Transcribed by Stephen Holt Organ Systems 18- Control of Breathing by Dr.

Pavlov

April 3, 2014

[33] So lets move on in this part. Just finished with the previous lecture and Im not really used to this like double lecture scheme but in anyway so this just kind of a last couple of slides just to finish with the gas transport and this the carbon dioxide transfer by the blood as I mentioned. So oxygen is fairly simple because it all goes through hemoglobin and then for carbon dioxide which is carried back from you know cells again by the blood and its like a little bit more tricky but not much and I guess we will not need to go through all of this like complicated schemes but I just kind of bring up 3 important ways how to transport it. So there are like 3 ways so its not really, theyre not equivalent but they arefirst is dissolved like any other molecule it can be dissolved in water and can be carried in. Then the second is carbon in compounds so pretty much it can modify the amine groups in hemoglobin so its not the same binding site as oxygen although it will be affected so pretty much what youll need to know is CO2 can be transported by blood cells in the form bound by hemoglobin. And the third one is the most important and it is CO2 transport in the form of bicarbonate ion and this is achieved like you know the enzyme which is located inside the red blood cells which is the RBC here. So what it does is it converts CO2 by interactions with water it converts it into bicarbonate ion and in this form it can be essentially carried through the blood and this process is reversible. This reaction is reversible so it can go back from bicarbonate ion to CO2 when kind of time comes for example when it reaches the alveoli like gas exchange place it can be converted back into CO2 and it can be diffused from the organism. So basically the idea here is 3 types of carbon dioxide transport: dissolved, carbon amine compounds, and bicarbonate ion and this probably all I have to say with this respect. [34] And just summarize what we just discussed about gas transport so its kind of very important concept that it is a passive process so it goes down the pressure cascade and then the ventilation, alveolar ventilation, links rays of ventilation and carbon dioxide production so this is the key equation, alveolar ventilation equation. And then diffusion rate, we talked a number of times about this already, so its the surface area and thickness is key things to defining the diffusion ratio going kind of in opposite direction. And then the ventilation and perfusion, they need to be matched so this matching is the parameter in which kind of characterizes the goodness of this information if you wish, the ventilation-perfusion ratio which is kind of close to 1 plus minus depending on the metabolic state of the organism. And so the key way how oxygen is transported in the blood in form of binding to hemoglobin and then in terms of carbon dioxide its bicarbonate ion which is the main way for CO2 to get along in the blood. And so now what Ill do, Ill do the last slide, let me do that, the last lecture sorry, control of breathing.

Transcribed by Stephen Holt

April 3, 2014

[1] So this is the last lecture for today and this is about the control of breathing so again we kind of reviewed most of the key features and key properties of the respiratory system and now this is kind of a look at how actually this is controlled by the organism and like how any other organ in the human organism it can be controlled by nervous system and here well just kind of review briefly the key signaling mechanisms in term of how the nervous system functions in order to provide this control over the respiration so well look at kind of general ways ventilation can be controlled and then well look at organization of the receptors and different control centers of the respiratory system and then well look at different laws like again not in terms of equation but in general curves like how this receptor which sends the goodness or the respiratory system how it sends the concentrations of gases or pH. And then well look at these links between response of ventilation rate and these concentrations. And then well just briefly look at the regulation of ventilation during exercise. So its kind of a fairly simply process. And at the very end Ill kind of mention a couple of slides about cellular respiration which I think is quite important its a little stand alone subject but again itll be at the very end of the lecture, again I didnt put it up here in the main points. [2] So in looking back at our main scheme so I just kind of wanted to introduce you to the general varying of the system so essentially this is kind of our main cartoon which kind of systematically represents the whole respiratory system from the lungs, capillaries, and cells and here you can see this system is essentially attached to the brain like in a way that kind of, the brain kind of has a sense you know in lungs or in blood and then so it kind of sense what is going on and then it responds and sending signals to the respiratory system how to deal with the situation based on the information it gathers. And here is the main kind of varying of the nervous system. So two things you would get. You would get information about the function through the bunch of receptors, youll get information how the system is functioning through sympathetic and parasympathetic nervous system and then you will send back you know signals like as a response signal through motor neurons through the skeletal muscles, like diaphragm or intercostal muscles to tell them what to do, you know like contract more or less, like whatever well look at that. [3] So again this is the overall schematic representation of how this system works like it in term of involuntary control system. So this is like pretty much it has this afferent and efferent input, so one is input information and one is output. So I will start from this part of the description so what well have is a bunch of receptors. So lung receptors and this behavior so dont worry about that for now. So say you have lung receptors, chemoreceptors in the blood or mechanics of the lung and they will kind of send some information, if there is something going on with the blood or with the shape of the lungs or some kind of behavior conditions. And then it will send it to the brain for the integration and for processing. So pretty much brain analyzes the input and then it will send output to change different parameters whether it be

Transcribed by Stephen Holt

April 3, 2014

ventilation or change in muscle contraction or secretion of some compound from the glands so it will kind of try to correct whatever input it receive if something is abnormal. And after this is correct this will cause the end point of this correction will be the change in gas exchange or mechanics of the lungs. So it will be like working harder or slower and this would kind of provide the feedback, so this change in the ratios of this parameters will send signal back to the receptor which will kind of analyze whether the situation was correct or not and send more signals to the central system. So anyway this is kind of circle of the mechanism of negative feedback. So afferent input, integration and processing of the signal, output signals sent and then this negative feedback which provides information about the change. [4] And so this is just an example of how neuronal system kind of regulates the activity and this is one of the kind of simple examples I just pulled it from the Johnson textbook just to show the exact control of the respiration of the simple like inhaling and exhaling air in total volume here. So this kind of normal breathing. As you can see as we discuss pretty much the inhalation is diaphragm and internal intercostal muscles and you can see the activity of the neurons so its not the kind of muscle this is the activity of the lungs like how they expand. And this is the corresponding activity of the neurons which is motor neurons which stimulate muscles for diaphragm for example. So they start firing, they stimulate muscle, it contracts and you get this inhalation. And you can see the neurons which stimulate external intercostal muscles and diaphragm they are active whereas the neuron which supposed to stimulate internal intercostal muscle which is responsible for expiration is silent. And this activity here changes when you have expiration so its probably some active exercise because normally you would not have this firing but here pretty much if you have expiration this neuron becomes silent and this starts firing so this pretty much an example how you have this relationship between proper contraction of the muscle and proper neuron firing so essentially this proper timing of contraction, expiration and inspiration and expiration is actually governed by essentially the neuronal activity. By good timing of the neuronal activity. [5] So this is the main kind of cartoon in terms of brief anatomy of the location of the control system for the involuntary control. So essentially there are like 2 main areas of brain like one is called medulla oblongata so you can call it just medulla for simplicity and another area is pons. And there are like a bunch of groups of neurons which are located in each of these areas and they are somewhatthey kind of based on experimental data are divided into different centers and it is believed that a different group of neurons is located here are responsible for different function. And I just kind of outlined here like main groups of the neurons so in medulla you would have dorsal respiratory group is just by the location right. You have dorsal respiratory group which is responsible for inspiration mostly and you have ventral respiratory group which is responsible for expiration and you have this prebotzinger complex which is essentially what it is is a rhythm generator which is one of the features of the respiratory system that it has kind of some, it can go like up

Transcribed by Stephen Holt

April 3, 2014

and down in terms of intensity but it also has some center which can be responsible for rhythmic breathing. So you have to breathe all the time at some basal level. Its kind of like the pacemaker in cardiac situation. So theres also some rhythmic generator complex which is also located in medulla. And for pons so youd have 2 centersapneustic center which is responsible for excitatory function and pneumotoxic center which is responsible for inhibitory function and again these kind of different centers they talk to each other and Ill give you some example of the varying kind of how it happens so well know its bunch of different groups of neurons and each are believed to be responsible for certain function. [6] So again and there is another important concept which will kind of, Ill just have to mention about breathing which is really I guess somewhat unusual because in addition to involuntary breathing which we are always breathing. So we can breathe when we sleep we also have this process of voluntary breathing which kind of originates in higher central nervous system. So what it is its located somewhere in the cortex and in some other parts of the brain. And well not really talk about anatomy of that but we need to appreciate that we can control our respiration to a certain extent, we can hold our breath. As I speak naturally its not really controlled by the brainstem but somewhere more kind of advanced places which allow me to remanipulate my breathing pattern and overall. But the end points is this is voluntary breathing control system which can override to some extent the involuntary system and you could probably hold your breath to some point but at the end of the day the final response is actually a combination of voluntary and involuntary signals and one of the good examples is you can hold your breath to certain extent and when it comes too problematic than involuntary system will take control. So you can override it a little bit but only to certain stage and you lose this ability so you have to breathe and its beyond your voluntary control. [7] So this is like again, just looking at some kind of position of the respiratory center in the brain stem, you can see here I already introduced this pneumotaxic center and apneustic centers so they can play opposite role in respiration. One is inhibitory and one is stimulatory and so again they connected to some respiratory groups like you know in the brain stem so one is dorsal, one ventral. So I just discussed a couple of slides ago, just putting them in some geometry of the system. And obviously they have this input neurons and also have this motor neuron output. [8] So anyways now going how this system is sensed right? So pretty much as I mentioned theres this input system and output system and now well talk a little bit more about receptors. So pretty much all this information which we kind of receive from different areas of the lungs and organism of the blood vessels it needs to be processed here and somehow kind of responded to right. And this is provided by the bunch of sensors which kind of spread throughout the organs, throughout respiratory system in different areas and well focus mostly on these two and also

Transcribed by Stephen Holt

April 3, 2014

mention some other event so well not really talk about these receptors. These are the two, chemoreceptors which kind of define the pattern of breathing and so the first central chemoreceptor which is located in the brain and the second are like peripheral chemoreceptors which are located in the blood vessels right and theres also like lung receptors and some other like you know nose airway and muscles and stuff like that. [9] But for now lets look at central chemoreceptor cells, so those are as the name implied they are central so they are located kind of close to the inspiratory area and they sense the change in proton concentration in the environment and this is [10] how this happens. So one of the important things about central chemoreceptor well as I said its not really anywhere in periphery but close to the respiratory centers. And what happens here is this is a schematic representation of how this receptor works. So essentially what they used for, they used for to sense the change in concentration of like partial pressure of CO2 in the blood vessel, like you know which comes to the brain, and heres this heme how this works actually they do not literally sense CO2. But what they sense if something changes with CO2 and its concentration becomes abnormal what this cause is it causes, like CO2 can diffuse freely through the blood vessel and it can be like located in the environment so it passes through the blood barrier and can be located in the vicinity of the chemosensory neuronal cells so the receptors which here and what happens is CO2 can be converted and proton and overall the end point of this reaction is the change in concentration of protons or change in pH in other words. Because pH is essentially the value of the proton concentration. And this would be sensed by chemosensitive receptor. And by doing so pretty much by sensing this concentration it can respond. So if CO2 changes to some abnormal levels then proton changes and this receptor starts responding and sending signals that something needs to be done and normalize the CO2. [11] And this is the response of central chemoreceptors so they respond to pH changes in extracellular fluid and this pH change from normal is caused by the diffusion of CO2 as I just mentioned here. So this is first concept of central chemoreceptor so the important point here is that they sense the change of CO2 and then immediate response is the pH change, so they respond to pH as a consequence of CO2 in blood. [12] And the second very important receptors are peripheral chemoreceptors. And unlike central chemoreceptors which is located in the brain so those receptor so those receptors are located in the arteries so essentially they are called carotid bodies. So located in carotid artery, and called aortic bodies so located in the aorta. The important thing about this receptor is they fire away and they sense their

Transcribed by Stephen Holt

April 3, 2014

condition so they sense the changes in arterial blood so its one of the important. So its not venous so both of them are sensing arterial blood change. [13] And here we will look how the sensitivity works so we will not look at biochemistry of how and why they change but we will look at how they respond. So pretty much the response of the carotid body receptors and overall in physiology I think most of studies have been done on carotid body receptors so pretty much they assume they are all the same, the aortic receptors and the carotid body receptors. So well look at that and the important message here is you can see, so this is the frequency of the neuron firing. So this is how it sends signal to the cell and to the central respiratory complex. And as you can see it can respond to both and to the concentration of CO2 and it can respond to the change in also in concentration of oxygen. And one of the important messages here is these receptors like carotid body receptors, they are not really all that active under normal conditions. So you remember this number 40 for pCO2 and for arterial O2 they are like about 100 so pretty much these receptors and not much involved in regular activity so there are not much firing. And when they become important when something dramatic happens. As you can see all the activity like bulk of the firing of this receptor of course if O2 goes out of normal range from 100 and again this is arterial O2 so it should be 100. But when it goes down for example if we have some abnormal diffusion or something wrong with oxygenation of the blood for whatever reasons like ventilation then this neurons kick and they start firing much more. And thats when they actually become important. And here its also the response to pH so you can also appreciate that they can sense changes in pH which will also be reflection of the abnormality of the blood composition and here is the same so pretty much if pH drops and you can see that this receptor will start firing more. But overall its the combination of 3 parameters which are carotid body receptors, sense, and 2 important notes that actually response is not important in normal conditions. And actually one of the differences between carotid and aortic bodies is actually only carotid body respond to pH. [14] So this is the summary of the properties again I just mentioned them but kind of to summarize this part. So it is like really, they respond to all parameters in arterial parameters, not venous, but partial oxygen pressure, partial CO2 pressure, and pH. So all the important note here is they will not sense hemoglobin-oxygen saturation which is kind of one of the important concepts but we will not discuss it much more than that. But you can probably appreciate that all neuron receptors do not know what is going on with hemoglobin-oxygen because they only sense oxygen in the blood, like dissolved oxygen so again its self evident but I just wanted to mention. So they dont play much role in normoxia and the normal conditions so theyre also located in areas of high blood flow. And this kind of determines their very fast response so they kind of sense the blood like very quickly so the condition of the blood they can assess it and if something dramatic happens they can respond right away, so very fast response.

Transcribed by Stephen Holt

April 3, 2014

[15] And this is kind of the combination, so we talked about the response of each particular conditions in terms of neuronal firing. So I guess what is happening here, is first we change condition the neuron starts firing and sends information. And then this information is sent back to the muscle for them to respond. And this is essentially the end response, the combined response of the you know of the ventilation. So this is ventilation rate, not neuronal firing. So this is the end point response which is like quite expectedly kind of corresponds to the stimulation of neurons but then again this is a process signal after it has been understood by the brain and processed and again here is the response. And again if you look at this rate of ventilation as a function of the partial pressure of CO2 and this partial pressure change is caused by the change of CO2 in inspired air so as you inspire more you get an increase of CO2 in blood and this leads to stimulation of the ventilation and here is essentially the function and it started quite well and this is the relative contribution to this particular response. So as I mentioned the end point will be some type of integral response of everything so pretty much anywhere from central nervous system if it knows you have too much CO2 and kind of thinks you need to respire better to all this components but in this case it has about 75% response of the chemoreceptors. Which will sense change in CO2 in the blood vessels in the brain and 25% will be from arterial chemoreceptors which sense instantly the change in CO2 concentration. [16] And this is again going to this ventilation response, so again this is combined response now its like were looking at pulmonary ventilation like which will be the integral response from different sensors and you can see it will depend on few parameters and here just comparison of how they sense the concentration of oxygen as a function of how much CO2 is present and its also fairly straightforward that if you have more CO2 you have increased response so pretty much at the same amount of oxygen ventilation will be higher because CO2 is high so the organism will think it needs to circulate blood faster to get rid of CO2. And the same is true, it will be lower if you drop CO2 to some point it will become slower ventilation at the same amount of oxygen. [17] And this again is the integrated picture so I dont really want to spend too much time but it kind of summarize the response of ventilation on all 3 parameters. So it will be oxygen, CO2, and pH. And I guess you can probably you know kind of try to look it up and to see but overall the overall concept here is that all these 3 parameters matter so pretty much the more oxygen you would have, the less will be ventilation, and the more CO2 you have, there will be more rates of ventilation and the same is true for pH. So pretty much if pH rises then you can tolerate more CO2 without more respiration whereas if pH falls then you need to have higher ventilation. So again just look at these 3 parameters and see how they all fit together. So repeated and if you carefully look at this plot I think its pretty easy to grasp about all these relationships like again you dont want CO2, you want CO2 low,

Transcribed by Stephen Holt

April 3, 2014

you want oxygen high and you want pH also high right? So thats kind of 3 things to review. [18] And now just a couple of more slides before we go to cellular respiration part and this will complete todays lecture. So this is ventilation during exercise and this is kind of fairly simple so this again is the ratio between oxygen consumption and the rate of ventilation and this is pretty linear so you can see how the more oxygen you consume, the more serious exercises, the more oxygen you consume and the curve will be a total ventilation. Which is like pretty much the same if you look at his other ventilation equation where we looked at CO2 production how its really linear so this is really similar. So oxygen consumption and CO2 production its kind of 2 sides of the same coin right. And you can see how linear it is and this all kind of nice and clear but actually I just wanted to point out at one thing. [19] Which kind of doesnt have any good explanation in current science but its really pointed out in the textbook and I think its really distinct phenomenon which describes like the very big complexity of the neuron control of ventilation and what it tells you that actually if you exercise. So if you look at arterial pCO2, so what we pretty much just described if pCO2 rises, then organism response would have ventilation right? And you can see as soon as you start exercise, pCO2 actually drops, so pretty much ventilation increase right away and pCO2 drops. And there is no really good explanation to that because CO2 is not dropping yet but the ventilation is already increased. So nobody really understands why it happens, perhaps its because if you start running you anticipate, your central system anticipates you would need more oxygen and thats why this curves but overall yes, its really not well understood in the end. But as you can see here, in the end what happens is you start kind of ventilating and you start running more, you ventilate more until you settle with your pCO2 at the exercise level which is back normal to 40 and then everything is kind of fine in terms of exercise. But the opposite is true as well, you would have you know after you stop exercise you stop ventilation, pCO2 goes up, and pretty much somehow you lose this control of pCO2 so pretty much it still goes up because perhaps you still kind of working. But the organism some how after exercising doesnt really feel that. So it really kind of drops ventilation despite the fact that pCO2 is fairly high. And this is not very well understood phenomenon. Im not really going to say more about it because I dont understand it either. [20] So in there are some other receptors which Ill just mention and we wont really go into details other than I kind of mentioned that they exist if you wish. So theres some pulmonary stretch receptors located in the lungs so they sense how much our lungs expanded or contracted in this sense, the degree of stretch of lungs is useful sensory information. Its considered by brain and it tries to tell about, tries to decide what to do with the respiration. And then irritant receptors like in the nose for example. This is like sneezing and to protect you if there is some big particle that

Transcribed by Stephen Holt

April 3, 2014

happens to procure in throat or nose then we sneeze to kind of, to get rid of it. Theres also some J receptors and some bronchial C fibers so some are positioned close to alveoli and again they sense the situation here in terms of lung stretch and in terms of conditions where there is some (?) margins and they send response to the neuronal processing center for the change in respiratory pattern. Again this I just wanted to mention and I really dont want to spend much time discussing those ones, just so you know so by far what well be talking about and on the exam is the central chemoreceptors and the peripheral chemoreceptors for this carotid body and aortic chemoreceptors but there are some others so just be aware of that. And they are important in certain conditions but not in the context of our course. [21] So to summarize what we talked about, respiratory sensors located in two areas: in pons and medulla. And their activity can be partially overridden by other systems in cortex. And central chemoreceptors located in medulla they respond to pH change, and then carotid and aortic bodies are peripheral chemoreceptors and they respond to pH, oxygen, and to some extend to carbon dioxide. And the pCO2 in the blood is the most important for control for ventilation when you have normal conditions. And I just want wanted to before we finish today to [22] I want to spend pretty much maybe 3 more minute, 5 more minutes talking about this energy metabolism. So essentially I think this is very important concept and it is in physiology textbooks but I dont think its very well described so I wanted to introduce it here and look at the actual respiration, the mitochondrial respiration and again just couple of slides and then well be done for today. So again this is a review of energy metabolism and as I mentioned in the introduction lectures so what youll do is youll have mitochondria here which consume food and what they do they actually consume oxygen produced in water and produce ATP and you release CO2 and using ATP later by the cell for useful work. And I just wanted to show [23] A couple of slides of mitochondria are and how they work. And mitochondria essentially theyre vesicle. They have 2 membrane vesicles and this is the structure of mitochondria. They have inside space called matrix inside 2 membranes. They have this cristae which form kind of continuous inner membrane so those are not separated stuff they are like really continuous membrane. And then there is intermembrane space between cristae and outer membrane and outer membrane is in the outside. And the mitochondria can be different in different cells and they are very important and so this a mitochondrion in a cell in the brain and this is mitochondria in cardiac cells. So this kind of illustrates the importance of respiration and energy production for cardiac cells for example because essentially all mitochondria, essentially more than half the cell space is taken up by mitochondrion. And so and here is how you know how respiration works. So essentially what you have after you have processed all food from glucose it sends up

Transcribed by Stephen Holt

April 3, 2014

to the molecule called NADH and what it is is an energy rich molecule. Its the last kind of energy step which kind of goes to the mitochondrial respiratory chain. And here you have an NADH molecule donates 2 things. So electron and proton to the set of enzyme in mitochondrial inner membrane and this enzymes are called respiratory chain. And what happens here is you have a bunch of process like electron starts to travel before it uses up oxygen to make water in the end. It starts to travel along this enzyme down its electrical gradient. So there is big energy drop from electron going from the first complex here down to the fourth before it goes to oxygen. And this drop of energy is you know its paired to the transport of protons through the enzymes from inside of the mitochondria to the outside right? So this is membrane inside mitochondria-inner membrane right- and the proton is going out. And this process actually takes up 98% of oxygen which we receive in terms of respiration. So essentially this is the essence of respiration is having this thing working. So using energy of food to create this flux of electron to the water and pair this for the proton pumping. And the end result of this process is the generation of the electrical potential in the membrane. So essentially what mitochondria work is they work as a battery. You would have this membrane which is like again like 2 sides of a battery and when protons are pumped they create a lot of positive charge outside and a lot of negative charge inside. So they create this energy source here which is about 180mV and this is the essence of respiration, thats what respiration does it uses food and oxygen to create this electric potential which our organisms is using. I guess one of the important concepts I wanted to introduce is actually mitochondria do not produce immediate ATP, they produce electric energy and essentially our organism is a battery rather than some ATP production stuff. And this is what respiration does, it creates this battery charge inside of every mitochondria and then what happens is it starts making ATP based on the use of this electric potential. And this is process called oxidative phosphorylation. So basically there are like 2 steps, and this concept I wanted to introduce because its very important for all kinds of life and its one of the basic concepts but its generally not well described. Not that I can describe it better but I wanted it to try. So there are 2 processes: oxidation and phosphorylation. And they have to be kind of broken down and thats what happening in mitochondria. You have oxidation which is basically using oxygen to create water. And you have phosphorylation which is completely different. So phosphorylation is after youre done with oxidation you have this membrane potential and second is phosphorylation and as name explains its adding phosphate to ADP molecule and making ATP right. And this process is really like has to be coupled to the respiratory chain but again respiration not necessarily leads to ATP production, it leads to the charge of the mitochondrial membrane and heres some example how respiration can be used as well. All mitochondrion know is they know to make membrane potential but then this can be used in different ways. So it can be used in phosphorylation for useful energy production but can be also dissipated like it can be used up for calcium transport or calcium signaling and but again this will not really effect the respiration as I said. So respiration and mitochondria dont really know how its used up. And whats important here is you can probably have normal respiration but not get energy if something is wrong with this membrane and this really happens in some

Transcribed by Stephen Holt

April 3, 2014

pathologies so you can have some conditions where mitochondrion do not make ATP but still respire quite well but oxygen is still consumed well and this is a bad kind of condition which could happen in chemorespiration(?) injury for example. And again well not go into this into details but I wanted to kind of stress that you would have respiration which is oxidation and phosphorylation which is separate and they have to be coupled you know for proper processing and Ill just [24] finish with that. Its really just to stress this point that this is mitochondrial respiration so now were going down not even down to cellular level but the level of oxygen consumption here. And you can see if you give mitochondrion enough food and then you give ADP so you ask them to produce energy this is the respiration. This slope is how fast they respire. So you will see that actually they will respire quite well because they need to make ATP from the ADP available. But at the end if you have special drug which would case the stoppage of the function of ATP synthase of this enzyme which uses membrane potential to produce ATP then they pretty much stop respiring here and do not produce food and are not respiring here. But then in the end what happens you can restore like really strong mitochondrial respiration not by asking them to make ATP but just by shortcutting this membrane potential. So you can give drug which will reset this potential to zero. And thats what happening here this FCCP drug what it does is the mitochondria tries to build up membrane potential but it resets is. So this mitochondria does not make any ATP so theyre essentially dysfunctional as far as cell concern but you can see they use a normal respiration so theyre really respiring hard because theyre trying to build potential. So this is uncoupled state when you have a lot of respiration going on so pretty much no ATP production. So I just want to finish here and these 3 slides dont worry about them, they wont really be used on the exam I just felt it was important to talk about those. Thanks.