| 00:00 | This is electric seven off neuroscience, we were talking about the resting membrane |
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| 00:08 | . We were talking about some physics , electrophysiology terms and is a reminder |
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| 00:14 | is an image off. What a equivalent circuit representing membrane looks like. |
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| 00:22 | so you should be able thio. some of the most important aspects of |
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| 00:27 | circuits, and also the symbols within circuits. As you remember, we |
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| 00:32 | three of these symbols and we said our or the same as G for |
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| 00:38 | because if you remember conduct, Ince's inverse of resistance so you can call |
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| 00:45 | resistors variable resistors for each channel for iron, or you can call them |
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| 00:53 | conductors. Then you have your your battery, which is your electro |
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| 00:58 | force, and then you have the and we talked about the fact that |
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| 01:03 | plasma membrane is a good capacitor holding lot of charge. The two plates |
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| 01:07 | the capacitor close together and the charge in discharge of this capacitor happens fairly |
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| 01:13 | in neurons over just, uh, you know, seconds of time. |
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| 01:20 | in these circuits, what you're seeing you're seeing all of these elements incorporated |
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| 01:25 | capacitance of the membrane. You also seeing in the sack the circuit, |
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| 01:30 | flocks of sodium and potassium, which against the concentration Grady int, based |
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| 01:35 | the consumption of a teepee and cellular and as well as you can see |
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| 01:40 | circuit for each individual channel on its , on flowing through that channel with |
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| 01:45 | respective batteries and their respect. variable conductors. Um, so we |
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| 01:52 | about the capacitor, and there's one that we also talked about. The |
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| 01:58 | that the membrane addressed it stores a of charge, but it is also |
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| 02:04 | charge. So it is leaking and it is most permissible to |
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| 02:09 | so address to sell, numbering its permissible to potassium. But we discussed |
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| 02:14 | fact that that permeability ratio potassium to chloride changes when this all gets the |
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| 02:22 | and initiates the firing of the action . And again, we reviewed two |
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| 02:28 | formulas. Lost lecture was an Ernst , which allows us to calculate equilibrium |
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| 02:34 | for each ion. And in this , where we're looking at is we're |
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| 02:39 | at Goldman, Hodgkin and Cats which incorporates the same terms, are |
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| 02:45 | natural log of concentrations outside vs Inside the most important thing that it also |
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| 02:56 | the premier ability term. And if you run through these calculations just |
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| 03:01 | changing the permeability p value for sodium A or P Value K, you |
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| 03:07 | change the overall number and potential Now we started discussing the action potential |
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| 03:16 | lecture, and we actually watched a about the squid giant Exxon. And |
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| 03:25 | movie is in your class supporting lecture . And what we we saw in |
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| 03:32 | movie is how the pioneering work was and how we understood with concentrations of |
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| 03:41 | are present inside the cells versus outside cells. Because we could. Scientists |
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| 03:47 | isolate these large giants could access ions millimeter in diameter and squeeze out the |
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| 03:55 | cytoplasmic solution out of these acts Sants sells to determine the exact concentration of |
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| 04:02 | different ions. And so we started about this arresting potential for for one |
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| 04:08 | two lectures. Now we're gonna dedicate lectures to the action potential. We |
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| 04:14 | already that you have rising face of actual potential that you have the overshoot |
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| 04:19 | it crosses the zero Millersville slime. means the inside of the membrane becomes |
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| 04:25 | charged compared to the outside, off membrane, momentarily over the one to |
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| 04:32 | . And then you have the falling off the action potential, followed by |
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| 04:37 | undershoot, which is the part of action potential where the membrane potential VM |
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| 04:44 | driven closer toward equilibrium potential for potassium is there for lower orm or high |
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| 04:51 | hyper polarized than the actual resting member potential. So to record this activity |
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| 05:00 | to understand what is happening, we several important aspects of science to |
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| 05:07 | We needed both. We needed a and we needed pharmacology only using electrophysiology |
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| 05:15 | pharmacology. We were definitively able to what channels are responsible for what part |
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| 05:23 | the action potential. In large what we know about the action potential |
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| 05:29 | determined and also modeled by Hodgkin, and modeled by Hodgkin and Huxley. |
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| 05:38 | . They received Nobel Prize in physiology medicine for their work on the action |
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| 05:44 | . So if you recall in the Professor Young, he was, |
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| 05:49 | stimulating on duh, he was able cause a contraction of the mantle by |
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| 05:58 | these long accents or squid giant But, uh, only after World |
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| 06:06 | Two there was strong and good enough equipment that was able to pick up |
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| 06:13 | very fast changing, uh, fluctuations the plasma membrane potential or the action |
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| 06:21 | . And to do that, you this particular technique, which is called |
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| 06:26 | clam and Voltage Clamp technique these days a lot more advanced that it was |
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| 06:32 | in this particular diagram. But this diagram will help you understand the rudimentary |
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| 06:40 | and the electron ICS behind how somebody able to achieve those recordings. And |
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| 06:46 | saw some of it in the last , where we saw where Squidgy and |
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| 06:51 | shown here, sitting in a Petri , squidgy and Axiron would be |
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| 06:57 | You would insert an electrode inside the squid John Axiron. So you have |
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| 07:04 | measurement inside the action inside the cell the side of Woz mc side, |
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| 07:10 | that electrode, one internal electrode measures potential, and that electrode is connected |
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| 07:18 | the voltage clamp amplifier, right. electrode is also measuring the member and |
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| 07:27 | in green and silver inserted inside the with reference to the green played outside |
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| 07:37 | the dish, which is the reference or the ground electrode. The reference |
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| 07:42 | says that the outside solution is equal . Therefore, the amplifier here on |
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| 07:50 | left and green is measuring the difference the outside solution and the electorate. |
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| 07:57 | the Axiron, this measurement of voltage measuring VM you're measuring voltage, and |
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| 08:04 | volts is communicated to the voltage clamp , the voltage client amplifier. What |
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| 08:13 | does, it compares membrane potential to desired command potential. And what is |
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| 08:18 | command potential? So, until you a voltage clamp, there was no |
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| 08:24 | of really, uh, tell for cell to stay in a particular command |
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| 08:32 | or commands potential. It's also referred as a holding potential. You couldn't |
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| 08:37 | the cell that I would like for electoral to pass enough current for you |
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| 08:41 | stay at minus 70 would record these potentials or broader action potentials cardiac action |
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| 08:50 | . But you wouldn't really have a to clamp them down and to command |
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| 08:55 | to stay at a certain potential. so the command potential is actually sent |
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| 09:02 | the experimenter. I'm commanding for this on to stay at minus 50 million |
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| 09:08 | or minus 20 million volts or minus million balls. I want to control |
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| 09:15 | current flow, and I want to the polarization charge across this Axiron and |
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| 09:21 | neuron for experimental purposes. Now, the VM, the numbering potential, |
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| 09:27 | different from the command potential. So say I'm telling you to be minus |
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| 09:33 | . Hold this. At minus 70 clamp amplifier injects current into the acts |
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| 09:38 | through the second electrodes. So this the injection electro shown here in |
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| 09:44 | and that injection elected is going into other side of the Exxon, and |
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| 09:50 | one is injecting current. Okay, first one in green on the left |
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| 09:55 | measuring current, and the second one is shown in the orange and started |
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| 10:00 | the accent is injecting the car. I have commanded, and this is |
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| 10:06 | allows me to command to keep a potential to stay at minus 70. |
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| 10:12 | if my green electorate says no, potential change to minus 60 then it |
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| 10:19 | communicated. The voltage clamp on voltage says Okay, I have to |
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| 10:23 | Mork are on to make it back minus 70. But all of the |
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| 10:29 | , the current flowing back into the and that's across the membrane can be |
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| 10:35 | here right through our measurements. And measurement that outputs the current and that |
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| 10:42 | is equal to any changes that is from the command potential is the actual |
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| 10:48 | off ions and synaptic and ionic Ince's across neuron is and in this |
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| 10:55 | , across, uh, squeeze John , so clamping of the membrane or |
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| 11:04 | a certain membrane potential on. Remember fact that if we wanted to determine |
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| 11:12 | a given ion flows through a channel a given potential, now that we |
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| 11:18 | this calculations for equilibrium potentials based on concentration now, we want to experimentally |
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| 11:26 | that. And the only way we experimentally confirmed that is if we're capable |
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| 11:31 | using this voltage plan technique if we're of clamping a potential at a certain |
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| 11:38 | . So if we said that sodium a positive 55 they should not be |
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| 11:43 | off sodium ions and member and potential positive 55. It's essentially this. |
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| 11:52 | this voltage client is essentially a negative system where the difference between the command |
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| 12:00 | and the membrane potential off the seller the ax on is equal the V |
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| 12:08 | . This output that gets put out constantly keep that potentially the desired |
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| 12:14 | So once essentially, you have deflection the given membrane. Potential voltage clamp |
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| 12:21 | the membrane potential to that specific plant by injecting mawr positive or more negative |
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| 12:29 | very much like a thermostat. If temperature goes up higher, they seek |
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| 12:37 | , so you just set the Sure low and the heat increases, |
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| 12:42 | then you will be pulling in cold . But in the wintertime, if |
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| 12:48 | set the heat of certain temperature and temperature drops, then you will be |
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| 12:53 | in more warm air through your This is also negative feedback system, |
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| 12:58 | this voltage clamp originally was constructed using electrodes in the reference electrode. Modern |
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| 13:06 | clamp has a very complex and very circuit, and you just require a |
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| 13:13 | electrode so you wouldn't need this, , gamut of two electors and pre |
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| 13:20 | and current measurement and additional equipment that needed. Originally, you can use |
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| 13:27 | controlled amplifiers. You can set the clamp or the command potential that the |
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| 13:34 | value using the computers. And you be recording and injecting because the electrode |
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| 13:40 | rates are so fast that you could recording and injecting currents with a single |
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| 13:45 | across plasma membrane, using in particular sell recordings that we discussed earlier on |
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| 13:54 | the class. Okay, And when say intracellular electorate, that's what I |
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| 13:58 | by wholesale, Uh, voltage Because if you do sharp electrode for |
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| 14:06 | students and you know the difference, sharp electrode does not. It's not |
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| 14:11 | very good way off clamping a voltage class. Remember it. Okay, |
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| 14:17 | voltage clamp was exactly needed to confirm are the currents where they reverse? |
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| 14:23 | are the current dynamics that are responsible creating the action potential? Once we |
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| 14:29 | the concentrations of the islands, we the liberal potentials. Then we had |
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| 14:34 | Goldman equation. We knew the member potential and D m, and that |
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| 14:39 | to the experimentally recorded member and Now we've developed fast enough electron ICS |
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| 14:46 | scientists and science developed fast enough electron and military for the recording of the |
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| 14:53 | action potentials. The voltage clamp circuits developed in Hodgkin and Huxley, along |
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| 14:59 | a couple of other scientists, use voltage clown to do the following. |
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| 15:05 | say they in the top graph here orange with red lines, which you |
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| 15:12 | on the left eye's membrane potential millet . Okay. And the second window |
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| 15:20 | , which is in blue and is membrane current. So it's showing |
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| 15:24 | the flow off the current. and by definition, the inward current |
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| 15:33 | positive car going inside is actually going cause a negative deflection. And in |
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| 15:39 | case it is measured as negative million percent to me to square. But |
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| 15:45 | reason for it is because essentially you think of it as electrode is losing |
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| 15:50 | positive charge or in the current. this is an inward current, and |
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| 15:58 | you d polarize the sell this red from minus 65 resting membrane potential to |
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| 16:04 | minus 26. You see it and increase in the inward current that is |
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| 16:10 | , and then after 23 milliseconds, see a line shifting into the blue |
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| 16:16 | , which represents an outward car. if you dip polarize the member and |
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| 16:22 | from minus 65 to 0 Millet The inward current gets much stronger in |
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| 16:28 | inward current A sodium. Okay, is sodium ions going inside. And |
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| 16:35 | outward current, this potassium ions going inside toe outside. Okay, so |
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| 16:45 | order for us to understand this I've prepared a separate slide that will |
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| 16:53 | for you, um, later, or tomorrow. But in the |
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| 16:59 | I would like for you to actually a drawing of the slide that I'm |
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| 17:04 | to show you. So let me this this is the slide that I |
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| 17:09 | that shows very important things that we already discussed in this course and that |
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| 17:16 | be filling out the slide and drawing it. And so it's not gonna |
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| 17:20 | perfect. And I want you to the same thing. I want you |
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| 17:23 | dedicate one blank piece of paper to this drawing whatever orientation you wanna produce |
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| 17:33 | A Okay, So let's go old here. Unless you wanna open the |
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| 17:41 | point and do this. But if taking notes as you're listening to the |
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| 17:47 | , which I hope you do because should be taking notes about the neuro |
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| 17:52 | neurological disorders that we're discussing throughout this and adding that information throughout the course |
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| 17:59 | well, but let's start here. we, uh, determine the fact |
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| 18:05 | we know how to calculate Acqua Librium so we can calculate acqua Librium potential |
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| 18:10 | potassium, which is about minus A minus 19 minus 100. So |
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| 18:15 | will call it minus 90. And fluctuation is dependent on slide variations and |
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| 18:21 | ingredients and different cellular environments in different parts. Gloria, it reverses about |
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| 18:29 | 70 million. Laws resting number in is actually very close toe chloride. |
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| 18:38 | , number of potential Andi it but minus 65 minus 70 I'm gonna |
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| 18:51 | it minus 65 because that's what is to be easier for us to understand |
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| 18:57 | that the chloride reversal potential is actually little bit lower on the scale than |
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| 19:03 | resting membrane potential. But the two very close, but resting membrane potential |
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| 19:10 | more than 65 million volts. Potential threshold is about minus 45 million |
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| 19:20 | . Okay, that means that once have this diagram here, this is |
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| 19:26 | membrane potential in the membrane potential is a random walk. Okay? And |
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| 19:32 | really represents the movement. The inputs positive inputs come in and the Sal |
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| 19:38 | polarize us, and then it hyper this account. And this is what |
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| 19:43 | would typically observe in this and the the recordings of the cells that they're |
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| 19:51 | generating action potentials. And so the deflections would represents deep polarization. Anything |
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| 20:02 | upward represents deep polarization. All Okay. Which equals excited story and |
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| 20:18 | or synopsis being activated. Okay, anything that d polarizes the cell in |
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| 20:28 | direction means excited Terry Impulses and and on their trying thio excite this |
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| 20:40 | On the other hand, anything that the member in potential this direction, |
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| 20:54 | hyper polarization. Okay, which is . Don't put on synopsis. |
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| 21:12 | so this is related Thio these two , but we're not seeing an action |
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| 21:18 | here. Why? Because for us see and action potential, we actually |
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| 21:25 | to reach the threshold for the action . Right? And that value, |
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| 21:33 | we indicated, is about minus 45 vaults. So is the number of |
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| 21:41 | where to reach that value? huh? Then you would generate an |
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| 21:48 | potential. All right, so now gonna erase this particular diagram. You |
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| 21:56 | store it underneath because, well, can draw on top too. All |
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| 22:02 | race. And I'll just leave these for us toe. Remember, |
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| 22:18 | if if the cell is now excited this is about resting member and potential |
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| 22:28 | it's getting mawr and Mawr positive And if this enough excited, very |
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| 22:37 | dip polarized the number of potential to 45 million balls, you then generate |
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| 22:45 | all or non event. And this are non event again. Excuse. |
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| 22:52 | drawing is in the form off the potential. I think I could do |
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| 23:03 | little better. So here we They did it, Did it? |
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| 23:09 | , I got an inhibitory. but excited to him. But mawr |
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| 23:13 | Torrey. Um, but action Oh, that doesn't look very good |
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| 23:24 | Well, now you'll learn how to an actual potential. So you get |
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| 23:27 | of the excited Terry input, and generate a very fast, deep polarization |
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| 23:35 | by re polarization and followed by the and followed back to the resting membrane |
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| 23:45 | . If it crosses again. This this action potential will repeat again. |
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| 23:51 | ? And so the Y axis is and Miller Volts and acts accesses in |
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| 23:59 | and milliseconds. We're we're talking about time frame being approximately to milliseconds. |
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| 24:13 | , so this this this bar is milliseconds CSR chat Is the undershoot the |
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| 24:29 | polarization? Yes. So let's discuss happening here. Let's discuss another important |
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| 24:42 | that we discussed last time. What V m minus? B ion, |
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| 24:48 | you remember that That equals driving Uh huh. So interesting, Member |
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| 24:59 | potential addressing number of potential, which on has the highest driving force based |
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| 25:10 | this calculation, the difference between membrane addressed and the EI on which iron |
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| 25:18 | the greatest driving for us. No . I can kind of see where |
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| 25:31 | biggest difference between resting member and potential equilibrium potential forgiven Ion is Nobody else |
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| 25:39 | . That's not good. So if look here, for example, from |
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| 25:44 | all the way down to the resting and potential, that looks like the |
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| 25:49 | distance, right? So calcium technical nature has the highest driving force. |
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| 25:58 | Thio, this calculation here but we that addressing number in potential the membrane |
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| 26:06 | most permissible. To which I on potassium ion. Maybe there's some |
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| 26:16 | Yeah, calcium. Keep ones. , you guess to You have to |
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| 26:23 | one. If you pick one, have to see you have to sit |
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| 26:27 | pick one side. Right? Calcium . Okay, so calcium has the |
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| 26:33 | driving force, right? Which other has a pretty high driving force. |
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| 26:40 | , if this is if this is driving force which which other ion? |
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| 26:45 | a pretty high driving force, it's ion that has pretty high driving |
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| 26:51 | Oh, remember that the driving forces equilibrium of the eye on the difference |
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| 26:58 | equilibrium potential between sodium equilibrium, potential time around and resting member in |
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| 27:06 | Right, So these these ions have strongest driving force. But we know |
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| 27:13 | in neuroscience, every rule has an . And what it means is that |
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| 27:21 | that the fact that calcium and sodium the highest driving forces interesting number in |
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| 27:30 | , the dynamics of the member, are such that it has potassium channels |
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| 27:35 | potassium channels, air leaking potassium from of the south of the outside and |
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| 27:41 | cell addresses most formidable to potassium, like we showed in the previous |
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| 27:47 | Once you have deep polarization and you the stretch hold, you have all |
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| 27:53 | non event okay, action potential is or none. That means that the |
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| 28:01 | and potential cannot come back from minus minus 43. Back just like |
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| 28:07 | it actually has to go through the of the action potential. That's what |
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| 28:11 | say that the action potential or spike lot of times can be likened to |
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| 28:16 | code 001 and this sub threshold we anything below the action potential thresholds a |
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| 28:27 | . Voltage fluctuations are almost like analog coding good. But once it reaches |
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| 28:36 | threshold for the action potential, then have influx off sodium very fast and |
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| 28:47 | strong. Influx off sodium ions from to the inside of the South. |
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| 28:57 | this is sodium and flocks. And sodium influxes doing sodium is actually going |
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| 29:15 | a positive feedback cycle. Okay, does that mean? That means that |
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| 29:25 | deep polarization, deep polarization leads to sodium more deep polarization leads to more |
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| 29:38 | more deep polarization leads to more Now you can insert little arrows in |
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| 29:46 | sodium, so Liam people ization. , so, um, deep polarization |
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| 30:04 | so on. So it's a positive cycle, and the reason why you |
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| 30:10 | this positive feedback cycle is Thio keep driving the member in potential to the |
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| 30:19 | potential for sodium. This is the , the overshoot when it goes above |
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| 30:25 | Mila balls. And what sodium driving because it's large driving force is trying |
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| 30:31 | do, is trying to drive the and the whole number in potential. |
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| 30:37 | a deliberate potential value, which is minus positive. 55 mil evolves shown |
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| 30:46 | . So it's trying to reach the potential value for sodium. But it |
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| 30:53 | not. Why doesn't it do And you'll understand why doesn't do |
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| 30:58 | There's to reason why doesn't do and one of them is becoming |
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| 31:04 | Here is the Mawr de polarized VM Mawr D polarized VM becomes. The |
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| 31:12 | they polarized it becomes, the less the driving force sodium has, the |
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| 31:22 | it comes to the equilibrium potential, less of the driving force it starts |
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| 31:28 | . But the further away. The is now from potassium, the equilibrium |
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| 31:38 | and the driving force for potassium And what you have now is you |
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| 31:46 | during the falling phase is you have e flux. That means positively charged |
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| 32:01 | ions. So leaving the cell, leaving the cell. And they |
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| 32:08 | at the peak of the action potential driving force. And they're trying to |
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| 32:14 | the whole number in potential close to reversal potential or equilibrium potential from |
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| 32:26 | Um, so it's trying thio hyper this overshoot, which goes below resting |
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| 32:35 | potential. Mhm, and it's trying drive it towards equilibrium potential for |
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| 32:49 | There's another reason why sodium does not its equilibrium potential despite its positive feedback |
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| 32:57 | . And that's the actual channel dynamics I hope we discussed the that this |
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| 33:02 | next lecture. So you have sodium . You have potassium e flux, |
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| 33:10 | then you have the re polarization and slow rebuilding of the potential back thio |
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| 33:19 | resting membrane potential value. This is thio a deep n A. Okay |
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| 33:33 | . Yeah, all right. One time. So sodium has great driving |
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| 33:45 | addressed sodium influxes inside the south. tries to reach equilibrium potential for |
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| 33:53 | It goes through the positive feedback but the driving force reduces. There's |
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| 33:58 | forces of place, such as channel . There's also an increase for potassium |
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| 34:03 | force, which then drives potassium ions inside of the cell to the |
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| 34:09 | hyper polarizing. The so below the membrane potential are slowly rebuilding into the |
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| 34:14 | number of potential value, and you repeat the whole cycle again. And |
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| 34:20 | frequency of the firing depends. That a good question. Last lecture. |
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| 34:24 | frequency of the firing very much depends what we call the relative and absolute |
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| 34:34 | period. So here I'm just overlapping second action potential to show that during |
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| 34:43 | the actual action potential during the rising and deep polarization phase and re polarization |
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| 34:54 | of the action potential, uh, to imagine the best they can. |
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| 35:00 | almost there didn't do such a bad after all. Something like that's |
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| 35:09 | So during this period, you are the absolute refractory period, this red |
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| 35:16 | that means you cannot de polarize the . You cannot does. It doesn't |
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| 35:22 | how many exciting tres synapses start citing cell. The action potential is not |
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| 35:28 | to get produced. There has to a certain amount of re polarization that |
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| 35:34 | when the cell returns very close to action. Potential threshold resting member and |
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| 35:43 | threshold value is when you enter this factory period which is shown here in |
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| 35:50 | . During this period, you can another action potential. That means that |
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| 35:56 | sellers repeated receiving strong enough input or lot of the exciting Torrey inputs. |
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| 36:02 | will be another action potential that can produced during the relative refractory period and |
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| 36:10 | further away in time you are from peak of the action potential and MAWR |
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| 36:18 | polarized. You are, the easier can generate the action potential, |
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| 36:27 | So these air relative refractory period's shown blue and the absolute refractory period's shown |
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| 36:34 | and and read. And I just with my drawing here below. So |
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| 36:42 | a very good idea that you have drawing that you can actually draw something |
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| 36:48 | this, that you can actually explain , and you can explain the driving |
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| 36:53 | , the equilibrium potentials and you know of these key membrane potential values that |
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| 37:02 | on the Y axis as well as relative and the absolute refractory period's and |
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| 37:12 | they mean. But I think this actually quite fun to do this. |
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| 37:17 | you're doing it with me, of course, you conduce to it |
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| 37:23 | , or you can do it in notebooks by hand. But I'm |
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| 37:28 | um, pause the recording for a . Let's see if there is any |
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| 37:34 | now. I'm not positing, but just looking through questions of potassium |
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| 37:39 | Let's see, What is the questions certain assured council was first potassium gated |
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| 37:45 | ? Start establish with them Certainly not . All right, Yes, you're |
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| 37:53 | . We'll get to the others. not understand what an activation this, |
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| 37:58 | we'll talk about this dynamic so you . So you're saying that the reason |
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| 38:01 | never reaches the value off sodium Librium is because there are other forces, |
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| 38:07 | as other channels that play. There's reduction in the driving force because the |
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| 38:13 | to the number and potential goes to Colombian potential to sodium. The smaller |
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| 38:18 | driving for us the equals I The because a far always law. |
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| 38:35 | , so the current, this driving . So now driving force decreases. |
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| 38:49 | then the other reason is the channel and the other reason is a potassium |
|
| 38:53 | force increases. And now you have drive of this other positive ion. |
|
| 39:00 | I hope this answers the questions gonna . According for second experimentally, this |
|
| 39:05 | what was used. Thio essentially record hold the potential that we were discussing |
|
| 39:13 | voltage clamp hold the potential that varied in potential. And so now we |
|
| 39:19 | that when we do apologize to sell early current going in this inward current |
|
| 39:24 | a sodium current, which is now by outboard current positive charge moving outside |
|
| 39:31 | inside to outside of the cell, that is the potassium current. If |
|
| 39:36 | do polarize the cell, even what happens to inward current? It |
|
| 39:41 | more deep polarization, more sodium or current. But at the same time |
|
| 39:45 | happens when you do polarize us? and you draw it further away from |
|
| 39:49 | equilibrium potential for potassium, the outward current also increases. You see the |
|
| 39:56 | difference here is that the sodium inward is early, so the dynamics of |
|
| 40:01 | sodium channel is that it is fast . It activates really fast, and |
|
| 40:06 | sodium channel on the potassium channel take time takes a couple of milliseconds to |
|
| 40:12 | activated. But once it does during sustained deep polarization here and you would |
|
| 40:17 | an increase in that outward current, more you do polarize the cell. |
|
| 40:21 | if this positive 26 you will now a really strong outward current here. |
|
| 40:27 | notice what happens at positive 26 to inward current. The inward current starts |
|
| 40:34 | . It's essentially the same thing is that all of a sudden the drive |
|
| 40:39 | the sodium that we said because the now be polarized to positive. 26 |
|
| 40:45 | force for the sodium starts decreasing, there's less of the sodium Ions are |
|
| 40:50 | driven inside the cell, but for , it's even mawr. Potassium minds |
|
| 40:57 | from inside to the outside outboard Look what happens in positive. 52 |
|
| 41:03 | balls. Positive. 52 nil They're essentially is now inward. |
|
| 41:12 | It's flat. What happens in 52 million balls. Positive. 52 |
|
| 41:20 | Evolved to this. The reversal potential the equilibrium potential value for the sodium |
|
| 41:29 | . So what we're seeing here once you clamp the voltage and you |
|
| 41:34 | the voltage of positive 52 there is more inward current, but you still |
|
| 41:40 | the strong, outward carved look what with positive 65 million bowls. Is |
|
| 41:49 | an N word cards? There is inward current inward current. Is this |
|
| 42:08 | deflection right? But you see this bump here, little bump at the |
|
| 42:15 | , very early on. You know this is? This is now |
|
| 42:21 | but the sodium ion has reversed its and instead of going into the Sallis |
|
| 42:27 | also coming out of the South. that's why when I said initially, |
|
| 42:32 | equilibrium potential for violence is also referred as reversal potential for islands. And |
|
| 42:37 | because if you dip, polarize the beyond the reversal potential for sodium, |
|
| 42:44 | the the current will reverse in the direction and flow in the opposite |
|
| 42:50 | So, using voltage clamp, Hodgkin Huxley were able to essentially describe the |
|
| 42:56 | dynamics and describe that there is an current that is early inward. Caryn |
|
| 43:03 | in green and that this inward carne sustained deep polarization. This transient. |
|
| 43:09 | it starts very early and it ends . And then there is the slave |
|
| 43:14 | that this late outboard car this sustained and it lost his longest. There |
|
| 43:20 | the deep polarization you see, despite fact that this is deep polarized, |
|
| 43:25 | Millwall's. There is no inward and it's over taken by the outward |
|
| 43:29 | current using voltage clown. These as well as many scientists involved in |
|
| 43:37 | studies, were able thio essentially describe we just talked about. What is |
|
| 43:45 | here is an action potential voltage member recording off the action potential with sodium |
|
| 43:52 | and potassium E flux. And here B, you have currents that are |
|
| 44:00 | through voltage gated sodium channel. So one of these lines represents an individual |
|
| 44:07 | channel that opens up and you have red current here and then it closes |
|
| 44:13 | you have this trace continue. So is showing is that during the rising |
|
| 44:18 | and sodium influx, face of the potential sodium channels open fast and they |
|
| 44:26 | it slightly different times because there's many channels that are involved. They stay |
|
| 44:32 | for slightly different duration, although about same amplitude, depending on the number |
|
| 44:38 | potential and the something current through all the sodium channels is shown here in |
|
| 44:46 | s. So this is the early that happens during the rising face of |
|
| 44:51 | action potential. And if you want record the same for that falling phase |
|
| 44:57 | the action potential during potassium e you would record these outward currents and |
|
| 45:02 | can see that the this is the phase and during the rising phase, |
|
| 45:08 | barely activate the outward currents, just and maybe the second channel here. |
|
| 45:14 | most of the outward current activations shown in blue again each Tracy represents an |
|
| 45:20 | channel indeed. And then e you the sum of all of these individual |
|
| 45:27 | averaged over producing the overall some the current through all of the channels, |
|
| 45:34 | that the awkward current doesn't activate until following the deep polarization. But when |
|
| 45:40 | does get activated that it's prolonged the , the flow off the ions through |
|
| 45:47 | channel potassium channel is prolonged, so can see how much wider and longer |
|
| 45:53 | blue signals are compared. Outward signals compared to the red inward signals, |
|
| 46:00 | the diagram on the top right shows net trans membrane currents showing that overall |
|
| 46:08 | is dominating the influx and the rising and the potassium outward current is dominating |
|
| 46:16 | falling phase and the re polarization phase the action potential. And so this |
|
| 46:21 | what we start talking about, the off the channel, what we call |
|
| 46:27 | to understand the dynamics of the we have to look into the structure |
|
| 46:33 | these channels. So when we talk sodium channels, so sodium channels are |
|
| 46:39 | of four sub units 123 and four one of these subunits will contain seven |
|
| 46:49 | membrane segments. So remember we told said that Alfa Helix is and data |
|
| 46:55 | segments that travels through the trans So these segments are one. The |
|
| 47:03 | units are in Roman numeral 1234 and Trans member and segments are noted. |
|
| 47:11 | s one s two s three s s five s six so important features |
|
| 47:17 | were actually determined in part by Roderick . Is this poor loop or a |
|
| 47:25 | loop where you can see that there a protruding enough amino acid sequences that |
|
| 47:30 | inside of this pro dam, essentially the selectivity filter and the most narrow |
|
| 47:38 | off the channel, where you would the interactions with sodium channel with the |
|
| 47:43 | charged amino acid residues of forest, of its selectivity filter function. Now |
|
| 47:51 | we're looking at is we're looking at sodium channel that is gated by |
|
| 47:56 | And so these sodium channels and trance and Segment four s four will have |
|
| 48:03 | lot of positively charged amino acid And so you're seeing these positive symbols |
|
| 48:12 | . As for they are representative of we call a voltage sensor. Uh |
|
| 48:19 | . This is all the sensor, the other feature of the channel is |
|
| 48:25 | it has gates on the cytoplasmic It has gates here. It shows |
|
| 48:31 | gate, but in fact it has gates and we'll discuss both of these |
|
| 48:35 | . So these are all of the morphological teach us that will play into |
|
| 48:41 | function off this channel For some Six Trans members segments in a poor |
|
| 48:51 | , Asus four as voltage sensor and on the side of Plas Mix side |
|
| 48:59 | the sodium, both educated channel. now this is what happens during the |
|
| 49:07 | potential. During the deep polarization, membrane changes the voltage across membrane |
|
| 49:16 | This positively charged amino acid residues on sodium channel, which represent voltage |
|
| 49:24 | are usually located closer toward the cytoplasmic because the positively charged amino acid residues |
|
| 49:32 | the voltage center are drawn by the by the negatively charged uh, membrane |
|
| 49:48 | this negative charge, which is drawing sensor to stay close to the side |
|
| 49:57 | Plaza Mick side of the membrane. the other hand, what happens during |
|
| 50:05 | process off deep polarization, This the inside of the membrane, becomes |
|
| 50:15 | polarized, so positive charge. It from minus 65. So let's say |
|
| 50:21 | to threshold minus 45 minus 40. will not be negative charge here on |
|
| 50:26 | inside of the number, and there be a positive charge accumulation. And |
|
| 50:32 | you have a positive charge, then this positive charge. Instead of |
|
| 50:39 | positively charged vaulted censor, the positively particles that accumulate inside of plastic side |
|
| 50:46 | now start repelling the small. That in the movement. The confirmation Allchin |
|
| 50:55 | in this three dimensional structure all of sudden Because the samina acid, positively |
|
| 51:01 | vaulted sensors are now being repelled by charge on the inside of the |
|
| 51:08 | They're actually changing the three dimensional structure changing. They're producing a confirmation Allchin |
|
| 51:17 | in this three dimensional, protean structure now opens up the gates and opens |
|
| 51:25 | the channel and allow for the passage sodium ions through this channel. |
|
| 51:34 | really, really interesting dynamics. So are the things that we have to |
|
| 51:41 | about sodium channels Is that first of , sodium channel kinetics or dynamics is |
|
| 51:47 | sodium channels open fast or fast If you have this deep polarization that |
|
| 51:54 | from minus 65 million volts to minus million volts, you can see individual |
|
| 51:59 | channels opening up. They're opening okay they're closing very fast. The deep |
|
| 52:08 | lost for 20 milliseconds here, but sodium channels just opened up once and |
|
| 52:15 | just opened up for 12 milliseconds. , they closed. So there's fast |
|
| 52:24 | , fast opening or fast activation of channels. There's also fast and |
|
| 52:29 | That means that these channels close very . They're open for a short period |
|
| 52:35 | time, and then they closed. get inactivated. And in order for |
|
| 52:41 | channels to open up again, what to be happened is this deep polarization |
|
| 52:48 | and the blue on the top has get released and the cell number and |
|
| 52:52 | to get re polarized again. And process will allow for more sodium channels |
|
| 52:58 | the same sodium channels to reopen So this hyper polarization of what we |
|
| 53:05 | Dean activation is necessary in order for to activate the same sodium channel in |
|
| 53:12 | for the same sodium channel to Otherwise, if the number is is |
|
| 53:17 | polarized, that sodium channel is not to d inactivate, and it's not |
|
| 53:24 | . Thio reopened again, so it's cycle. 1234 in one the channel |
|
| 53:30 | closed into the channel is open in . The channel is inactivated. You |
|
| 53:39 | open the channel until you hyper polarized membrane. And then for you, |
|
| 53:44 | , activate the channel, which now can open up. So let's look |
|
| 53:51 | this within the context off the actual here. Okay, sodium channels have |
|
| 54:03 | gates you can see here one of gates has shown here is is to |
|
| 54:09 | coming together like this in closing the at the bottom and the other gate |
|
| 54:15 | shown a sort of a ball on on A on the chain is swinging |
|
| 54:20 | below. So this is conditioned one which the channel is closed. When |
|
| 54:29 | number of potential dipole arises, there's activation. There's a sliding of this |
|
| 54:36 | sensor and opening off the activation So these arms I called activation |
|
| 54:49 | These arms are activation channels. What in three is as you produce this |
|
| 54:59 | will change and you open the activation of this channel. This ball, |
|
| 55:07 | is inactivation gate two gates to the two doors to the channel. One |
|
| 55:14 | them is activation. Gate activation gate opened The confirmation of the channel protein |
|
| 55:20 | , But now inactivation gate, like ball on the swinging chain, comes |
|
| 55:26 | on plugs up the Channel hall and this stage and number three, just |
|
| 55:35 | to the electrophysiology chart here above number , you have inactivation of sodium channel |
|
| 55:45 | in order for you, Thio, back to one you have thio hyper |
|
| 55:52 | cell membrane, and when you hyper cell membrane, what happens? The |
|
| 55:58 | sensor will slide down toward the side plasma Exide. This will allow for |
|
| 56:05 | activation gates Thio Swing back out of channel and for the activation gates to |
|
| 56:12 | again and the number four. It closed, which is also equivalent to |
|
| 56:19 | one. You cannot go 1 to You have to go 1234 And if |
|
| 56:29 | go through the sequence closed activation. open. Channel open channel inactivated because |
|
| 56:39 | the second gate closed it. And the inactivation is removed, which is |
|
| 56:46 | D inactivation. That's what it's called inactivation. You remove it the inactivation |
|
| 56:53 | or inactivation gate, and you close activation gate and your back in the |
|
| 57:00 | state. These are the dynamics. didn't make up these terms activation and |
|
| 57:06 | doing activation, but you have to them. And it's not that difficult |
|
| 57:13 | you can visualize this ball and chain and understand the the two types of |
|
| 57:22 | , not the two gates but the types of gates and one is the |
|
| 57:28 | gate, and that is Inactivation If you understand that once the vault |
|
| 57:35 | sensor moves the activation, it's active . Gators open. It's open, |
|
| 57:43 | play. It's not sustained, its and then inactivation get close, is |
|
| 57:52 | ? And now you hyper hyper polarized cell inactivation gate removed, activation gave |
|
| 58:00 | and ready. Thio produced deep polarization sodium and produce more action potentials. |
|
| 58:11 | . So how does this compare to potassium channels? Potassium channels are slow |
|
| 58:21 | , and they're they're persistent. Remember you looked at these graphs here potassium |
|
| 58:28 | or persistent, they don't get activated deep polarization. So these air fast |
|
| 58:34 | fast and activating sodium currents that air . They're not persistent, and potassium |
|
| 58:42 | late activated, and they're persistent As long as there is deep |
|
| 58:46 | there will be outward potassium current happening then the dynamics off the sodium channel |
|
| 58:53 | sodium channel kinetics. Either way, is a reminder of how what I've |
|
| 58:59 | discussed in the past with you how you record single channel activity or |
|
| 59:05 | you record action potentials on this is Pipat and a Patch clamp recordings or |
|
| 59:10 | lot of Francis referred Thio, Asshole patch clamp, recording and what it |
|
| 59:16 | . It's essential you bring this by , like I showed you in my |
|
| 59:20 | and oh, microscopes. And by the diameter, is a glass |
|
| 59:25 | a silicate glass, typically and the here. If the micro electorate is |
|
| 59:31 | one micro meter or so and inside electro do you have the solution and |
|
| 59:36 | solution represents typically what you see intracellular on the side of Plas Mix |
|
| 59:42 | and now you can patch on to piece of the membrane, sort |
|
| 59:46 | ah, cling on. Hang on a piece of the membrane, and |
|
| 59:51 | can also rip out that piece of membrane. You can rip out the |
|
| 59:57 | of the member, and it can attached to the peace of the |
|
| 60:00 | And in either case, if you a patch of the membrane that will |
|
| 60:04 | some of the sodium channels of interest you, you will record and you |
|
| 60:09 | be able to pick up sodium channel . And when you do the single |
|
| 60:14 | recordings again, you can do polarize cell and a single channel will |
|
| 60:19 | and it will not open again. will remain closed until you hyper polarized |
|
| 60:24 | cell. So these are the types recordings that are very important for studying |
|
| 60:30 | but also studying the pharmacology off these and protein receptor channels. And there |
|
| 60:40 | several different types of recordings. There's ash recording where you are essentially just |
|
| 60:48 | on to the plasma membrane. With election, how does that happen? |
|
| 60:55 | micro electro that is sitting under the . Let's imagine this. Micro electrodes |
|
| 61:01 | in a microscope is connected through tubes syringe to an experimenter, so some |
|
| 61:08 | maybe 4 ft away from the actual . We have a way of controlling |
|
| 61:14 | lecture than resection likely forming a tight tied contact between Pipat. Remember these |
|
| 61:21 | called cell attached recordings? He's there important for graduate students, but it's |
|
| 61:28 | important for you to know the difference . Why you will know in a |
|
| 61:34 | if you attached thio the plasma membrane by suctioning lightly. You have a |
|
| 61:42 | attached mode, but what you can And actually, if you walk in |
|
| 61:48 | lab during active patch clamp recording you will see these guys like you |
|
| 61:56 | , nerds or whatever you wanna call electro physiologist and they're sitting boxes |
|
| 62:03 | you know, call it the You know, we called electrophysiology |
|
| 62:09 | It's like 203 $100,000 rig car that driving this microscopes you're looking the pipettes |
|
| 62:17 | . You see these guys sitting with syringes and sexually on the syringes and |
|
| 62:23 | they're doing, You know what they're ? They're ripping the membranes once they |
|
| 62:29 | the number and you have a whole recording. Now you have the side |
|
| 62:34 | , and that is continuous with a at interior. So by giving the |
|
| 62:39 | pulse of function off off suction, we we call it a kiss. |
|
| 62:47 | actually can break into the plasma Now you record all of the currents |
|
| 62:54 | essentially all of the cars that would the flow off all of the currents |
|
| 62:59 | the whole patch of the plasma membrane the whole cell that you're recording |
|
| 63:04 | That's what's called wholesale recording. instead of doing this very strong kiss |
|
| 63:12 | movement Once the attached to the you can slowly vibrated and withdraw |
|
| 63:21 | But once you withdraw it, you rip out a piece of the plasma |
|
| 63:27 | and with that plasma member and you out a channel awesome. And this |
|
| 63:32 | of recording is called Inside out recording the reason why it's called inside |
|
| 63:38 | Because all of a sudden the inside this channel inside of this channel is |
|
| 63:45 | to whatever extra cellular solution to whatever solution, do whatever chemical you wanna |
|
| 63:52 | into the solution. Why is that ? Remember, we talked about Roderick |
|
| 63:58 | and we talked about different chemicals and toxins having specific binding sites on these |
|
| 64:04 | and the receptor proteins and other And so we want to know. |
|
| 64:09 | example, if we have a chemical does not pass through the plasma membrane |
|
| 64:15 | that chemical bind on the side of Mick side? Is it coming from |
|
| 64:20 | of the South? Would it have effect if it was inside the |
|
| 64:24 | Or is it on Lee binding on outside of the cell s. So |
|
| 64:29 | is the way that you can apply chemical, for example, on the |
|
| 64:33 | , on the on, the exposing chemical to the inside. That's why |
|
| 64:37 | exposing the inside to the outside and you could determine how the flow |
|
| 64:44 | the car on through this sodium or channel is affected by whatever chemical is |
|
| 64:50 | with them on the side of Plas side of the channel, especially if |
|
| 64:54 | cannot cross through the channel. It's than the channel cannot cross through plasma |
|
| 64:59 | , and it's not live insoluble. Last Technician and the slide is called |
|
| 65:06 | out recording In this configuration experimental. do combination off a strong pulse of |
|
| 65:17 | and drawing the buyback out at the time. So if you're lucky and |
|
| 65:26 | air difficult recordings, if you're what's gonna happen? This pay |
|
| 65:30 | Thio the the geometry of the channel , cytoplasmic side of the channel is |
|
| 65:36 | narrow side of the channel, and happens in the outside out recordings is |
|
| 65:43 | have a breakage of the plasma membrane now Rhian kneeling of the plasma member |
|
| 65:52 | remember possible lipid molecules will find each hydro, probably hydro filic, and |
|
| 65:59 | they will match up again, reforming number, and that's what happens in |
|
| 66:03 | electrode. This membrane will get reformed it got broken inside. You see |
|
| 66:09 | broken from inside and outside, and it Rhian eels on the outside side |
|
| 66:16 | what it does. It now exposes extra cellular domain to the extra salary |
|
| 66:22 | space. So the inside out recording exposing the cytoplasmic domain to whatever experimental |
|
| 66:30 | you want to subject while you're recording card through the channel. And in |
|
| 66:34 | configuration you have the extra cellular domain exposed to the extra cellular space or |
|
| 66:41 | is exposed to out versus inside of program is exposed to the outside these |
|
| 66:50 | very complicated recordings are a lot of . Um, they're challenging because, |
|
| 66:56 | I said that you have to work so many different variables and just to |
|
| 67:01 | the tissue for these recordings, if working with living tissue and with living |
|
| 67:07 | tissue and take hours just to get the point where you attempt to do |
|
| 67:12 | complicated recordings, But nonetheless we wouldn't modern neurophysiology and modern understanding of neural |
|
| 67:24 | function. If we didn't have these techniques, we wouldn't understand without voltage |
|
| 67:29 | . The dynamics of sodium and potassium understand how different Legans affect channels on |
|
| 67:36 | side of plasma car, extra cellular in sides. And again, we |
|
| 67:43 | to thank nature in part for giving these guests. That that we see |
|
| 67:53 | and what we're going to talk about the sliced slide ists, mouthwatering tails |
|
| 67:58 | toxins. But that there for a . Let me. So, |
|
| 68:04 | I'm sure most of you are familiar with The Simpsons. And so the |
|
| 68:13 | decides Father decides to go thio, Japanese food. And just a disclaimer |
|
| 68:24 | Simpson's are offensive thio everybody at some , or at least in some point |
|
| 68:29 | their lives. And, uh so be offended by this, uh, |
|
| 68:35 | . Maybe offensive. I think we all handle this cartoon that is on |
|
| 68:40 | you. Okay. What happens is Simpson is eating a lot of |
|
| 68:47 | and he's ordering a lot of different . And this is the master chef |
|
| 68:52 | here in the front. And master gets distracted. A Simpson is |
|
| 68:58 | And so this is where we start . Pick up this episode. |
|
| 69:26 | yeah. Yes, right? This paper. Yeah. Yeah, |
|
| 70:11 | . Yeah. Okay. Okay. right. For me, Right? |
|
| 70:24 | month. Okay. Yeah. It ? Uh huh. Perfect years. |
|
| 70:37 | huh. Okay. Right. Yeah, which is all right. |
|
| 70:53 | , Yeah, yeah. Country All . Cricket. Yeah. Mhm. |
|
| 71:08 | . Mhm. Yeah, Yeah, . Yeah. Yeah, as |
|
| 71:19 | All right. Yeah. Talk, think. Courage. Yes. |
|
| 71:28 | Your career. Yeah. Yeah. point was that to dissect and to |
|
| 71:47 | food bluefish, which is delicacy in . You have thio have believe about |
|
| 71:54 | years of training, and it's a delicacy in Japan. The puffer |
|
| 71:59 | also called fugu fish. That's what said. Mouthwatering tales of toxins. |
|
| 72:05 | the thrill of eating frugal prepared in way is that the most toxic parts |
|
| 72:11 | that mostly liver are eliminated during the process and minute amounts of toxin are |
|
| 72:22 | in this fish. And this fish a toxin that is abbreviated here in |
|
| 72:27 | T X, which stands for tetrodotoxin tetrodotoxin is quite dangerous toxin. The |
|
| 72:36 | idea of eating food grew fish that light levels of toxin is thio cause |
|
| 72:46 | numbing sensation while the person is eating raw fish essentially and there's quite a |
|
| 72:55 | thrill seekers, uh, that try every year. It's quite popular. |
|
| 73:01 | a delicacy in Japan. Onda I think there's still one or two |
|
| 73:08 | of poisoning, which could be deadly it's not treated within, uh, |
|
| 73:14 | of minutes of time. Following the Tetrodotoxin story is that it was |
|
| 73:23 | and in Japan and scientists, socio has access to the center of the |
|
| 73:31 | . And so socios whole drive now to determine what exactly does that talks |
|
| 73:39 | . So they you goes to Cem pharmacology meetings where people are starting in |
|
| 73:46 | fifties late 19 fifties, going to , starting to talk about these things |
|
| 73:53 | channels and the pharmacology of the channels iron channels. And this new techniques |
|
| 74:01 | air coming out, voltage clan techniques electrophysiology. And they're discussing the action |
|
| 74:08 | . And they're thinking, Okay, have this early rising current, and |
|
| 74:12 | Narahashi sees that he discovers attention to blocks action potentials. But he doesn't |
|
| 74:19 | what exactly it does to block action . And so Toshio Narahashi has the |
|
| 74:27 | to go to the United States. gets on the plane with a vial |
|
| 74:33 | d. TX is deadly toxin and a year later has the opportunity to |
|
| 74:40 | with voltage Clamp, and when he into the lab, he uses the |
|
| 74:45 | clamp and he applies tetrodotoxin and what sees this tetrodotoxin in the presence off |
|
| 74:54 | . As shown here, this is polarization, inward currents followed by awkward |
|
| 74:59 | . And if you add tetrodotoxin, block the inward sodium current. And |
|
| 75:05 | was the definitive demonstration. The tetrodotoxin sodium Kearns, And if you block |
|
| 75:13 | inward sodium car, you cannot generate potentials. So this was very |
|
| 75:20 | and it does not affect the outward potassium card. But there are other |
|
| 75:26 | , such a cetera, still ammonium . If you add T A, |
|
| 75:31 | will see that you don't affect an car. But you, in |
|
| 75:35 | the fact the outward carbs. So blockers, toxins and chemical blockers such |
|
| 75:42 | still ammonium can be channeled specific, so there's a lot of toxins in |
|
| 75:48 | that they're very potent because they have strong binding properties and the fact ing |
|
| 75:54 | of these protein channels. And we talks in such a sexy toxin, |
|
| 75:59 | comes from clams, mussels and during periods. Uh, you will hear |
|
| 76:06 | red tide, where some of these and mussels because of the warm |
|
| 76:12 | temperatures may contain sexy Dawson, and might be an advice not to eat |
|
| 76:19 | shellfish during that time. You have Creek toxin, which comes from Colombian |
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| 76:27 | and below I have, say, that it's over activation or inactivation. |
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| 76:33 | toxins target different functions and different So, for example, Batra could |
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| 76:41 | of ttx blocks vault, educating sodium . But bachelor could toxin or other |
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| 76:49 | may, uh, affect inactivation gate may affect activation gate, therefore causing |
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| 76:58 | firing of sodium channel. So some these toxins of blockers and some of |
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| 77:04 | toxins will actually promote, uh, were there agonists. If they're |
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| 77:10 | they're antagonistic. If they're opening the , their agonists mhm. Now nature |
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| 77:20 | very potent and what I have below , one binding sites helped deduce three |
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| 77:25 | protein structure. So if we know binding signs and we know how these |
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| 77:31 | toxins from spiders from clams from frogs fish, how they affect and where |
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| 77:38 | bind to these proteins, they actually affect the function of these proteins that |
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| 77:43 | us deduce this three dimensional Prodi instruction was necessary and was used by Roderick |
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| 77:50 | . These talks in allowed to study specific channels and how specific channels could |
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| 77:56 | blocked or specific channel activity could be . Number three Tangle Message. Nature's |
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| 78:04 | So there's a lot of potent a lot of potent chemicals said |
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| 78:09 | get replicated in the lab, synthesizing lapse and produced as either scientific tools |
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| 78:18 | medicinal preparations. So when we come next lecture, we're gonna talk more |
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| 78:24 | I V curves. We're gonna talk about other sodium channel dynamics and regenerative |
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| 78:31 | as well as back propagating Spike and believe that we will be caught up |
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| 78:36 | all of the material that we have on the syllabus. And I'll have |
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| 78:42 | updated version of the syllabus with some point share links posted later. So |
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| 78:49 | you have any questions, go ahead shoot them over the chad. The |
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| 79:03 | recordings on video points central neurotoxin, , blocks the channel from opening blocks |
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| 79:18 | channel from sodium channel from opening. , there is no deep polarization. |
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| 79:27 | . I love it. Uh Questions and answers and thanks and thank |
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| 79:34 | very much. And I hope you the rest of your weekend. I |
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| 79:38 | see you back here on |
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