for good morning everyone good morning uh I hope you I'm glad that you are very energetic this morning so am I so today we're going to continue talking about uh with a major focus on electrical for the reason that before um today we're going to start with this uh a quote by ber Russell and he says we know very little and yet it is astonishing that we know so much and still more astonishing that with so little that we know you can give us power um the last line is actually or the last part of this very powerful right we really know a lot um but that a lot you know is model that look like plan planet or around the sun he says that an expert is a person that makes all the mistakes in one thing and I think that this is a better uh to understand this book all right uh you guys are going to learn a lot you're going to be feeling over well with all the information and everything that you have to think and even though it's a lot just a very tiny part everything that we know which is also very simp so one thing that you should learn is that the more you learn the more you should realize how you know and be very home about right uh so you can always TR for um but just be careful don't think that you know everything the moment that you believe that you know everything you're in trou you are in trol think about that all right all right let's start with something more less so more entertaining hopefully all right so we're going to start diving into all right so what we're going to discuss today will be the basis for what is going to be um all the neurology that we going to start right so what are we going to discuss today we are going to understand what inwardly and outwardly Corr uh this is in C of course we're going to see how the some electrical properties cells can be represented with electrical circuits um we are also going to understand very basic stages for Action potentials and action potentials in this case is just going to be a mod to understand any type of signal you can extrapolate everything that was saying to them to many many other situations all right um then we're going to uh dive a little more into details on how solent channels work all right and I'm talking about the B dependent channels and then we're going to determine what is uh or we we're going to discuss what is what change an action potenti in time and then some examples of which is more or less a preview of what we're going to be discussing for all right so this one is a very fundamental question what determine the time por of a act all right because as you're going to be learning in the next few weeks that is going to be the PO for understanding how phology can help a patient right so this is a very very important F so let's get it started so what we're going to do is dive into very basic concept in right so I hope you remember a lot of your physics in the P okay so first of all we're going to start with a cell all right so far we have been worked with cells and we're going to continue to that probably have this right so what happen you can take a glass electrical and stick that inside a cell all right uh why we're going to do that because that can give us electrical access and we can use an amplifier to measure what is the potential the electrical potential inside all right I would recommend that the next few slides you really pay attention we just start typing typing typing typing okay all right because it is important to understand this it's a very simple concept but a lot of people tend to fail to understand all right so so what happen is that you can put a stick a glass El that is just it's just a little cap that we in the LA and when I say we it's not only we my student and I do this almost every day right so with you pull you hit up a cap you pull it you make a very fine hor bre time okay and it's so small that you can be sticking inside all right so that give you access electrical access to the interior of a cell and then you can use an amplifier and with that amplifier you can measure the loation all right then we use the exterior of the cell as a ref all right because there is no and you should know this by now okay there is no Absolute Energy the energy this case the potential that we're measuring okay it's always with respect to something El all right so having those two points we can measure the difference in potential between the interior and the exterior of the cell and that is what we call the okay which is as I said here the difference in electrical potential between the cyop plasm and SP so for instance if the interior measure - 5050 Ms and the outside is plus 10 ms this is respect to gra okay the membran potential is just going to be the difference between the two point okay and that will exactly - 60 M so when I'm saying that the membran potential the rest potential all right is 60 M what I'm saying is that the difference between the inside and the outside is- 60 m not that the potential inside or outside are - 60 M or something for instance if inside was- 30 and outside was plus 30 will remain to be - 30- 30 is that understood right perfect now you can go back and start typing every single word that I said all right so now when we talk about Corr all right we there is a convention and the convention is pretty much the same one that we follow in okay what it is the currents are caused by the movement of positive charge in physics we learn it right and in fact it's kind of funny because in in in electrical circuit all right that is no Lo the current actually is due to the movement of the so we always have this confusion however in biology it's different because a current can be actually Carri by a POS charge in this case sodium but also you have chloride all right so and that is the case for chloride when we are when when we measure a corrent all right a positive corrent can be if the corrent is going through here to the door all right that means that a positive is moving to the the door but when we are referring to Chloride is the opposite that means the the chloride moving away from the door my position all right and the reason for that is because chloride has a negative charge okay it is that simple okay if we were talking about chloride it would be exactly the same okay we were talking about any other negative charge okay will be exactly the same all right so now in general okay and this is I'm explaining this to you because when you read paper okay you need to understand this okay so when we talk about a corrent that is inwardly rectified that mean it's going into the C we always I going to refer to that as a negative this is just a convention this is just a convention okay it's convenient we can discuss what it is but just take my all right if it's an inward cor you will say as going down that's a negative refle all right now if we're talking about an outwardly prying cor like potassium leaving the cell okay then we say that that's a positive it's a that is going out okay so just keep those two words in mind inwardly and outwardly rectifying fors we're going to see this several times and then to okay any questions so far all right SL so if we have a corrent all right that corrent is moving somewhere all right and in some cases that current which we Den note with that ey don't ask me why I don't really know I I do but I have no idea why or okay that sometimes it will find some obstacles okay so as you canag imine it will be harder for that charges to move all right so the more obstacles you have the harder it is that means that effectively it it will become um uh slower or in another way we can say the slow will be decreased okay so for instance if I was to to run to the the back wall there using this path okay there is nobody along this path so for me it will be easy there's no resistance here but if I want to go from this path to that picture back there all right a lot of a lot of people will be baded because I'm going to be stepping of people right but also it's going to be very hard all right so this is a high is that understood all right well that's you need to all right so if we have energy all right so the amount of the energy for charge that's what we call potential okay and we have a higher res things move slower if we have a lower resistance things move F all right so what is that relationship that the current will be the energy which is the one propelling the movement right divided by the resistance all right so if the resistance is infinity how much will be the corrent Zer zero right if the resistance is zero how much will be the current 10 to Infinity right or if the if the if the resistance very little current will be very right that's what you mean that's all what this equation is okay the flow is proportional to the energy do that makes sense right it's like pressure okay if you have high pressure on on a tank you open the B Flo going to be very right but that you can regulate how much it goes out by regulating resistance so if you put High Resistance like the B close what is the flow zero but the is flow like when you open the know like with a it's exactly same IDE all right so this omous equation that's all that's all okay any questions on this fantastic so when we have a b all right with some problems this case we're going to talk about a membran so it's a b proteins okay we no great right just to make it simple so we have two components a capacitor and a resistor what is a resistor a device where current can go what is a capacitor is a device that can separate both charges the place of a electrical right all of you should know that because you're here all right so capacitor they can store energy why we can store energy in a capacitor because it can you put an electrical field all right and you can charge it that that you're separating charges in charges like to be separated yes or not so if I put a positive charge here and a negative chart here they will run away from each other or they try to come close it come close right and for me to take a positive charge and a negative charge and separate them do I have to invest energy or not yes right separate and what happen is I can take those two charges now that I separated you know this energy that I I'm across a capacitor my capacitor now can store that en is that idea clear that okay so it keep the charges separate and then for last you can measure what how many charges you can separate depending on the potential the more energy that I use the more potential that I apply the more charges can separate therefore the more energy can is that clear yeah okay perfect so let's go with a resistor resistor is just the passway to move that Char right so it's just for conduction chares all right the only thing it does you can measure that current okay per of potenti and like last but not least to make it simple instead of talking about resistors or resistance okay that it means what is the impediment to move a charge we're going to talk about conductance that is the ability to move the CH why we're going to do that for the very simple reason that is that when channels open we have activity so and when the channels open the resistance decreases so it's more natural to talk about the ability of the channel to condol rather than the inability of the that's the Reon we talk about sorry this is that idea clear all right so the lipid B layer constitute the capacitor in why for the reason that we have been discussed the lipids is very hard for ions to go through right theid because hydrophobic effect so the B layer constitute the capacity where you store that energy while channels Transporters atps any that allow the passage of will be the resist okay perfect so what happen when we add a gradient how does the change the story Chang well the only thing it changes is that now we have the source of energy to separate charges and to move all right so when we have a battery the only thing we do is to have that ability to move uh our charge right it's like you have a little LED you have a battery you connecting in a circuit you get light right and that light is happening because those electrons are going through the jump from in the LED all right and the battery is the electrochemical R so all that annoying word we were talking about the dam and the fishes and everything that is just to show that the bical the battery that move in cells all right all right's all right so what happened in a m and this is the main difference between between a biological battery or electrical system and an electronic system because the electronic system only the only ions that they sorry the only chares that they in elect is only onee one type of CH but in electrical systems biological electrical systems we have for instance a potassium and that would be but then we have sodium and chloride all right so what you can see is that this is the lipid by layer and then you have the conduct that are constituted by potassium channels Solium channels chloride channels HS and everything else and each one has its own exclusive pattern and this equation that we discussed before that I don't ask you to memorize the only thing is telling us is like what is the contrib of each all right because for instance is the resistance here will be super high infinity or like I cut the pathway with a sissor then this permeability will be zero but that doesn't count any is that idea clear clear any question all right of course we can also add Cal but I told you that that will make this equation much more complicated and you I'm going to put it here but not the right and of course we can have L anything all right and this is normal I told you that the membranes are very gray structure to separate chares but they're not per and there are places in which and conditions in which they can allow leakage that's the Reas that the membran potential is not exactly the potential because there is always some all right so electrically speaking this is a thir representation of a c that that me a me okay and again the combination of all of them is what determines the membran protection all right yes why is the battery fori the same direction the why the battery for potassium is in the same direction for chloride the gradient from potassium move potassium from the inside to the outside the gradient for chloride move the chloride from the outside to the inside but chloride has a negative charge and potassium has a positive charge so even though the the gradi in the chemical part is inverted because chloride has a negative charge in so move opposite the yeah so as we're going to see in the next I think the next to that's a good question so solum and and and and potassium are moving in different directions yes absolutely correct so the potassium in natural conditions will move toward the outside the cell assuming the outside is in the top I forgot to put out here in here here all right so potassium will take always to go out while Sol will tend to go in that's a good observation perfect any other question all right this is just summary what I just say so there is an app that a student of mine buil a long time ago I I can share with you and is in the is in uh some canas so if you want to play with it you can find and just play how these different condolences can determine the M but that I just wanted to let share with that with you all right so so c electrical signals what do they do all right and this is something that I have been mentioning uh a few times during these past few days all right electrical signalings are involved in many things for instance they are involved in controlan activity right triggering skeletal muscle contraction that also generating pacemaking a Sy in the heart in the pulmonary system in the brain okay they also trigger CRA as well all right they are invol in development okay and I kind of came to this did on the first class think it was the first one the second LED so they involving controlling the cell all right there are also a involved and this is fundamental they are involved in G regulation gene expression regulation all right also they are allowed us to have an interaction with the environment all right so we can for example are the basis for sensory systems all of them are Elric all right and this can be mean Elric Elric all of invol elri all right reproductive reproductive is a fundamental uh process for life and electrical signaling is essential for this particularly on fertilization and when I say fertilization I don't know if I have the other but more two things Sperma mobility and fertilization itself the the O side the cell when he gets fed by an sperm it triggers an acual potential and that action potenti poten what it does is to tell the cell hey we got a guy inside seal the whole thing and the ovel doesn't allow for more the entry of any other that's very very important because you don't want to have more than one more than two CS two Al of chos okay or any okay so this is also very important conition don't have to explain that I think it's basically the operation the basic operation of the central system all right and here there are just a couple of good revs for you to see this all right any questions no all right so how electrical signals are generated so the process is clearly involving channels all right these are two the type of channel that you're going to find in term of the architect the type ofi Chann that you see that you have the four or sorry six transm segments where some of them are constitute the sensing domain others are the PO domain or big ones like sodium and calcium that they have all these 24 trans membran sets in reality this is a very narrow view of what is happening there are many there are other type of potassium CHS that we're not discussing in this in this course okay I might U I might mention them later the structur are a little different but fundamentally they all depend on the on the on these two not for the for the purpose of this lecture today we're going to focus on these two type of chall and particularly we're going to focus on the Sol why the Sol CH we have been speaking about potassium fundamental because allows for the passage selective passage pass toward the interior from the interior to the outside and that makes the MBR po more the me potential negative however as it was asked before well will be moving the direction yeah that's very very very good observation because what is happening with the Sol we actually Trump with this mean negative me potential all right and that ability to do that is what allow so Chan to produce right F all right so this is something that you have seen in the past okay so when you for you take an examp for example you take an amplifier and you measure in a neuron what you will see is that you stimulate the neuron all right before you will the neuron will be in the resting state so the membran potential will be negative all right and please pay attention to this then you can just write everything we're going to see this kind of schemes you're going to be high see so just pay attention to this because this is a very fundamental idea okay so the membr potential is negative here and notice I made this note here I'm only showing the B dependent Chan sodium and potassium but you have to assume and please assume that we have voltage independent potassium channs in the B otherwise the membran potential will no exist my all right because these channels are closed and this channel right so something has to be producing this negative membran potential those are theend okay I'm not drawing them just because SP okay always be you always always always always has potassium channel that independent in the is that clear is that clear Perfect all right so what happen is that we are in the resting state okay the membran potential is negative okay and for meing this with respect to that okay and what happen is that now a stimulus okay and that stimulus what it does is to produce a partial depolarization of the M meaning the membrane is being depolarized meaning that is less negative and the solid channels are very reactive if you pay attention to the Sol channel the sensor of the Sol Channel start moving and start moving toward the outside then what happen is that that movement continues and the Sol channels get activated and when they get activated sodium start rushing in and carrying a positive charge and what it does it to make the m potential for POS right I know you're right right right right and paying attention to the drawing which is very important okay so what happen is this this Corral is making now the membr potential positive inside okay but what happened is that immediately the sodium Channel inactivate all right you remember that I said yesterday you have to remember one thing inactivation deactivation very different things so what happened is that how of the Sol Channel prevent the channel from continue to condu Sol all right so the membran potential now is high the sodium channels are inactivated and slowly but surely the potassium channels have been activating slowly behind system so what happened now is that the sodium channels potassium channels is start um allowing the passage of potassium and that brings a in very high quantity very strong flow and it bring the membran potential back to negative when the negative the membran potential goes back to negative values then the entire system chocks down sodium and potassium channels last but not least and please pay attention to the green part here is green when you see is done now the so Channel relax and it goes back to the DEA okay so the channel the Sol Channel need to reset so they able to cre that period of time between the channel going from being inactivated to being deactivated is what determines when and the next action potential some of you have heard about this at refractory period all right and a lot of people think that the refractory refractory period is have magical number that determines specific timing for this please that that is not true in any it does determine when the next add to potential is going to happen yes sure but it's not a fixed time okay it actually is highly regulated it's modulated by all kind of things okay even by the activity itself okay this is important to remember to remove the memory about the refractory period to be a magical number with the cirle time it's a part of the process all right so in general to have this type of process you need being in the resing state get a stimulation of some sours then the polarization inactivation repolarization and laboration okay those are the stages right if we wear for instance in another system like the p in the heart solum we will replace it with calcium and the same story more or less will happen why C why C what is the trading of is there more or less calcium outside than the inside just say something and then we see if it's wrong or right outside there is about 10,000 times more scum outside than in the inside in ter concentration so what happen that if you open a pathway for calcium you will see calcium rushing in and calcium have no one but two positive charges and that will produce a depolarization so can you have an potential driv by calcium yes you can right those are the on that we see in the B was a question here for when we reach the de floration state is that like at zero or that's when we starting hting depolarization no usually that is about that will depend the question is when do we reach the depolarization stage okay the depolarization is this phace where the membran potential is becoming more positive okay in order to to reach that you need to activate enough sodium channels in order to overcome the background potassium okay once overcome the background potassium C then uh the The Sod chn are able to take over and produce that rapid depolarization okay the critical point here is what is called the thres okay and the threshold that's another misconception a lot of people feel that the threshold is a magical potential I which everything an that is not true okay the Press is simply okay the potential at which the sodium corrent that is coming in becomes exactly equal or a little high than the potassium going okay this is something that we're going to learn right what happen is that the sod the potassium corrent that is is always present not the water depending the the the the independ the dependence potassium so there so what happened that as soon as you allow a little bit of sodium comine that deize the membran that Corr is there and compensates for that so the membran potential is always more or less the same is just when the sodium current become bigger than the background for then you can produce answer question any other question yes right that's a very good question so what is what is the stimulation we talk about the stimulation but we're not mention it yet yes we're going to reserve that for L just trust me that there is a process actually there is no one process there are many processes that will do this bring you okay we bring the M potential to thres okay and and those can be mechanical it can be electric it can be also chemal or combination okay so that question for one any other question all right and again always remember you always have both independent to the vir all right so these are the full mental stages resting stage just I want you guys to remember that all right uh then depolarization so positive charges coming in all right making the membran potential more POS then repolarization okay and this is a fundamental issue you have to have also the s chel right we're going to go back to to this in one second so we have resting depolarization repolarization and then finally lay repolarization in which the in rectifi sorry the bassum dependent potassium channels will bring the whole system and recover the sodium channel from inactivation all right now going back to this point so here depolarization starts because you have positive charges coming in all right here you have repolarization because you have a big flow of potassium corrent happening potassium going out of the cell all right so here you have mostly current coming in here you have mostly current going out what happen this is my question to you and this is the kind question ask what happen if this current doesn't inactivate in other words you have sodium corrent coming in andium at the same time and let's say to make a simple the same M what it will happen the membran potential will be zero perfect absolutely perfect that is the perfect answer if the two Corrs are the same there is no way to keep the gradient and the membran potential will be zero so a lot of people believe that the repolarization is due to the potassium channels depend potassium channels activation yeah to but the sodium channel has inactivate if you do not inactivate the S Channel M potential will remain or at least it will be partially the okay and these are the bases for many many many dis including AR epilepsy okay this is something that clinical Pharmacy will deal every single day particular the all right so this is a concept that you have to understand especially you're Pi all right so now remembering that we have always a potassium conductance in the backround theend what happen if we don't have potassium that are hold depend will we be able to complete the cycle yes or no okay no no no anyone anyone V to say yes I will yes you can complete the side you can in my demonstrated that a few years ago all right and what happened is that if you kill this Channel all right the cycle will be complete because you have I said voltage independent potassium channel so if the S channel is inactivated and you have that slow cor small corate background for that williz the problem is it will take a long time okay an actual potential takes about one or two milliseconds and neur without thist the B depend in potassium CH will take about 100 years still being less than a second okay so the potassium Chan the the the presence of a potassium CH what it does is to determine the timing of repolarization no if the cell is going to be and this is a very important con okay so the presence of the B depend potassium CH will determine the timing of the action potential KN the AC potential is going to be is that idea understood it will hinder it I mean the backgroundi is canot deal with the Sol Channel make possible problems but strictly speaking this will help a lot the background I should put the reference okay is that idea understood question probably not how when do we know the okay the question is what is the condition to inactivate the correct is that is that the question yes yeah so the Sol channel has a between the we're going to actually I have a couple slides about that so but it's a confirmational change that is triggered by depolarization okay so one of the let's just go there okay let's just go there I guess we're coming to a 5 minute break I need a break no no this is coel so let's let's take a five minute break and hold that question because that's that's important I just have a quick question a curiosity so very question please keep bringing them to me so um Okay so we have been talking about in the in the previous slide about how potassium and sodium are moving in and out of the cell right potass Sol coming in potassium going out and if you have a flow of solum or a flow of potassium one expectation is that you might be changing the concentration right and of course you will know more about it because we have Sol but if the changes in concentration are high you might might you might interfere with the way the signal is so fortunately the physics of the system uh guarantees that the changes in concentration are actually very minim or minimum all right so I'm just going to go very very fast through this slide uh because I I just wanted you to have these calculations but you don't need to memorize this calculations okay so what happen if we have a cell that is about five microns in diameter this is about the size of a very small sensory new okay you will have a given capacit and I'm not going to go into into details but there is a capacitor for area of the membran and then this will be the area of that membran and you can get about three three capacitor which is pretty high for the size all right so again you don't need to memorize this all right I just wanted to go through the flow of this calculation so we can calculate the capacitor so we know how much we can how much energy we can store meaning how much potential will be change right so if we consider a changing membran potential is about 100 MTS which is a change in M potential all right uh for that we we we need given the capacitor we need this amount of char all right uh that is in the order of pink col okay and if you don't remember you keep those links it will tell you what it is okay so what happened is that that will represent a change of about 2 million I all right and if you remember your Chemistry very well you know that 2 million okay in fact when we divide that by the avocado number and we calculate where it is but we the whole calculation take us to say that for a 100 molt change in a five Micron cell the change in conentration is about 6 mic Okay so again if we have a very small cell like 5 microm in in in radius 100 m volt of changing in in in membran potential will imply about changing concentration due to the flow okay of about six micro why this is important because oh and and I probably should have to this add so and that changing concentration that you see here it actually depends uh on the side of the cell and in fact the smaller the cell is or sorry the bigger the cell is the lower the changing concentration why it should be logical to the concentration is a function of the volume the surface is a is is is incre with square of the r while the isre the volume inrees faster when you increase of the cell changes are changes in the OR Char this is all to say that if you have cell okay and for a change of 100 m into to a solum Col and assuming that you have 140 M sodium outside and about 10 m of sodium inside after that changing potential you only will have change the concentration 006 that's less than 1% when point right if we were talking about potassium the changes is relativ small okay so this is just what tell you that these changes are very tiny okay so any consideration that if somebody tells you oh yeah if you have too many a poten you're going to change the whole concentration of potassium sodium F absolutely okay however there are pathological conditions in which this could happen but not a really big conent one more thing is okay the activity in the C system is so high that it does change the me sorry the contion but the changes are in theorder of 10 to 20% you would as far as I understand all the cases that I know you never get to the point that you completely the that doesn't happen okay that will definitely kill the cell okay so I just wanted just to point out this because this is a common misconception okay that you will change the concentration very dramatically and that is all right so the calulations that I put there is for you for your enjoyment or not don't have to memorize it but I just want all right any question all right get out of the way um no break all right so the initial stroke of the ACT potential all right so we were talking about that sodium this big protein okay have all these um uh transmembrane settings also you can find solum uh that might have a p that means there another protein that is associated with it and it provide changes the property of the sodium Channel even though it remains a sodum channel okay and you can modulate for instance the speed of inactivation how fast it records how much Channel ising etc etc ET it can also change pharmacology even though it was same all right as I mentioned before the so Channel looks pretty much like a poan Channel all right even though it's a different is this six trans instead of having six trans member ass it has 24 remember the potassium channel is four of un that they come together while the sodium Channel only one single polyic uh chain plus of course the sub units the sub units but when you see the structure the way they fall and they make and they are present in the membrane they look pretty much like a all right so again like the potassium channels this is the PO domain and the these extensions that the pro pro from the from the structor those are the Sens right now the difference is that in solid channel for Trans or the for all the Sens domains T to be different okay and um and that's the way the system has all right so what happened in a Caron form when we are in the Clos or deactivated State okay the channels the charges are in the negative the interior of the cell because the membran potenti is negative right so what happen is that we are in this condition in the rest loation okay and we're only focusing on the soil channel right so what happened at the very beginning the channels are closed or deactivated all right and then the stimulus comes and I know I won't explain what the stimulus is but trust me you will learn about that a lot okay so when that stimulation comes what happen is that the channels the the the membr it changes partially more a little more positive and the Sol channels get activated okay sensing domain the Char move up open the channel and you have a flow of so coming into the cell because we have a flow of sodium are positive charges then that brings that final stroke that very big and fast depolarization of the okay at this point we say that the channel is open or activated okay because it's allow the pass passage of um Sol inside now this produce um uh this very fast process okay and then what happen is eventually the channel being activated there is a changing confirmation in the channel that prevents the channel to continue to um flow the flow of Sol through it all right this is a old idea this is is called the B chain um model uh by playstrong Ania in in the 1970s very recently it was discovered to the of many people including myself that this model actually doesn't find out work however the concept of blocking the core by the protein itself remains body in any case when we are in this conformation the channel is not conduced but the channel is not closed okay the channel is actually open but inactivated so this is what we call the inactivated so please do not confuse inactivated with deactivated those are very very very different confirmation and conceptually that very very okay so when we talk about an inactivated channel it's a channel that has been open and the channel itself stop the conduction when we're talking about a close or a deactivated channel the channel is in the resting position and is not active is that idea clear is that idea clear okay so if I'm speaking in class in an s in a demonstration about inactivated Channel we're talking about this we're talking about deactivated we're talking about this okay perfect so the inactivation what it allows is that when you have aium ch for them to repol it will have what channels we will have faster polarization if we have a volage independent only be a slower however we seey that are very slow and allows that's a fantastic question what happened in the are prong open that means that they don't inactivate F yeah so that the typical what what happen when they inactivation is impair let's say because that inactivation particle let's keep using the old mod because it not that quite different but doesn't matter so if we have an a mutation there that makes the inactivation slower what happen is that some of the you can trigger all the Lo okay and that can lead to what is called a hyper hyperactivity okay techical example of hyperactivity are cor pain and epilepsy in the case of um the heart it can it can lead to after the polarization or high polarization polarization or late depolarization so what it means is that you have an action potential and in the process of coming back down you trigger another one what is the problem with that that what happens is that that can to produce that is considered an AR or you other words it can be Pro aric and it can trigger an AR that it can end up producing F fibrillation and we will understand all this in details progress in two months or a month no okay and relation what happen is that now the heart instead of Contracting in a a very nice synchronous way now it's Contracting like this and it doesn't really form blood and that's what we call okay so that's what happen when that inactivation is not uh fasting okay there is a problem when it's too fast as well because then you don't have activity enough and that okay but this is a very fantastic question any other question okay so what you can see is that the process is not really a linear process uh that it goes back and forth in reality you go from close open inactivated and then you go back to close the system doesn't go through the the open state which is actually an intermediate state in their cycle so that's it's called a cycle the more cyle here and not really the activation deactivation okay any question for all right so the so Channel have I mentioned before it has four super domains right one two three and four okay and then you have the bensing domains and the four domains these are the one that come together and form that Cor in the center right this Linker between the the third and form uh super domain uh it was used to call in activation Le all right now is uh the w now they call it but it's just because the me the molecular mechanism but we're not going to get into into details on that so what happened is that inactivate the process when you see it in term of the Corr the very beginning you have zero corrent this is about zero corrent here I should have put a here zero okay the channels are closed you don't see any current coming through okay and then there is a stimulation in this part here and you see the activation so you see inward okay coming to the inside of the into the inside of the cell all right and that produces a depolarization but again here we're looking at the flow for all right so once that the the the the activation is fully complete or almost complete inactivation start happening and then when you can see is that the corrent is start decreasing in amplitude and eventually there is no more okay so this cycle last about 20 M all right depending on the channel but it's about that's the average is have different typ so in this case we have a channel that is deactivated then it gets activated in this first part okay it's conducting so okay and then the inactivation UE so what it does bring the C okay and during this timing where thei Chan we get okay and is this clear is this clear all right so the way we see this process from the structural point of view of course this is a cartoon and this will be super domains one two three and four you can see this is the membran being negative inside positive outside and what happen is that when the membran becomes positive at the beginning you see how domains one two and three are activated domain four is a little slow okay and and what happen is that we have what we call the first open State okay there is conduction of solum here then eventually a couple of milliseconds later all right the main four is gets activated and that is what it triggers the inactivation okay when domain for is activated there is a second open state but then now the channel eventually inactivates meaning that the conduction uh stops notice that sensing domain remain activated the p is open but now the inactivation has happened okay so these are different regions of this the protein that are in charge of each one of these okay the sensors to activate the current the port to conduct and this inactivation lead that now we should call A W I should have a DAT that okay the wge sorry uh is what it producing okay remember you have to think about this like Mach right and they have different parts and each part has a I don't remember what notes I make here yeah so it's pretty much what I any questions on this on this problem no question yes sorry so do this make the inactivation of the sodium Chad event uh what kind of event timing yeah so yeah so the process yeah so there is a sequence of events okay that the one will lead to the next one technically speaking is an stochastic process meaning that we don't really have a specific sequence but there is a probability for those sequence to have happen and it happens not in interest but that's philosophy all right but this is this is there is a sequence for instance if the the sensors are not activated deactivate inactivation doesn't happen and inactivation is very stable unless the channel is in the deac so in order to recover the channel you actually have to be activated so there are conditions rather than time there are conditions that you have to match in order for each step to happen so that makes sense okay perfect all right so we're focusing all on all this because uh there are conditions like for example the question that was before what happen when you have a this this Motif here actually that's the next slide right that you can Target with drugs particular for instance this drug I know all right is regarded commonly as a sodium Channel block all right and you will hear this over and over and over this are is used to treat epilepsy no it's not a solution because it's not blocking the Chanel what this Dr is doing is to stabilize the inactivated why that's important because what is doing is not completely preventing the activity of the channel which you need for sign what is doing is reinforcing the inactivation so you can gain hyp okay like happened in the case of EP right so it is important to understand all right the mechanism that's the reason that we are trying to understand this molecular process step by step because the drugs are not like we think in the past have to understand the pro usually they target a specific state of the pro all right question here yes so the tror the lann affects the Bing mechanism right yeah but it does is to once it's inactivated it make it yeah all right any other question is this idea clear all right so this is very important because in because you you you could ask yourself well I can have all these so channel blockers why they different why they ask it's because of the um how strong they are how affinity for the channel for this drop sure but you can always compensate for that put more L right okay when it's because there are more hydrophobic or hydrophilic sure but you can always compensate by putting an to Ser all right but when it comes to mechanis then things are much more clear why F allows at least one potenti why answer the yes exactly cor why all at Le actual potential because you have to go through the open St in order to get to the conation that the Dr targets is that idea clear right so it's not as that just silen in the whole thing what happen if we block our ATT well we would die we have to potential in our heart heart will stop right our all our Central function out right so this is important to understand okay any questions all right all right do we need another five minutes yes okay five minutes we come back all right so I think you can now figure this out right know or expect know all right and I think this is an expectation from what we have been talking all right so we typically learn that a potentials are the self generative stereotypic responses or signals that we see inside of our cell all right the implication is that they're always the same they always look but that actually is not true uh they display of course different time for amplitudes um for instance you can have a potential that have these FAS repolarizations for example this is cell this is in the cere some big big cells big big neurons all right you can have for example um Action potentials that they have very relatively fast repolarizations and then a nowhere late face for repolarization all right you can have for instance slow very slow Action potentials like this one this is in thepa and bra and and they they are involed in the system so you can see that even though the are neuronal they have very very from each other and that will depend on what doing um the characteristics that they have in ter to phology which implies like why cells yeah okay that why why cells are different of answer that part of that is what sodium have um in fact even with the same cell okay for instance this is I think this is for a Pam C cell all right and you can see that the actum Potentials in the S fairly different in all right and why well because in the and make CH the poti even the me even the same all right so this is important to all right so why they not the same all right and I think we have the answer for that we have talk about it right and it's because we have a number of chance that can be present all right in many places all right and there is a variety of them and last week and yesterday I kept insisting on telling you that for example if you you get a drug and you said this is a blocker for Sol CH your first question should be which one and why you should ask that because that which one will allow you to understand what is the pharmacology and what is the cellular localization fundamental function so the sub cellular localization is a fundamental issue because as I was showing before all right even within the same cell add to potential what okay so again going back to this list you have great variety of CH and again this is just a partial L right and they can be located so in general Sol CHS really are only involved in the upoke the some of them are slower some of them are faster but in general they always work within a Min all right a ob on the other hand the rep polarization phase it can vary quite a bit it can vary to be from just a couple of MCS not even a couple of MS less than Mund so this a big ret and that F mostly invol the act different CH all right so potassium channels we have been talking about them uh let's just go on some details okay they cond we were say and that is in aend okay there are 13 families of and each one has so that give us about 70 Tye of different potassium but they also can combine among each other all right so you can have difference of units making a potassium CH so that increases the variety of potassium oft all right that's the reason there is more than 100 type of different potassium I'm talking about only the all the depend all right so member of this F is King one two three four the best one K7 are the one that I saw in my K 10 three POI Channel depending for potassium potassium channel that depending on S that happens in in and our human there is also the to be we hav mentioned that the that have we we might talk about that later in this course so these are what I called the functional Chang because when they you press them byel they produce Al there are other families five six8 and nine that they don't really produce a for a forun channel when they are alone however and that's a result that CA Silence of UNS however they can combine with for example k2s and produce a complete different type of right so it is important to understand that they can combine and make different type of CH in addition to that there are a number of accessories of UN which we call beta sols okay these are different proteins that they are expressed they associate with the channel and then modify we're going to see a couple of examples this course okay and and they they will really theity okay so these are things to keep in mind all right and depending on the channel and there is great variet you really need to focus trying to understand which one okay any questions this you want us to know like the specific or just what is the specific like the general names for like the members of no you just seem to know that this exist that they are that are fun by themselves they are Silence of but they are mod of all and you have also okay any other questions all right so for instance in a neuron this is just a cartoon okay this part will be the dries and these are the aonic and then the pratic ter so in this case the conduction of electrical signal goes from the left to the right okay unless you have back propagation that can happen in some sensory all right so what you see is that depending where you're located okay these neurons are interacting with different parts and the subcellular sub they very different along the entire body of the of the cell okay the D is what allows neurons or is the place where neurons communicate with other neurons the S is where the nucleus is located but also where a lot of the integration the m m that the do is part of that is done in the S and then the axom all right is pretty much the place where that the result of that computational work that being done the sues is delivered to the next neural in the pr all right so you can see that this is a very complex structure and as as you would expect the protein distribution different protein no only the channels of the will be located also in different places so just focusing on the Sol channels you will see that for example k4s k2s and k3s can be located in the spread um in the somatic area Okay are very particular channels and I wish I had time to explain this to you but we will be it will take a long all right while in other cases you can have ACN channels which are the ones that are responsible for invol typically producing or period signals these a channel that I told you to you later because they open poti negative POS all right also we have cing channels that are also involved in signaling okay as allow the calcium allow calcium to which is a a very common second method all right then in the initiation segment of the a you can have for example cas Q 87 this is just old name all right and so Channel all right and in the nor from you can get also a 3 3.1 and this is a particular B3 channel that it had that invol in a very interesting process that confer nocular mem to is conduction this is a topic that is beyond the the scope of this um class but what I wanted to point out is that for example in the in the the pr teral you also have a very so you can see that even with within uh the same cell the distribution of these proteins is is nor something very and it had to do with the fun that's what I I function so when you get a blocker or a mod4 you need to understand what is okay the in the it's everywhere it's in the in the pr ter because that way you will be modulating a different function or different part all the all the activity of the in this case this is receiving information in this case this is delivering information so you for example are going to Target K4 you should think about that you are affecting the way neurons are receiv receiving information the way you okay so is that idea clear that concept okay so again you don't need to memorize every single one of them you just have to understand right right that even if this the proteins are located two proteins are located in the same cell they might be located in a very different part of that c and therefore the function and even the interaction is that idea understood yes really quick so in the previous Slide the actual potential of the so much wider than prestic part of D7 because the S is receiving a lot of signals from the different proximal rights it needs to be able to as it has a wider poal not necessarily was just an example the idea asking the stion potential was wider than practive one right not necessary no it's not that always the S action potential is wider and in the prestic is short it does make sense though because in your s when you are integrated what you're doing is suming all the different signals that are coming from all the D drives while in the preap terminal what you want to do is to have a very fast signal so you can really B so that idea is appealing it might be true in many but all of them it's not like a wide R it's like a overarching rule that you can apply okay but it does make sense but it doesn't mean that it's true all right any other question okay perfect so even within very small structure like the nor R you can see how channels in very small places we're talking about here a couple of M they can be located in very specific part of the structure in the so this is the m this is the nor from here you can see kv7 here 3.1 and then K1 in the on underneath the the mining she that it produces insolation of the of the at all right so this is just an example I don't I don't really remember which cell is this this is might or this might a peripheral but the point is that depending on what cells and what are your location you your channels can be segregated in a very particular space in areas that are so small like one micro much more all right so just this is to keep you in mind you want your cous just this is old article from L but it's actually still very Val thisal observation all right so so far I have been giving you examples of neuronal at all right but not always you have to have not all happens right the most weird examples are for example the ventricular Action potentials all right the ones that you will find in the part and particularly in the ventricles which are this part of the mus all right so you can see this very long at potential before we were talking about potential they lasted a coup millisecs some cases even less than here we are talking about act potential they last about 200 Mill very very okay and there is a reason for that that we discussing about okay um regardless of that uh these action potentials follow more or less the same rules that the that we were disposing M okay for instance we still we have channels which are the potassium channels and those are the one responsible to keeping the membr potential there then you have a Sol corent that is involved in the up stroke for the AC potential all right then in this case you have c channel that are Import in keeping that producing this hesitation in the repolarization of the mutation right there is also for that they grief are activated during the very first part of the repolarization okay then after that you have this final repolarization being done by K 7.1 in combination with K and her channels all right so it produces this slow and then very turning slow but turning very fast repolarization and at the very end we go back to having chance maintaining the res potential okay so you can see here that something that I forgot to mention here think I didn't put it no is that of course so Channel have to inactivate in for the rest of the proc in a more way all right so we're going to study this process in very much detail in about two months so I'm just going to keep going um for example when we talk about the ESS node which is the one responsible for generating periodic signals these are actual potentials even though the atos are the the different the um the the cycle remains okay so we have a solum channel in this case that produces this initial depolarization this is due to hcn then what happen is channels now in this case are the one producing the off stroke of the atation and then last but not least potassium channels okay are the ones that it brings the repolarization back or the membr potential back to negative values and then the cycle starts we have ch right in this case even though I'm not saying it we have 30 chance of working in the resting level keeping the B membran potential to be negative even though it's not stable okay not stable because this is a b it's a different type but you always have ch those are the Vol independent CH okay hn is the one responsible so this so important and we're going to get into those details when we all right any questions on this all right so G channels are very important we're going to talk about a little bit of them there are three families uh the old name was L Type these are the one that the the family c one then we have the p q n and R and this know these names were because they were like the ones in the heart in the neurons and different places the Rena ones so they end up being only three channels even though they were characterized as many different ways but we genetic we work out as a ro we beenin down to be only three G producing all these Sol CHS sorry calcium CH and the difference is the beta soles or the accessory solut then we have the tiny type of CH tiny corrent channel that very small cor and there is also three members three te so there are four different types of units accessories of units and what they do is to modify their activity that's the reason these were T to be very different C CH only be three gen for that okay and all these accessories of units of course trafficing activity and pharmacology which is very important okay to keep in mind okay so another type of a poti and that's I'm mentioning CH are the ones that find this wasn't know Longo you can see how you see these very active potentials happening and these are linked to the release of insulin and notice the the the the the time scale now we're talking about time scale of several T of seconds okay when this is happening all right so you can have an actual potential that last about um about about the so it's are very very very slow ATT okay and they can be treated by glucose so this potation when when you increase the concentration of glucose you can then this electrical signal that produces the relas or are involved in the release of insulin so glucose can be sequest right and the is the depolarization is mostly responsible by an Ty channels even those solid channels are involved as well okay and the repolarization is driven mostly for a a fast Channel even though theorization is very slow that is the very first phase is due to a kv2.1 and also calcium activated potassium channels are involv the late phase of the so this is this are very interesting po that you can find all right so uh these are different facts that I just put in the slides for you to know um different Sol channels are involved in different functions I'm going to let you guys read those through uh one thing that I want to emphasize if that I will never ask well I'm going to say never I will very rarely ask ask you to memorize something okay but this is the only thing I'm one of the few things I'm going to ask you to memorize NAB 1.4 is the sodium channel for skeletal muscle and NAB 1.5 is the Sol channel that is the heart Sol channel is the main calcium Sol Channel present in the heart However the fact that everybody refers to na 1.5 part CH that doesn't means that they are only in the Sol Chan in fact they are present in all type of cells so this is important to know okay so this is one again this is one of the few things I'm going to ask you to me na 1.4 all right is the skeletal muscle the and any is the it can be found all right so in the morning before you brushing your tee you're looking at yourself4 skel right all right so these are all uh reiteration of what I have been saying combination of Channel sh the temporal temporally responsible for the temp potential and all the things that we can see so you can get reviews very good uh on different type of CH and draws that UC uc5 all right and with that this is the summary this everything that we have disussed today and due to the lack of time to have any questions please ask forever P yesly so 1.4 is skeletal and 1.5 isar it's not everywhere it's found in all the type of tisue but it's primarily found in the heart 1.5 1.5 1.4 is just yeah perect all right all right guys I'll see you on Mond right and for those who sign up for I'm sorry I Haven sent an email y What's happen long long day um those who have sign out to be the agent uh tomorrow we have supposedly we have class we don't uh so we're going to use that time to tomorrow in my okay so thank you for signing up uh I will send more detail information uh later today so be aware that we're going to be meeting tomorrow uh at the time of the class thank you yes sir no I just like just over the concept like when we have the discussions here on Monday so that's the best way to start try to understand the concept what you can use is the summary and the very first question at the very beginning ask these are question this is what you need to know and what you need to the of course yes sir that's what I was answering no I don't yeah second going going