this is where we left off on Thursday we had been sort of talking about the structure of skeletal muscle as in the organ and then we talked about some of the cellular details of skeletal muscle we talked about how the vast majority the internal uh skeletal muscle cell internal volume the vast majority of that is taken up with myofibbrals and as a reminder myopibbrals are technically a type of organel they are the the really the biggest organel in a skeletal muscle cell skeletal muscle cells have lots and lots of myophibbrals the number would depend on type of cell we're talking about the maturity of the cell the use of that cell the type of skeletal muscle fibers so there's a lot of things that would impact how many myofibbrals a cell would have but it still has a lot and then we talked about how um these organels like mitochondria and psychoplaset reticulum which is really our focus for at least half of the class today um are just absolutely sort of beholden to the shape that the myophibbral set so that's we see really strange shapes like the cycloplasmic reticulum looks like a sleeve that surrounds a myophibbral and then outside of that we have another organel that looks like a sleeve the reticular mitochondria all of those structures and sort of strange shapes are due to the fact that myophibbrals take up the majority of the volume and if you want to participate in the cell you will conform to the myofbral so that's where sort of left off on um Thursday i talked about how you know calcium stored in the SR the lumen of the SR it doesn't just store it but on the right time releases it and resequesters calcium and resequesters means it takes it back that's an energy intensive process so the timing of all of this the release and actually the take back the resequestering is all part of the action potential so this is why we call it excitation contraction coupling which really does represent um sort of a union where an electrical event is going to lead to a mechanical event um and then we talked about how calcium interacts directly with actin a myofilament inside the myophibbral so again this is where I left off on Thursday but pretty like Thursday was a long time ago so I like to kind of warm you up to where were we when we left each other so that's where we were and so that's where we're going to move today are there any questions remaining questions you may have on this after you sort of thought about it wondered about does this work that way or this way any questions before we move into really details of the myophibbrals moving into slowly into the sarcimeir the sarccomir is the contractile unit of skeletal muscle and it is found they are found within myophibbrals but it's all sort of part of the structural process you got to get the cell structure down correctly before you can really appreciate the other sort of biochemical processes within so far so good very good well we're going to talk about on this next bit really why it's so important to understand the proximity of the SR or sarcopplasma reticulum to myofilaments specifically actin now there are other myofilaments like meosin but it's actin that really interacts with calcium and all this is happening within a myophibiber so if you think about what a strange relationship it is to have this myophibbral that runs a length of the muscle cell and around that is this sleeve that we call the SR the psychopathic reticulum that's an unusual arrangement inside of the cell so hopefully when you see something kind of strange like that you at least stop and go I wonder why it's like that because curiosity is really the start of being a good scientist you know it's like that's weird i wonder how it came to be like that and so we're going to see that the proximity of the cytoplasmic reticulum is very close to actin as close as it can possibly be and that's because it minimizes diffusional distance calcium once it's released from the SR moves with diffusion is diffusion a fast process no it's the slowest process we have and it works okay in small distances but diffusion can be disrupted by increasing the diffusional distance or having like a lot of uh cell debris in the way maybe you've got some intracellular debris that's in the way it's really easy to disrupt the process of diffusion so we're going to minimize the distance that's the number one thing that we can do to make sure the fusion happens pretty well um so here's what we're going to do we're going to start by taking a look at the inside of a muscle cell we're going to draw circle we're looking at a longitudinal aspect i've taken this cell and I've cut it right down the middle flattened it out and looked at it we are looking at just two myophibbrals now this is unrealistic most muscle cells would have hundreds of myophibbrals and I guess if you're feeling extravagant and you want to draw 100 myophibbrals totally fine i'm going to go with two i feel like two gets the job done when you draw the sarcomma I specifically left spaces here those are going to become something so leave those spaces this is where we're going to see the T-t tubules emerge transverse tubules and then over here I have a list of things that I want to go through and talk about so I will let you as always draw give yourself a little bit of room above or below if possible add in some details talk about some vocab as we go remember it's really critical that you sort of manage what I consider the hierarchy of vocabulary with muscle you've got a myio cell you've got a myofro an organel you have myofilaments which are contractile protein so there is a hierarchy to the vocabulary it's not exactly straightforward but I think it's good to sort of start to see you can nest different words under other words because they are smaller structure so just be very very diligent about keeping up on your vocabulary for this next exam there's always weak spots in every exam and for this next one by far the weak spot for people is vocabulary like myofilament versus myophibro if you get that backwards the question doesn't make any sense and it's harder to answer it so be diligent about that you can wait and write this out later it's going to take me a while to sort of describe this so are we good on the drawing got our tubes within a tube drawn tubes within tubes we're just basically tube constructions actually does describe the human body plane we are described as tube within a tube we're just all tubes all tubes all the time all right i'm going to start at the top kind of work our way down i'm going to be talking about the structures we're looking at i will probably by default hit a lot of these but this is just to make sure that I am thorough i have a way of getting distracted because I get pretty excited about physiology um and when you're studying make sure that you know you can be thorough and hit all of those points comfortably so it's sort of a a bullet list for multiple purposes so again we're looking at a portion of a typical skeletal muscle cell or a meioite and I'm going to be looking at the saroma so again this was you know this cell was round columner had a a diameter but that doesn't really help when we're trying to look at the stuff on the inside so the first thing I want to talk about um is the sarmma it is a phospholipid billayer we've seen that before so saroma there would be ECF on the outside of this both sides and of course surrounding that would be your endomiscium so just kind of like good habits to keep up with things we've talked about before what I'm going to do now assuming you have this part drawn is I'm going to like slightly mess this up we're going to draw T- tubules and what I'm going to ask you to do while I draw this is just watch don't try to copy while I go along because this relationship is super crucial but it's a weird relationship and it doesn't really um get portrayed too well in some textbooks that I've looked at even like medical phys textbooks that they use in med school they describe it they kind of show it but if you don't draw it a certain way it just doesn't quite make sense and so that's why I ask you just hang on let me draw it let me fumble around i'm not saying it's going to be perfect but I would at least like to try i'm going to try to make this has a threedimensional tubal structure so you see the relationship between the two very important structures that are not yet up here which is why we're going to start with the basics you got to have your foundation down which is what we have i'm going to draw T-tubules and then I'm going to add cycloplasmic reticulum on either side we're going to create what's called a triad so there's going to be three and right now there's none so that's why we kind of have to build this as we go along so I'm going to fumble around in real time in front of a real live audience so what could go wrong so T-tubules are a hard thing to understand um they are a phospholipid billayer they come in from the saroma the sarmma on the surface would look like it's perforated or has holes and those holes lead into the tubule i don't have a nice purple marker here um that I had at home when I did this over the weekend so you're going to see a color change and that is simply due to uh lack of appropriate material on my part i'm also going to coalesce the saroma down into one line just to make it easier to draw it's still a phospholipid billayer but trying to draw it as a lipid billayer just becomes unusually difficult so these T- tubules come around and they hit almost right on top of the Zline which is what I'm now drawing on top of and they also go around behind so what we end up with is a ring like structure that encircles every myophibbral at all of the V lines this is a weird thing this is why it's hard to draw if you can get this down mentally you're going to be so much farther ahead of the game if you just sort of blow it off this will on a superficial level make sense but you'll never truly appreciate sort of the complexity of the architecture so I'm going to do it again and then I'm going to have it end here and I'm going to tell you what do we find inside of this T-tubule so think about that as I draw this this T- tubule is part of the saroma it starts on the surface of the saroma lima like you might expect comes all the way through the muscle cell and then ends and this is kind of a a wide little opening here but it ends on the other side i'm just going to add that fossil billayer back in there i got some space so everything that you see here we're going to pretend this is all the same color um this is all part of the sarcomma it takes a dive in it invaginates it circles around and I'm going to do it again over here now you see why we're only drawing two myophibbrals you can imagine drawing this multiple times gets difficult so if you didn't quite see the first time I'm going to do it again um a T- tubule is an invagination or an infolding of the saroma which again I'm just going to condense down to one line here because it becomes unwieldly otherwise and what we have is the sarolmma encircling every single myofbral at every single zline when early scientists discovered this shape they thought well that is you that's really bizarre there's not a lot of other cells that have this shape and it really took them a long time to figure out you know this is a unique cell with a unique membrane why is it like that and you know there's not a lot of other cells like this cardiac muscle cells are similar but not exact so we knew for a long time these T-tubules existed but the significance was really hard to elucidate as typically happens technology gets better you can start to see things in real time sort of functional aspects come clear and it was then that they realized that these T Tubules transverse tubules coming all the way through that muscle cell allow the action potential to spread all the way through the depth of the cell almost seemingly at the same time as it's going along the saroma and that answered a lot of questions which is how can you have a cell with a pretty big diameter and yet the action potential which is created at the neuromuscular junction doesn't just go along the surface of the cell it comes down into the depths of the cell at almost the same time such that all sarcimeirs contract at the same time such that your muscle cell now has this nice fluid motion when it contracts and relaxes this answered a lot of those questions and so it truly is a remarkable invention that nature came up with she puts it in all of her skeletal muscle cells um and it really just answers a lot of questions so everything that I have drawn here and as you draw this be very diligent about the placement it can't be over here it can't be on the ends it has to be right along that Z line for reasons I will talk about in a moment again diffusion is a slow process that's your hint so we're trying to bring things as close to other things as possible transverse two i'm going to add in some fluid and I think fluid may help i hope you visualize the relationship of the T- tubules to myopibbrals and actually the outside environment of the cell so saroma saroma but as T- tubules so it's all saroma on the outside of the saroma of course we'd find extracellular fluid and we've seen this before this is not new so here's our extracellular fluid is there anything stopping that extracellular fluid from coming into the T- tubules absolutely nothing those extracellular fluid go right in the T- tubules it's why it's really crucial to balance your extracellular fluid because in cells like muscle cells and cardiac muscle cells that fluid goes all the way through the cell if you have an ion imbalance in your ECF you just invited it all the way through the cell so that can spell big problems so it turns out whatever fluid is um in the ECF outside of the cell also is the same exact fluid same composition it's continuous it could flow to different parts that comes all the way through the T-tubules so we now have going through our cell at regular intervals thanks to these T-tubules an extracellular fluid environment all the way through the cell you got a calcium imbalance in your ECF you're going to have big problems in your uh skeletal muscle and cardiac muscle as well so we want to maintain that ECF uh through homeostasis questions on this before I continue so far so good it takes a while to get the drawing down so if you don't get it first time don't worry yes is it all the Yes if you were to look down at a whole muscle cell and you had the ability to see all the details it would look like it's perforated perfectly like something made by a machine there would just be rigid series of holes if you're looking down on this and those holes each it's a crazy cell all right before I draw any more I'm going to come over here and make sure I hit these because what I'm going to add down here is going to make this hard to work with so um I'm going to add just a few it's really just vocabulary terms nothing big um we have for your viewing pleasure two myophibbrals and so here is a myofbral and down here is a myofbral and again these are just organels that contain myofilaments myofilaments so myofilaments in skeletal muscle cells come in two flavors um one is actin and I always try to draw actin in blue because I think it just sort of helps reduce your cognitive load you're like "Hey it's a blue filament it must be actin." And then I'm going to draw the thick filament usually in red if I'm paying attention and that's going to be meosin and actin and meosin are the myofilaments these interact when they're told to do so based on calcium and when they interact the whole sarcimeir shortens so that leads me to my next point sarcamir sarcimeir is the true contractile unit of skeletal muscle cell its boundary goes from Zline to Zline so everything here Zline to Zline this is one sarcomir full of thousands of myofilaments sarcomir is a true contractile unit of skeletal muscle and cardiac muscle notes one sarccomir if it contracted would do absolutely nothing you would just waste a little bit of calcium a little bit of energy nothing would happen you have to get the majority of the sarcimeir in a single cell to contract and you need multiple cells to contract usually to do any work so we're just looking at sort of a a micro unit of this and then of course it would scale up substantially based on how much work we would expect this muscle cell to be able to do all right I'm going to use this to color over and add these things so we got everything labeled sort of feel good with the placement sort of feel comfortable with uh like you could walk around a skeletal muscle cell and know where things are located good okay i'm going to come down here and add some other things uh to explain and illustrate that placement and and sort of where things are located in relation to other things is absolutely crucial so I've already added the T- tubules and everything on my list kind of is something that has to do with T- tubules so I couldn't fit all my list on there but I can now so I'm going to add these things don't feel like you got to write them all down now i'd rather kind of have your eyes like where are these things so I've already hit T- tubule i'm going to add in the detail of the sarcopas reticulum and organel and when I do I'm going to get these three next bullets these all go with these are things that have to do with the sarcopasiculum like if you're sort of that kind of person who likes to you know think about things in an organizational scheme the SR or sarcoplas reticulum once I have this drawn will hit terminal that's how you say that and longitudinal tubules different parts of the SR different functions different relationships with the cycloplasmic reticulum anti-tubules so I'm going to zoom in on this and as before I just ask you to sort of watch and then I'll give you a chance to do it so We're going to find a single pychopplasic reticulum within the borders or confines between these two T tubules and it turns out that the cycoplas reticulum has a really specific shape and that shape is very important to its function so on the ends of our cycoplaset reticulum we have kind of a flat broad end that runs parallel to our T- tubule and then once we get towards the middle we see a very different pattern emerge a very different structure this one has longitudinal tubules it it still sort of acts like a sleeve or encircles everything here but the structure gets really kind of exaggerated until we get close to the next T- tubule and that's where we're going to see another sort of flat or blunt end so I'm going to color this in just to highlight what is the SR and I'm going to add just a little bit of detail again I hope you got the sarcimeir down underneath because this is going to change but as I draw this think about things that have I'm actually a different color this is the lumen this is all going to be encompassed within the SR to think about sort of a common theme we've seen in this class and in human body one which is when something an organel or a cell has a very exaggerated structure or feature what does it usually enhance or provide service area that's right and this is no different everything that we're coloring in here is all about surface area so this cyclops reticulum works like a sleeve that wraps around completely encompassing the myofiber it runs from T- tub to Tuble doesn't quite touch the T- tubial but it is close there are two different parts to the SR and they have a very different purpose and the purpose turns out to be really important for skeletal muscle contraction and skeletal muscle relaxation because we can't leave a skeletal muscle contracted not only would you run out of energy that would cause a cramp but if we're talking the diaphragm that would be fatal because you could not exhale and you couldn't take another breath so it turns out we have to be able to think about how we're going to relax all this not just get it to contract so within our sarcoplas reticulum the lumen or interiors green that's going to be full of calcium absolutely just chocked full of calcium and even has special proteins that help it hold more calcium calcestin i'll come back to that it has like so many tricks up its sleeves for holding calcium releasing calcium and taking it back this is really great at that so I'm going to talk about two areas here one of these areas is going to refer to the flat end so I am going to have a flat end here and then I'm going to have a flat end here so this area right here I'm just going to sort of underline the area I'm talking about that area there and this area here the two blunt ends that face their T- tubules uh these are called I'm going to write it over here terminal sister so or sister is a sort of like a wellistn is a well see water but it is a large storage area terminal because it's the end of the organal so that's part one the other part probably makes a little bit more sense it's a little bit more logical and that's everything in the middle here these are all the longitudinal tubules so I'm just going to um do like a dotted line to sort of explain the spans of that and so this is the area of the longitudinal tubules and believe it or not even though we're talking a really small area of one organel these have very different roles which I'm going to explain on the right hand side of this drawing but right now we're just trying to get the sort of cell anatomy straight so the building thing done we don't so terminal sister longitudinal tubules two parts to one organal they have different purposes let's talk about a triad we don't quite have our triad built yet to understand a triad I'd have to actually go on the other side of a T- tubule and draw another saroplaset reticulum so I'm going to do that just to illustrate the last bullet point on my list which is a triad i have two parts i'm going to add the third and then talk about the significance of that so the T- tub will kind of is the um demarcation where the saroplaza reticulum would end and the next one would begin so I'm just going to come over here and draw another terminal i realize I'm now using the wrong color and that slightly annoys me but we're going to go with it and so here we have another example of a flattened end up here that's our terminal sister notice that blunt end faces the T- tubule and we would still have inside of this calcium so once we have a T tubule our circle and two terminal cesterna that's a triad and they work together as a unit the triad which again consists of a terminal a tubule and another terminal that's our triad three that makes sense if you're you know more practice you could draw another terminal over here going that way that would be a triad these work as a unit and this is where we're going to see the action potential that started in the neuromuscular junction come down and start the calcium release process so everything here works as a unit so that's a triad questions on structure or vocab before we continue and see how this works for muscle contraction yes so just to be clear like sorry those two are the same things that terminal so this is one and every tubule which go the other side of the tub itself would have two terminal I terminal sister together so triad is one and two terminal two different other questions on this as you guys kind of work through yes yep longitudinal tubules so terminal certain kind of right here or right here and everything in the middle where you see a lot of more flattened increase service area that's your turn to good question other questions tricky organel evolve from the smooth endoplas reticulum so it's part of the endommembrane system of the cell it's interesting how these things get rearranged retoolled to fulfill a new purpose other questions on structure Right i have some questions for you before we continue these are sort of um warm-up questions for where we're going question one says "What triggers calcium release from the cyto reticulum and where is its target?" Question two do my fibbrals have membranes let you work on this for a little bit i'm going to walk around and stare at you awkwardly i haven't done that in a while feeling like maybe you're sorry about that i'm not sure i'm going to give it a shot see what happens once it looks like you've tried it talked about it i like to hear chatter come back up here and talk about this together before I continue the right hand side of the page i don't know so good can't wait it'll be frozen but we can go up to the the lounge warm up okay in the interest of time moving the answer to question one what triggers calcium release from the SR think big picture i haven't gone into the nitty-gritty yet this answer would change after I get to the right hand side but so far if one thing that's responsible for triggering calcium is the action potential good job so what triggers calcium released in the SR big picture again this is going to be the action potential which started remember this starts at the neuromuscular junction and that could be pretty far away I mean in a you know a long skeletal muscle cell if we think rectus forous could be easily 10 in 12 in a neuromuscular junction could be six inches away and that's kind of large distance for cells So it has to travel fast so that's the big picture answer is it starts at the neuromuscular junction due to the action potential where is the calcium that's released from our reticulum where is it target myofilament specifically act yep so if you'll notice we have a really interesting relationship structurally that nature has provided us we're going to see the majority of the calcium comes out from the terminal and it's going to be sucked back in the longitudinal tubules now everything the lumen here is continuous such that calcium could move around the lumen but if we let calcium out on the terminal cya or out of the terminal cya both ends and our target is actin do you see what we've created we've created the perfect situation where we've stored calcium we're going to release it right on top of the myofilaments specifically actin that need it and that is a beautiful thing even more as contraction begins and this circum shortens having the calcium released here ensures that that calcium is likely going to hit a portion of act that is not yet involved in that contraction you're continuously flooding a part of act that has not yet been involved in my interaction like it's brilliant like this is such a brilliant design like every time I look at it and think about it I'm like that is that's brilliant so we're going to see basically you can think of calcium as taking a a circle it's going to be released from here it's going to come down go into the myotuble or um the myophibro hit act and when it's time for this muscle to relax as part of that relaxation that calcium is going to be sucked back in feel free to use your favorite sound effect and get it back into the long so it's really interesting question two given what I've talked about I've talked about diffusion's great over a short distance diffusional boundaries and obstacles make it hard for diffusion to happen having said that do you think myophibbrals have membranes they don't have a membrane myophibbrals are nothing more than a tight collection of sarcamirs now if you're thinking why do you keep drawing these red tubes this is a good question i have internal debates about this myself if I did not provide some line some form for you to look at I think this would become even harder to understand i've got to give you something i'm gonna give it to you and I'm gonna take it away it's like the best form of learning so the red line here just shows you the combines or the borders when we have a specific collection of sarcamirs but in reality no membrane it's one of the few organels in a cell that doesn't have a membrane what's the problem if this did have a membrane take a long time to contract yeah calcium could be released from here but if you had a membrane that surrounded it wouldn't that form a great barrier for calcium diffusion absolutely potentially there would be no contraction so everything you see here the red line that I draw for myophibbrals is just to make the point that my fibbrals are nothing more than collections of sarcomir it would run the entire length of the myophibbral and there'd be some depth you know if we turned and looked at a myophibbral we'd find many many sarcimeirs making up that diameter are we okay that noise threw fruit at me there was no nonverbal communication that said I'm going to riot this is good this is good you got your hand in there so I'm going to move into how all of this works in relation to muscle contraction i feel like we've got all the pieces put together we have entered a non-verbal agreement where we don't like that there's no membrane for myophibro but we're willing to accept it it's like taxes i don't like paying them but I got to do it right it's an option otherwise it's not good um now that I've tried it right there so I'm going to move into making this functional this is a good time to ask are there any questions on structure because we're going to be using this to understand function and it goes a little bit more into function and less on structure yes directly no there's a membrane the T- tubules have a phosphoriler but what happens in the ECF within a T- tubule will definitely impact what could happen physiologically inside that so I guess your question I would say better is it depends are we talking direct or in a sequence of events does that make sense other questions okay well I'm going to move into the right hand side of this drawing and we're going to follow calcium we're going to see why and I read an article about this the other day and this was such a powerful statement i wanted to read it to you directly i don't I don't want to scramble it so these muscle physiologists were talking about how calcium is such a central part of muscle fizz but we always talk about you know strength and power and size but from a cell perspective this is interesting put this up here and read it to you the magnitude of calcium release from the soplaz reticulum is the primary determinant of the amount of force generated during muscle contraction just think about that i'm going to read it again because I just thought wow that really sums up the importance of this the magnitude of calcium released from the SR so what comes out of every terminal and there'd be a lot of terminals the magnitude of calcium released in the SR is a primary determinant of the amount of force generated during muscle contraction so calcium is so so important not just from a physiological standpoint for those of you going into athletic training or interested in athletics it's all about the calcium and you're going to have to increase and boost the ability of the cell to store it resequester it and let it go when it's time that's all part of athletic training is getting the cells to do what they need to do so okay now I am moving into the right hand side of this i'm going to readjust i always have like people looking in the window back there if you ever see me like staring at the doors because I always see like it looks like floating heads it's a little I want to say unnerving given my industry but it's a little it's a little weird i assume they're curious i'm not sure i'm nosy but it's never it's never the same sometimes there's three heads back there and that's like how is that working so you ever see me look off in the distance i completely lost it i'm just wondering who's who's looking um okay we're going to look at sequence of events follow the calcium and I'm going to break down what we just did now that you see big picture I want to break it down i want to add to it but also remind you things we've already done so we're building and we're renewing so this is a sort of a physiological sequence of events with a visual to help sort of enhance the process now that you've seen the big picture so we're going to start at a potential remember it's generated at the neuromuscular junction or NMJ and again that could be that could be far away you know in in in cell terms that could be really far away and so the wavy parts that you see here we've looked at that before that's going to be the neuromuscular junction the motor in plates of that muscular junction specifically and we're going to see that what happens there has to depolarize the entire circle there are no other cells in the body that work like this cardiac muscle gets close but cardiac muscle is really short so it has a lot of advantages when it comes to contraction zoom in a little bit here so I'm going to bring in a motor neuron remind you of some vocabulary and then I'm going to show you what it looks like and right now I don't have any myophibbrals involved i just have a neuromuscular junction some saroma on the surface and then a bit of a T- tubule where sarma dips in is going to form those T- tubules so if we think about kind of how amazing all this is we're still looking at an axon terminal of a sematic motor neuron and there it is axon terminal of a sematic motor neuron this whole thing is our neuromuscular junction and this wavy part here of our circle that's our motor end plate so always good to kind of revisit these vocabulary terms make sure you know kind of check in with yourself do I still know what this means and of course we would only be talking about acetylcholine in this area that's the only neurotransmitter that works and if we receive neur um these neurotransmitters correctly with our nicotinic acetylcholine receptors which are not looking too great right now um we would get the creation not of an action potential but as something that proceeds an action potential what is that something called a skeletal muscle similar to what we see in neurons but not quite the same vocabul so if everything goes well the neuromuscular junction at the motor in plate we will create an inflate potential a little spike it will increase the mill voltage and if everything goes well we should be able to create an action potential what see if I can ask this without giving away what specific protein in the membrane sort of the periphery of our motor implate do we need to convince to open to get this action potential to happen what protein there's only one protein that's going to make this action potential happen something about protein i think voltage gated what keep going voltage gated sodium channels so remember our nicotinic acetylcholine receptors would create our inplate potential but if we want to make a full-blown action potential and get a lot of sodium in we're going to have to use our voltage gated channels and if we get enough sodium in we should create an action potential now that action potential is going to go two ways so we sort of have like a a a point a dividing point to think about there are voltage gated sodium channels here which I'm just going to I'm drawing them very quickly but these are all voltage gated sodium channels we find voltage gated sodium channels down here because remember this is just sarcolma so we have voltage gated sodium channels here so that tells us the action potential once generated it's going to spread out in all directions just going to go across and and you know along the surface of the cell and every time it hits a T- tubule it's also going to go down into the cell so we see action potential spread along the surface and we see it down into the T- tubule so this thing really when I say entire saroma that's what I mean i literally mean the entire saroma not just in the service but remember T- tubules are made of saroma same composition same proteins everything's the same it's just the circle that goes down into the top so we're looking at how we going to get this action potential to do its next job which is depolarize this cell in a very consistent and uniform way so we're going to take a look at number two and here's where we're going to start to talk about what the act potential does so this is now T-tubu saroma it's this but a little bit farther down into the cell so the action potential moving along the saroma and those T-tubules right here stimulates one of several new proteins I'm going to introduce to you these have names that are not exactly logical i'll explain what they mean a lot of them are named due to the compound scientists used to localize where they were and so the name of the channel doesn't always tell you what it does that's a thing you will see this more and more i don't know how to describe it's a thing you will see this more and more as you continue in biochemistry and for sure physiology everything has two names usually one tells you what it does and the other tells you what they use to localize it isolate it find it and here's our first introduction to that so step two the action potential in our T so the action potential is going to come down the inside of the T2 group on the inside T that's going to stimulate a voltage channel and this voltage channel has two names i'm going to give you both because I don't know what you're going to get in the future so I like to tell you there's two names for this they're both correct one is DHPR dihydro pyramidine receptor that's the compound they use to localize it it has there's a reason why we call it DHR nobody wants to write that out but I use this L type calcium channel this is descriptive first of all it tells you what it does it's a calcium channel and L we can think of this as longlasting this thing opens slowly it stays open a long time and it's closes slowly so we can think of L as longlasting so in your future physiology or biochem courses they may refer to it as the DHP receptor totally fine most physiologists use L type calcium channel because it just makes a lot more sense so just be aware of what we're correct so now that we kind of have some vocabulary down I'm going to talk more about what are we looking at i'm also going to add in some fluid fil environments to kind of help steer you into what is still technically external to this cell and what is technically internal to this cell so I'm actually going to start up here remember on the outside of our saroma we have extracellular fluid and that extracellular fluid comes all the way down our T-tubules as we saw so here's here's this but bigger and so we're going to have extracellular fluid the same that maybe was flowing past up here day before now it's moved down here so we still have ECF got to balance that composition so we don't cause trouble for the cell and the intracellular fluid i don't have another light color that makes sense i'm going to use yellow i kind of feel like I already regret this but you never know till you try and you're like "Yeah I regret that." Um but we're going to try it i just trying to make two fluid fil different colors so you can see the ECF and the T- tubial is not the same as the ICF which I am now coloring in so ECF and ICF as always separated by a phospholipid billayer which is this circle this is looking like Easter colors is it not did you see they made a giant Cadbury egg this has nothing to do with anything the thing weighs 100 pounds and is 3 feet tall that's your useless fact of the day um back to this i'm going to talk about DHPR which is also L type calcium ch but can you imagine like a three foot it's a You know what a Cadbury egg is right like if you don't you need to get out because that's my favorite big three foot tall egg and it weighs 100 pounds and given what they make this out of I bet it would last like probably without molding for 50 years so you could eat on it forever i think this is a good deal anyway what does this have to do with muscle nothing nothing so these things right here are channels that we find in the sarcoloma two names DHPR for receptor or L type calcium channel and we're going to see L-type calcium channels in the heart so you might as well just cozy on up to it because they're not going away lype calcium channels are a type of voltage gated channel lype calcium channel these are voltage gated what does that mean voltage gated channel is it open all the time no it's gated what opens its gates change in voltage good what do you think's changing that voltage the action potential so we're going to add in coming down from the top what is approaching a big old bololis of sodium and that sodium is the change in mill voltage because it has a positive charge so as this as the sodium approaches moving with its electrochemical gradient it triggers a type calcium channels to open and they're slow to open and slow to close so they're going to be doing their effect for a while and in skeletal muscle their effect is not at all what they expected when scientists first found DHPRS or alt calcium channel they found them in all strided tissue so skeletal muscle cardiac muscle and in cardiac muscle which is where they were discovered first they did exactly what you would expect a voltage gated calcium channel to do is like pretty cut and dry i mean I wasn't there but the history it makes it look pretty cut and dry so the voltage increases the outside calcium channel opens and in cardiac muscle cells calcium flows in from the ECF into the ICF this makes sense it's a voltage gated calcium channel so then when they found these same channels in skeletal muscle that's what they thought it did because that's what it did in other tissue they found them in skeletal muscle similar placement along the T- tubules they expected this as usual action potential comes down triggers the opening of our voltage gates calcium channel these open so you can imagine like a little pore in what looks like closed channels now and calcium should enter and no matter how hard they wanted that to be true it was not true it was just not true and so scientists sometimes get too hellbent on an idea and they will go for it and go for it and drive to the ground before someone said "You know I don't think this is going to work we should try again." And that's what science is it's trying again and so it turns out these outside calcium channels open in skeletal muscle cells but they don't let calcium in and if they do it doesn't matter so this I don't know if this was a let down it was like what so anyway we're going to see these are going to open but what they do is not at all what we expected here's what happens building up a little bit more we still have sarcolmma i've now changed these voltage gated calcium channels to look like tubes and these are open because our act potential came and these are going to have a very interesting impact on another channel with a name that doesn't really mean anything the ryr also named for what they used to find it localize it and it stuck it doesn't have a second name all right as you finish this up oops not on all right as you finish this up I'm going to I had made the SR lumen kind of a green color before i'm going to change that this is still the SR this is still our lumen but I think if I switch colors sometimes that can be problematic because you're like wait is that ECF it looks like ECF all right so I'm going to fix that what we're looking at is just a different aspect of some things we've already talked about but different aspects make you look at a little bit closely more closely examine your understanding do I have a triad in this picture what do you think do I have a triad in this picture i do have a triad in this picture really big one because I'm trying to explain the significance of a triad um so just as a reminder what's a triad it's two terminal of two different cycoplas reticulums and one T-tubule and these act as a unit so everything you see here with our DHPRS or L-type calcium channel both are correct i just drew them a little differently so they look like they were opened because they need to be open now and our new tubule our new protein this is the R YR the Ryanodine receptor named because they localized it using a compound called ryanodine so I'm going to make this work now but just again got a triad two terminal sister and a T- tubule and we're going to now see how the function of that triad unfolds and why it's important to talk about it to this level so where we left off in the panel above we had the sodium approaching this is the action potential and our closed DHPRS or LT type calcium channels now they're going to open so the confirmational change going from closed to open that's what I mean by confirmational change going from closed to open as a result of our action potential the action potential by this point has come and it's already gone it's it's moving on it doesn't stick around so the action potential has already come and moving down even farther so it's done its job and in this particular case the job is again changing the confirmation of these channels so the confirmational change here does open a calcium channel and as I mentioned before scientists truly expected calcium to flow in from the ECF into the ICF because calcium is higher in the ECF than the ICF always it's just like neurons it's a magnitude several magnitudes higher in the ECF than ICF so they're like well calcium channel opens you have a diffusional gradient of course calcium will enter and even if it did it wouldn't matter even when they reduce the calcium levels in the ECF it didn't change skeletal muscle function and I was like well that's strange so it turns out what this is doing when it changes confirmation from something closed to open is I like to say it high-fives it gives a little high five to the RYR and it tells the RYR "Now is your time to open." So this has what some medical textbooks describe as it's a little iffy uh a physical relationship with the Ry so take from that what you will i like high five that seems safer doesn't it from an educator perspective it's going to high-five it because that's what we're going to do so Lype calcium channels open high five the RyR and it turns out the Ryr that's our giant calcium channel that just absolutely allows a massive amount of calcium to go from the terminal cesterna of the of the SR into the ICF it is the RRS that you can think of as really your calcium floodgates so I'm going to add a few labels to this so these orange tubules here both sides I'm just going to label this one this is the R YRR and there would be many on your terminal sister RNA just like there would be more than one L type calcium channel but these are absolutely massive calcium floodgates and we have a ton of calcium stored in the saropas reticulum and if given a chance it definitely wants to move down its concentration gradient such that we now get a bunch of calcium in the ICF so let me take a moment and talk about where did this calcium come from usually I get some questions on this so action potential came down inside of the T- tubules opened our L-type calcium channels L-type calcium channels as a result high-fived the Ryrs and that is what allows a lot of the calcium stored in the SR to leave and come out into the ICF this is called a calcium spike do we have calcium ions that could have possibly entered from the ECF through this channel and into the ICF could we yes we could does it matter no it doesn't so are they there from the ECF maybe but in the end it's not enough to matter and even if you had hypogalcemia and not enough in the ECF your skeletal muscle cells would still contract and that's because they store enough calcium inhouse to prevent sort of lowgrade ECF ion problems from impacting skeletal muscle and that turns out to be crucial for survival like making sure the diaphragm can contract and you can still run away from danger so a lot of the ion management that skeletal muscle cells have come from an evolutionary standpoint which is well we can't do it the same way other cells do because we'll run out of an ion gradient that supports function we don't have that many ions so skeletal muscle cells do things a little differently to make sure that you can survive and I I think nine out of 10 people would say that's a good idea and I don't know what happened to 10 person i guess they didn't have the ion concentration who knows so we're going to see what happens now as a result of these opening and then asking these to open and then just an absolute calcium spike in the ICF so we're going to go to panel number four so it's the opening of the RS which I drew a little bigger kind of gave them more volume so it looks like they're you know like open um that permits the calcium e-lux from the sarcopas reticulum lumen and this is sarcoplasm i'm not sure what was happening there um but that's sarcoplasm so I'm going to change the color again here so lumen of our SR here terminal cesterna and I've given the ry just like a little bit more structure and volume to help you understand they do change shape or confirmation and now they're fully open and and we're just getting an absolute massive um just spike of calcium in the ICF here where is the target of all this calcium where's it going is it going to go into the myophibbral yes what is it going to target inside the myophibbr actin good a myofilament known as actin so your sarcimeir would be in here i thought about drawing those in there but it just gets too messy your Zline would be about right here and your sarcimeir would be under there so again what a cool function here we're dumping calcium right on the actin filaments that are likely least involved in contraction at this point the timing the structure everything about this is just so incredibly precise and just really like like well refined so Ryr's rayanodine receptor again that's their name and they're going to dump calcium into the ICF or cyoplasm cycloplasm is ICF your L type calcium channels are still open slow to open slow to close could you still have calcium coming in from the ECF yes would it matter not really so sometimes things happen it's like you know as much as we'd like there to be significance to that if it exists we have not found it yet and I feel like that's the most accurate way to say that because as soon as I say it doesn't matter at all and it never will somebody will come along and go "Look it really matters." So I'm not going to say that but right now it's the SR that has the calcium okay now we're really getting serious stuff's getting real we're going to see where the calcium goes because hiding under our cycloplasmic reticulum has the whole time been sarcimeir i don't have the circles reticulum drawn here i don't have rs i don't have lype calcium channels drawn here i can fix that but right now I want to remind you where is the target of all this calcium well it's in a myophibro which is buried underneath and not just any myophibbral part i have a specific part of the acting this and that's called C introduce to you a complex of proteins fondly known as the troponin complex again I I put a line up there to represent where the my fiber is it's still red and in reality it still doesn't exist so if you don't want to draw that that's fine i If you're showing people a visual you need to have something to look at um but the red line there is just as a reference that would be the area of the particular my fiber that we're talking about sarcimeir are just held together by reticulum and the proteins that make up the sarcimeir themselves which is why you can add sarccomir if you're building muscle with a membrane surrounding it that would really limit muscle growth so two reasons why we don't want a membrane so I'm going to add some detail right here really just for clarity just to make it match other things we've looked at this is still a T- tubule we're still looking at extracellular fluid nothing new there still have a phosphipid billayer to our saroma we still have a myophibbral with an imaginary membrane and what is a myophibbral made of sarcamir and so sarcimeirs true contractile unit skeletal muscle um I don't have another Zline over here i regret that i'm going to fix that uh just to make a point a little bit clear so what we're looking at here is this aspect i've taken this sort of left side moved it down zoomed in and I'm really interested in you know what's happening as a result of this calcium spike that came as a result from the Ryr's opening so these two kind of go together because it's showing you like top view and then like inside view so the calcium that came from the RS that were just opened diffuses it's got to have a diffusional medium and that's cycloplasm or ICF so it's coming out and it would go inside the myophibbral i've yet to figure out how to draw this such that it looks like it's going in but if we came down here this would be surrounded by the SR i'm not going to draw that right now because it's going to make this harder but the SR would still be surrounding this we would still have you know terminal in this area longitudinal tubules here terminal cesterna here so that's kind of business as usual but what I want to talk about is where does the calcium actually targeting and that's part of a complex the traroponin complex and specifically in our traroponin complex a very particular protein called tropponin C now the nice thing about traropponin C is C for calcium so it tells you what it binds and the others are not so kind so it's nice that this kind of tells us what is it doing well it's binding calcium so on actin remember actin's our thin filament I always try to draw it blue we have this complex three dots this is the traropponin complex so the three dots here which are they always exist as a complex so here's a tropponent complex and here's a tropponent complex some over here the tronin complex exists on actin in very regularly scheduled spaces It's a complex meaning it has subunits one of those is tronin C which I try to draw green to match calcium but I don't really think it's showing up too well but this is traropponin C right here i'm going to make it I don't know is that making it better worse tarpon C is what's going to bind the calcium that just came from here takes two calcium ions to activate troponin C so the green here that's tronin C binds two calcium ions and those two calcium ions activate troponin C and as long as calcium is in the cycoplasm C will be activated and that can be both great for muscle terrible for muscle depending on where we are the other two dots we're going to see in a moment what they are but there's tronin I which drives a complex act and then tarpon T your point of T is going to bind this whole complex to a very different protein which I have not um introduced yet so all of this is showing you the target of calcium so don't lose you know sort of the big picture goal here the goal is to say where is calcium going once we get it out appropriately timed well we're going to see it binds to troponent C takes two calcium ions per troponent C to activate the complex what does tropponin C and calcium have to do with anything this binding of calcium changes the confirmation of the entire complex even though troponin C is what binds calcium it changes its confirmation in turn changing the confirmation of the complex and that actually leads to the ability to reveal the measin binding sites on actin so binding calcium changes the confirmation of the entire complex and that causes tropomyiain which is this small blue threadlike structure to change its confirmation on the picture I've drawn in I moved it even smaller i picked this area right here and that's what you're drawing the T- tubule is kind of irrelevant at this point we've already got the calcium out what you're looking at here is a more accurate structure of actin actin is the thin filament but technically it's two distinct proteins that are wound around each other much like um you ever try to get two necklaces that are chained out of a jewelry box and not have them come out in a giant wad and you spend 30 minutes undoing them only to figure out I don't really want to wear this anyway so um actin actually is two separate filaments stringy filaments wound around each other still thin compared to measin but the the little sort of circles here are are meant to sort of illustrate that actin has some interesting protein structure and actin with the help of some other proteins attaches to the zline here so the the blue circles that's actin the blue thread sort of weaving through actin that's tropomyiain and tropommyiain is a a regulatory protein it regulates when the meosin binding sites are open available to bind with measin so I'm just going to label some things here the blue there this is actin our thin filament the threadlike structure here this is tropomyiain and the kind of upside down red looking commas that's our measin binding site and so just to add what could bind there is a meosin head which looks like it definitely wants to fit in that measin binding site so each of these red upside down commas this is our measin binding site and right now the measin binding site is blocked and that prevents muscle contraction when we're not wanting it because we don't always want muscle contraction we have to very carefully control it oh and we finished and on time wow uh there you go this is the natural stopping point and we're out of time so how lucky are we so I'll pick it up on Thursday let me know if you have any questions