the channel and by mutating certain parts |
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| 37:59 | this channel, which is shown here the middle, the red dot in |
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| 38:03 | middle is a potassium ion. He able to understand which parts of the |
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| 38:08 | are important for the conductors of potassium . In other words, if she |
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| 38:14 | one part of the channel, it not affect the conduct. It's it's |
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| 38:18 | as important, but one small amino mutation, a single I mean acid |
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| 38:25 | . All of a sudden, they very important for this very complex, |
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| 38:30 | dimensional protein puzzle and the function of three dimensional protein. So you discovered |
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| 38:38 | very interesting things. First of you discovered that there is this hairpin |
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| 38:44 | , then the inner poor loop inside channel that restricts the flow off, |
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| 38:51 | , off, off the ions and the flow of the ions. He |
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| 38:56 | with flies that had what is called Potassium channel. So the flies had |
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| 39:03 | mutation in this potassium channel and they shaking. They were resembling epilepsy, |
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| 39:11 | seizures or tremors. So it was model where potassium channel gets mutated and |
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| 39:18 | flies so that we can understand if mutation is important. Turns out that |
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| 39:25 | of these mutations were very important, Shaker flies became almost one of the |
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| 39:31 | rudimentary models. Experimental models flies for activity for studying seizure activity and for |
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| 39:40 | abnormal potassium channels. Um, a of the potassium channels is important, |
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| 39:47 | you use fruit flies as models because acids and amino acid arrangements. A |
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| 39:54 | of times they're concerned across species, we could have ah home ology or |
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| 40:03 | replication off the same sequence on potassium with other animals like fruit flies, |
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| 40:12 | our potassium channels are 80% homologous to fruit fly channel so we can derive |
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| 40:23 | start thinking that maybe some of the amino acid sequences that we see in |
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| 40:28 | fruit fly channels if we find them species and higher species like humans, |
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| 40:33 | also going to be very important for potassium channel function. Why is this |
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| 40:39 | ? This is drug development Now. identified important amino acids important structures in |
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| 40:45 | channel by using electrophysiology, recording the , the current flow through the channel |
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| 40:54 | using the side directed Mewtwo Genesis. using the mutate and flies, he |
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| 41:00 | able to start solving the structure of channel. So for medical doctor, |
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| 41:06 | transformed himself into an experimental neuroscientists in to solve the structure of this |
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| 41:12 | This is his quest. This is he's after, and he's smiling in |
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| 41:17 | picture because he says, that's not for me. I want to see |
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| 41:22 | channel. I solved the structure. all of this electric physiological recordings I |
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| 41:27 | to see the channel. We discuss electron microscopes can visualize 0.1 nanometer in |
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| 41:35 | so they can visualize synapses, and can show you the collection off neural |
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| 41:41 | vesicles on one side of the membrane Recep turd Boston attic densities on the |
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| 41:47 | Athletic side of the membrane. But cannot show you the structure of an |
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| 41:53 | channel, So Roderick MacKinnon says, gonna do this new thing. This |
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| 42:00 | technique mints come out recently. It's X ray crystallography. So, needless |
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| 42:07 | say, his spears, probably looking him, are saying okay, successful |
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| 42:15 | D career huge accomplishments and solving the off the potassium channel. You're going |
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| 42:23 | do what? X ray crystallography. know how complicated this is. You |
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| 42:29 | how many people can can do it effectively. It's not like a very |
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| 42:34 | thing to do. You're committing, and a suicide, a academic and |
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| 42:40 | suicide now, and he says, you, I'm gonna do it. |
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| 42:47 | just like he builds slowly his first in the solution of the structure of |
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| 42:52 | channel, he's on a quest not to solve, but now to confirm |
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| 42:58 | to look at the channel to see the channel actually looks like to visualize |
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| 43:05 | . X ray crystallography is a technique you capture protein in this case, |
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| 43:11 | protein channel in the crystal. And you capture that bird in channel in |
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| 43:17 | crystal, you know, pass X lights through that crystal, and you |
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| 43:22 | the diffraction properties and depending of light for that crystal when it has nothing |
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| 43:29 | . But now you place a protein trap a protein inside that crystal and |
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| 43:34 | of the light, is going to different. And that's what allows you |
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| 43:38 | visualize the actual Prodi, um, how that protein looks like in three |
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| 43:46 | and whether your model your calculated model completely with now observed structure off this |
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| 43:56 | channel. So never stop is you pursuing your careers for undergraduate students and |
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| 44:04 | for graduate students. Never stop and from these lessons that we're discussing in |
|
| 44:12 | . The Monica how did not agree Golgi with his mentor about neuron |
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| 44:20 | but they both received the Nobel He was so forward thinking, or |
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| 44:26 | Hall, that he's influenced neuroscience for next 100 years, is one of |
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| 44:31 | master thinkers, the fathers of but without Golgi stain in his invention |
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| 44:40 | would not have been possible. His was to answer the questions about what |
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| 44:46 | these circuits look like? How they to convey the beauty of these neuronal |
|
| 44:53 | thio to the whole world, not to the scientists, but how many |
|
| 45:00 | look at these images off Ramon Ika drawings and think about brain and brain |
|
| 45:07 | without having formally or science training. it's very interesting for them, and |
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| 45:12 | reveals the image, the picture of your brain looks like on the |
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| 45:18 | Now Roderick MacKinnon wants to reveal has structure of this potassium channel. What |
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| 45:25 | it look like? Not only what functions, whether the important parts of |
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| 45:31 | side directed me to Genesis the solved , but the observe structure. How |
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| 45:38 | that actually compare to what exists out in nature? It's a great |
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| 45:45 | We're solving potassium channel structure, but and in general, for pursuing a |
|
| 45:52 | . Pursuing a solution, pursuing something life, not pursuing a degree. |
|
| 46:01 | a degree is great, but you a degree for a reason. You're |
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| 46:06 | of pursuing a degree so that you check off in your books. |
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| 46:11 | masters, PhD g D. You're it for a reason for that quest |
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| 46:20 | solve something, to find the And so the knowledge that you use |
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| 46:26 | this course another courses you should really toe to some solutions that in some |
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| 46:32 | are urgently needed in the current world . Before I go into the action |
|
| 46:40 | and want to mention one thing is today we will stop around 12 35 |
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| 46:49 | about 15 minutes, and that will holding ah, session with the graduate |
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| 46:57 | on their extracurricular assignment that counts toward grade through a different zoom link. |
|
| 47:04 | , uh, that's just a preemption . Now, before we go talk |
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| 47:11 | action potential, I want to tell the following thing. I want Teoh |
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| 47:16 | to you about the fact that membranes be represented as electrical circuits and that |
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| 47:22 | are very important features of the circuit that you need to have this understanding |
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| 47:27 | order to understand their science. You to understand some physics and north |
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| 47:32 | and so you have to understand these that each one of these Ionic channels |
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| 47:37 | be represented as a resistor or is conductor a variable resistor R variable conductor |
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| 47:44 | there is a symbol for the resistance the symbol for the resistor is shown |
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| 47:49 | are okay and each one of these also has its own battery or |
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| 47:58 | And this is represented by this symbol and minus symbol for battery or for |
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| 48:08 | . And each one of the ions you can see sodium ion potassium ions |
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| 48:12 | on the each are variable resistance or and they each have a battery. |
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| 48:18 | drives of science across one from outside inside her inside to outside. So |
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| 48:26 | we mentioned last time the driving force is the driving force Now? You |
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| 48:31 | be able to understand what the driving is Driving force here is arms law |
|
| 48:38 | equals I are written in the driving Electrochemical driving force is the difference between |
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| 48:44 | , which is the member and potential then equilibrium potential for an ion, |
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| 48:49 | this case for potassium ions. So bigger is the difference between equilibrium potential |
|
| 48:55 | the membrane potential. The greater is driving force for that specific ir. |
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| 49:03 | , so if we're calculating, if calculating some of the conduct Ince's for |
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| 49:11 | ions. What we have toe know the current I for potassium depends on |
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| 49:19 | conductors through potassium channels, which is okay or gamma K times the difference |
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| 49:28 | driving force V M minus c. . That's how you will calculate the |
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| 49:33 | . The amount of current will depend on the size off the driving force |
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| 49:39 | the conductor's off the potassium channel and total conductors of potassium total potassium conductors |
|
| 49:46 | depend on the number and K and number of channels and individual conductors through |
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| 49:52 | individual channel. Okay, so this how you represent members and circuits, |
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| 49:59 | this is how you think about the . It's really the current amount of |
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| 50:04 | of that ion will really depend on difference between the voltage and the equilibrium |
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| 50:10 | for that I am. And this M minus G K is the driving |
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| 50:15 | . The greater is the difference between and equilibrium potential, the voltage of |
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| 50:20 | membrane and equilibrium potential for a given . The greater is the driving force |
|
| 50:26 | that island. That means that I is going to be driven mawr across |
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| 50:31 | membrane either from the outside insider inside the outside. Another very important feature |
|
| 50:38 | the plasma membrane is a capacitance So we've been discussing resistance. But |
|
| 50:43 | also have to discuss the capacitance on the left top a one. What |
|
| 50:49 | shows is a diagram off current flows on five, Nana am Paris. |
|
| 50:56 | a change in current is you injecting current and you can see that this |
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| 51:00 | all square wave like steps. And is what you would see if there |
|
| 51:05 | no resistance and there was no capacitance plasma membranes. This is what you |
|
| 51:10 | see in a one and actual electrical . If you didn't an electorate in |
|
| 51:14 | solution without penetrating the cell. You positive card and you pass negative card |
|
| 51:21 | you would see the square way step increases. But the cells they have |
|
| 51:26 | a bit of capacitance. And in two you have on the Y Axis |
|
| 51:32 | in potential and on the X axis . And what it shows is that |
|
| 51:37 | you stimulate an increasingly more so either de polarizing, the seller, hyper |
|
| 51:43 | , the solid takes time for the to reach its maximal current. |
|
| 51:48 | this arrows indicate a slow rise, it's not so slow. Just a |
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| 51:53 | milliseconds, which is charging off the membrane. There's some resistance. There |
|
| 51:58 | a capacitance that accounts with this slow on when you release the stimulus |
|
| 52:05 | it slowly within milliseconds, actually, pretty fast rebuilds to the normal |
|
| 52:13 | So let's look at the resistance. he equals. Are are the inside |
|
| 52:17 | of the cell Depends on the resting density. What does that mean? |
|
| 52:22 | many channels are in the plasma You can have a plasma member, |
|
| 52:27 | it has 1000 channels to 10 The one that has 1000 channels will |
|
| 52:33 | formidable. That means it will have resistance will allow for things to pass |
|
| 52:38 | through 1000 channels versus 10 channels. depends on the member and surface |
|
| 52:45 | The smaller the neurons, the higher resistance input resistance. The input resistance |
|
| 52:51 | in or inside the cell. Resistance the inside of the cell depends on |
|
| 52:57 | in resistance R M over four by square where a stands for the radios |
|
| 53:05 | a spherical neuron, so the larger radius Uh huh. The larger the |
|
| 53:15 | , the smaller the resistance, the the a, the smaller the input |
|
| 53:23 | in this equation for capacitance and in . Why is it important? Because |
|
| 53:30 | way that you could represent the change voltage V equals IR is by representing |
|
| 53:36 | change in Q, which is charged capacities. How much charges changing over |
|
| 53:44 | capacities to change vaulted charge has to moved or removed from capacitor. So |
|
| 53:51 | look at this equation here below. the capacitance input, capacitors is equal |
|
| 54:00 | membrane capacitance times four Pi Alfa Square opposed to resistance where it's over. |
|
| 54:12 | Pi Alfa a square in this is four pi a square times. |
|
| 54:19 | the larger the membrane area, the the capacitance. And so these are |
|
| 54:26 | good features of the capacitor, and is the symbol for the capacitor here |
|
| 54:33 | its stores positive charge on one side negative charge. On that aside, |
|
| 54:39 | good features of the capacitor are that supposed to have a lot of surface |
|
| 54:45 | seek. Ambassador should store a lot charge. And if you have a |
|
| 54:50 | of dendritic ramifications, pardon me or protrusions. You have a lot of |
|
| 54:59 | area and it expires. You have lot of surface area. Capacitance is |
|
| 55:02 | be greater. Okay. The capacitor supposed to be close to each other |
|
| 55:10 | plasma membrane. A capacitor is separated by two molecules. Phosphor lipid, |
|
| 55:15 | layer. The passenger should charge up and discharge fast. That is the |
|
| 55:22 | also. So this capacitor in the membrane and the cell charges up within |
|
| 55:27 | few milliseconds and discharges within a few seconds has a lot of surface area |
|
| 55:32 | store a lot of charge on the top and be. What is shown |
|
| 55:37 | what we refer to as voltage current or ivy plot, where you have |
|
| 55:43 | changes and current changes. So if are deep polarizing the cell, if |
|
| 55:49 | putting positive current inside the cell or you're putting negative current inside the |
|
| 55:53 | this plot is a linear plot or ivy plot, voltage current plot or |
|
| 56:02 | lot of times it's referred to as IQ from arms law Ahmed plot. |
|
| 56:07 | means for equal amount off one Nana positive you change the member and potential |
|
| 56:13 | 10 million balls and by one Nana , injecting negative currently changes by 10 |
|
| 56:19 | volts, hyper polarizing it into more direction. This would be what we |
|
| 56:25 | an Ivey core for channel, but reality a lot of the channels will |
|
| 56:30 | have these linear curves, and we'll it when we come back in the |
|
| 56:34 | lecture, your left the slide so you can draw your own number in |
|
| 56:39 | circuit. But it's already being drawn so disgusted that at the top you |
|
| 56:44 | see on the top right that each has a conductor. Each one of |
|
| 56:49 | ion sodium potassium chloride has a It was a passive flock circuit on |
|
| 56:54 | bottom. You have a more realistic because you have the C M, |
|
| 57:00 | stands for capacitance of the membrane and store. Which of the charge positive |
|
| 57:05 | negative you have in a K which is flowing sodium and potassium against |
|
| 57:11 | concentration. Grady, Um, and have, of course, the conductors |
|
| 57:16 | ions sodium coming from outside to inside protection going from inside to outside. |
|
| 57:22 | this is the active circuit representing the circuit here of the bottom, which |
|
| 57:28 | the capacity. It's very important thing , capacitance. So what we've learned |
|
| 57:38 | and we've learned a lot is we , first of all, that we |
|
| 57:43 | no Ernst equation for calculating equilibrium Proton that we want. If we want |
|
| 57:49 | calculate number and potential, we used . We have to use Goldman |
|
| 57:53 | It's also referred to as Goldman, and Cats. Cats equation a steady |
|
| 57:58 | equation, and we have to incorporate term of permeability. You can pull |
|
| 58:06 | potassium, sodium and chloride and see the membrane potential changes. And of |
|
| 58:13 | , it will, because the top here PK ratio permeability to PN A |
|
| 58:18 | sodium to PCL chloride indicates that oppressed 20 times 40 times more. Permeability |
|
| 58:28 | has 1.0 permeability over 0.4 for sodium addressed cell membrane and these permeability ratios |
|
| 58:36 | also slightly different in different textbooks. the permeability ratio is the highest of |
|
| 58:43 | oppressed, and so if you plug the known concentrations of potassium, sodium |
|
| 58:48 | and the permeability ratios for potassium sodium , you will derive the membrane potential |
|
| 58:55 | . However, what happens during action that we will discuss over the next |
|
| 59:01 | lectures, but the action potential. actually switch the permeability, and the |
|
| 59:08 | becomes mostly permeable to sodium. It's times more permissible to sodium now than |
|
| 59:15 | potassium. This is during the rising of the action potential. So now |
|
| 59:20 | you were to take the same concentrations change the permeability ratios for these |
|
| 59:26 | you will get a completely different member potential value, which could be more |
|
| 59:32 | of the polarized member and potential, a member and potential that is starting |
|
| 59:37 | generate an action potential or during the of the action potential. All |
|
| 59:43 | so it's a good exercise if you to plug in this permeability ratios and |
|
| 59:48 | known concentrations for potassium, sodium and ions and ran through this calculation off |
|
| 59:55 | membrane potential because you will see what big change it actually causes in the |
|
| 60:02 | potential when you change the permeability and can see how drastically the permeability changes |
|
| 60:08 | sodium, address that 0.4 and during firing off the action potential 20 Hugh |
|
| 60:17 | and permeability for the science. huge change in the membrane potential. |
|
| 60:22 | the next two lectures I'm almost finished today with the undergraduate students. For |
|
| 60:27 | next two lectures, we will be all of the dynamics about action potential |
|
| 60:33 | will gnome or than you wanted to about action potential. You'll know what |
|
| 60:39 | during the rising phase of the action . There is influx of sodium. |
|
| 60:44 | is an overshoot, which is over 100 0 Mila vault value. And |
|
| 60:50 | is the sodium flexing inside the cell to drive the Celtics equilibrium potential, |
|
| 60:56 | is positive 55 million volts. And is a very strong driving force here |
|
| 61:02 | sodium. And then there is a e flux potassium, leaving the cell |
|
| 61:08 | balance the membrane potential. Because now is much stronger driving force for |
|
| 61:14 | Potassium tries to drive it equilibrium potential potassium, the member and potential |
|
| 61:20 | which is minus 80 million loss for potential for potassium and therefore generating this |
|
| 61:27 | and the re balancing of the membrane back. The resting membrane potential is |
|
| 61:32 | in Florence, generated by the pumps the ATP A sperm. So when |
|
| 61:41 | come back next lecture We will also about both clamp. We will talk |
|
| 61:46 | Hodgkin and Huxley. We'll talk about , scientists that recorded action potentials. |
|
| 61:56 | can view a movie that I posted the a lecture documents will review next |
|
| 62:04 | to on the initial work with Squid acts on um and it's gonna be |
|
| 62:11 | interesting next couple of lectures discussing ah about measuring currents and understanding the action |
|
| 62:19 | and how action potential is generated and . So at this point, I'm |
|
| 62:25 | end our undergraduate lecture portion and for of the graduate students, will log |
|
| 62:33 | to the separate link, and we'll start a separate recording from that zoom |
|
| 62:40 | . So please all of the students this, like just savior questions for |
|
| 62:46 | . We will repeat and overview some this material on Wednesday, and you |
|
| 62:51 | save them for after Wednesday lecture if mawr. Serious questions or if you'd |
|
| 62:57 | to review anything else, a Z I'm sorry on Thursday. Keep confusing |
|
| 63:03 | with Wednesday on Thursday. Please ask questions on Thursday after the class of |
|
| 63:09 | onda uh, wishing you a great , and we will connect back with |
|
| 63:15 | on Thursday and now will connect with students in a different |
|
