Action Potential & Synapse - Physiology PDF

Into a repolarized state we have a state the loss of cations, in this case now it's potassium leaving our intracellular space and now we are going to repolarize. We're going to come back down into a negative state along our resting or along our membrane. Potassium channels are very slow in general,...

Into a repolarized state we have a state the loss of cations, in this case now it's potassium leaving our intracellular space and now we are going to repolarize. We're going to come back down into a negative state along our resting or along our membrane. Potassium channels are very slow in general, and there are different types of sodium channels. Obviously, I'm trying to kind of generalize this when I'm explaining it. But in this case, potassium channels move a little bit more slowly than the sodium channel so that sodium was open, floods sodium into the cell, and then kind of almost immediately is inactivated Well, once that potassium channel opens, it's slow to open and then it's slow to close. So we're just constantly losing potassium to the point that we overshoot our original resting membrane potential. And so our cell membrane becomes even more negative than it normally kind of lives at baseline. So we call that hyper polarization. So you get a nice little dip If you're monitoring kind of the electrical signals of this. And then how we get back to resting and brain potential is your sodium potassium pump. So we have all this sodium kind of sitting intracellularly of course we typically have more sodium outside of the cell. That's where sodium more so lives. Its plasma level is usually like 140. So we really don't want all that sodium in the cell and all of our potassium outside the cell. We want to get back to our homeostasis. And that's where the sodium potassium pump will kick in. We're going to pump our sodium pump. Back where it likes to be and kind of bring some of that potassium back in. So we're going to exchange the two so the pink guy in the center is kind of activation of that. So you can see it trying to exchange sodium. And potassium so that we can get back to resting membrane potential. The other thing you'll note here is that our sodium channel The configuration of that has changed a little bit. So you can see our little tail that was kind of closed off the channel when that's receptor was inactivated. That has now kind of moved back to its original position However, that channel is not open. So you can see the interior part of that channel has closed off. So we're still not letting sodium ions in. That's actually a different conformational state for that sodium channel. So now it's in a closed state. Generally, the difference is that in this inactivated state. This channel should not be able to respond to a stimulus. Once it gets to the close date. It's now ready to respond to the next stimulus. If that membrane potential gets back to that negative about 55 level. This is also very generalized. This is a very complex process of interaction between electrolyte levels inside and outside of the cell So, you know, this is not just a kind of a black and white description of this, but in general. There's some changes that we expect if we have electrolyte abnormalities. So for example. With calcium, hypocalcemia. That prevents sodium channels from closing between our action potentials. If our channel doesn't close then we're going to sustain our depolarization, right? We're not able to bring that membrane potential back down to a negative level and for that Sell really to rest So that has the effect of kind of this repetitive firing Which is similar to what you get with tetany. A titanic response. Hypercalcemia decreases your cell membrane permeability to sodium. So if we can't really get sodium in, then we're not really able to excite that neuron. Potassium hypokalemia means you have a more negative resting membrane potential. The reason for that is because if in the setting of hypokalemia, so too little potassium in our plasma. The cell is going to be it's going to be kind of triggered to give up potassium. So it's going to lose potassium in an effort to kind of restore potassium level levels in the plasma. And if you lose potassium, just like when that potassium channel is open. And our membrane potential went way down into the negative it has the effect of hyperpolarizing your neuron. Or your cells. So you'll have decreased membrane excitability because of that kind of extra negative state, it's going to be a lot harder to get all the way back up to threshold and then generate an action potential. Sodium channel blockade can prevent getting to threshold potential and getting that action potential generated as well. If I can't get sodium in. You know it's hard to you know it's hard to continue that process on. So the synapse. So basically, obviously, you guys all know when you generate an action potential, it's going to travel down that neuron. It's not just kind of a one and done. It's going to get to the end of that. Neuron and then cause something to happen to communicate with the next neuron. Or other cells and tissues are going to have kind of the same effect. So enter the synapse. We have a presynaptic cell with a membrane. And a postsynaptic cell across a synaptic cleft. So that presynaptic membrane, you guys all know there's usually going to be vesicles packaging our little neurotransmitter hanging out down at the bottom. If we have calcium channels at the bottom of that membrane. You know, when calcium binds, causes a voltage gated change that vesicle can now merge with the cell membrane and dump out neurotransmitter. There's also going to be reuptake pumps along this presynaptic membrane. The reuptake pump is usually used to help bring that neurotransmitter back into the presynaptic cell. Or if the neurotransmitter is broken down. It'll bring pieces of that neurotransmitter back up into the presynaptic cell So that cell can make more of that neurotransmitter. So we see this with catecholamines. We see this with like acetylcholine coming out of a neuron. At the neuromuscular junction, acetylcholine is broken down in the cleft and then you'll have part of that acetylcholine go back up presynaptically by reuptake pump merge acetate and choline to form acetylcholine. And then that's packaged again and sent back out. And so you're getting this ending of this neuron Saxon's getting that first action potential, it's going to receive that afferent action potential And get ready to kind of change this area so that we can now Ignite or start an action potential in the postsynaptic cell and send it forward. Postsynaptically, we're going to have neurotransmitters now flooding this area and they can bind receptors on the postsynaptic cell generate an efferent action potential which is sent down the cell to communicate to the next one. What you can't see from this image, but there are And maybe you can kind of appreciate there's kind of a lot going on on this cell you can see compared to the presynaptic cell. But all of these like proteins and other like different receptors receptors and structures that are kind of along the membrane in like right underneath within the cell is what we call postsynaptic density And it actually helps maintain homeostasis and integrity in that particular environment. So you can see all of that better on this image. Where it's all it's where it's all cartoonized, we'll say, is where it's a little bit easier to see exactly what those mechanisms are. So the synapse, modulation is when we have some change in synaptic function. So it could just be signaling from cell to cell It could be some change in depolarization or change in response. There is a delay. So again, it's very, very quick, but there is a slight delay between you know, when you're thinking about one neuron communicating with the next. It's going to take a moment for that neurotransmitter to be kind of you know the vesicles diffuse with the membrane, release that neurotransmitter neurotransmitter to diffuse down to the postsynaptic cell across the synapse bind and then generate the next action potential. The reason for that delay, also it's beneficial in that it can help reduce like fatigue or just constant triggering of the postsynaptic cell. Fatigue can also occur If the conditions are right for repetitive stimulation. It can reduce the response of that postsynaptic cell. So if you think about We talked about down regulation. Of receptors and how if a cell is just constantly bombarded to respond, it may start to undergo genetic changes that say, I'm going to respond less. I'm going to reduce the number of receptors I have up there that are looking for a response. And I'm going to reduce my sensitivity to something binding to a receptor that would have a response. And then fatigue can also be related to depletion of neurotransmitter. So this is kind of what you would see As an example, in the heart failure patient. That has catecholamine depletion. If you think about that patient is just constantly stimulating their sympathetic nervous system. To try to get the heart to pump and try to maintain blood pressure and things like that and perfusion. Well, that constant stimulation in that case will eventually lead to a depletion of those catecholamine stores there. Trying to pump out so much norepi and epi to have an effect that eventually you know the cells just can't keep up Like, would that be another comparison in the older person as well? Like they're releasing or epi all the time too like in their um vasculature I would say if they have a disease process going on, I don't know. Okay. I don't know that how common that is with just normal aging, but for sure if there's acute illness or even a chronic illness that is just constantly you know, they're trying to compensate or something like that then possibly Post satanic facilitation so This is something we do. You might have done it in the ICU when we're monitoring neuromuscular blockade is if you have a patient with zero out of four twitches if you're using qualitative. Neuromuscular peripheral nerve stimulation, I should say qualitative and you're looking for a count So you're counting, you're looking for four twitches. So let's say you have zero twitches. Basically, in that instance. You have so much. Neuromuscular blocker sitting on receptors on the post synaptic membrane which is your muscle that there's nothing that can stimulate that muscle to have a response. With post satanic facilitation If we, instead of just hitting your, you know. Train a four button to stimulate four quick times If we now hit the tetany button and hold that for a period of time. What we're doing is we're stimulating that nerve to release just a lot of acetylcholine. And we're pushing out so much acetylcholine. So this first bullet point, repetitive stimulation of the presynaptic terminal. We're releasing so much neurotransmitter that now We have enough neurotransmitter to compete with rock uronium sitting on that membrane And if we have enough to push that rock uranium off of the receptor and acetylcholine sit on the receptor. Then we might get a muscle twitch. So the idea with post satanic facilitation is to stimulate that presynaptic terminal flood the area with neurotransmitter And then the idea is that the receiving cell, that postsynaptic neuron. Is now going to have an exaggerated response. And we'll definitely talk about this when we get to neuromuscular blockers but even beyond the synapse, you've got like cell synapse, cell. If you kind of spread kind of along the membrane outside of the synapse. There's extra receptors out there And they're very sensitive to neurotransmitter. And so if you flood that synapse area with neurotransmitter and some of that neurotransmitter is going to kind of spread out it's going to target actually extra receptors that don't normally get hit with neurotransmitter. So that's the idea of post titanic facilitation. Neuronal responsiveness. Factors can affect the ability to respond. So beyond just kind of fatigue and neurotransmitter depletion or depletion increasing neurotransmitter and getting an exaggerated response If you have changes in pH, That can affect the excitability, alkalosis being increased, acidosis decreasing. Hypoxia can decrease. Excitability. As well. Any questions? So far. Sam, we're glad you made it. Receptor pharmacology. I know this slide's a little bit busy and I added all kinds of things to it to make it look like how I wanted it to really look. But this is a nice little zoomed in picture of your phospholipid bilayer. And as you guys know, you've got these polar heads and non-polar tails. And those nonpolar tails like each other, right? They're not going to repel They shouldn't be charged or anything like that. So they're going to hang out together and that means your polar heads are on either end. And then we have receptors and channels and all kinds of things in the middle. You've got some steroid ions kind of hanging out Sorry, steroid molecules kind of hanging out on the inside oxygen here. I threw an oxygen molecule here. You can see that can easily diffuse SIVO fluorine molecule just to be fancy. I threw that in that can easily diffuse across the membrane. But we have bigger things like ions, potassium, drugs. That actually need a channel to get through that membrane or carrier of some sort. Glucose is another one. So not everything can just readily across. We need it to be lipid soluble, small enough like a gas, something that could easily kind of diffuse. And then down here at the bottom, you see all these different proteins these strands These filaments, that's that postsynaptic density that helps maintain kind of the integrity of that area. Okay, so the receptor, we said receptors are proteins And they can be other substances, but generally they're proteins and they bind Either in endogenous chemical or a drug. Properties of the receptor. So sensitivity is the concentration that you need for cellular response. We'll really start looking at sensitivity when we get a little further in this lecture. Selectivity just means can your molecule fit into the opening of that receptor? So we can see here A3 fits on this top receptor A2 looks like it would need to be kind of rotated in order to fit A1 does not so A1 has no selectivity. For this middle receptor. Specificity is a cellularly determined response So depending on activation of a receptor, the response you get from that is going to depend on the tissue that it's in. There is a spectrum of weak to strong bonds that are formed. So whatever molecule it is or endogenous chemical. It's going to form a bond with your receptor. Receptors are often somewhere along the membrane kind of could be like inside the membrane or on the surface Or they can be intracellular. So once we give a drug to when it actually has an onset It's going to, of course, like we said, get to that bio phase or that area where it's going to have an effect And then it's going to have to orient itself into the right You know position and attached to that receptor. Typically, this involves hydrophobic bonding, hydrophobic bonding and why hydrophobic bonding. If you guys remember if you guys from last week we talked about To be pharmacologically active, we did not want that molecule to have a charge. If it didn't have a charge, if it wasn't ionized, if you remember our HA and B. Forms for a weak acid and a weak base that uncharged molecule is also lipophilic. And lipophilic and hydrophobic are basically the same. It's not water loving. It's not water soluble. So this is going to be a nonpolar molecule that's going to react with another nonpolar molecule being your receptor. So that is hydrophobic. Bonding. Conformational change will occur. So meaning when you have a molecule that fits perfectly on that receptor. Something is now going to change. So the receptor may change. It may be attached to some other protein that changes in some way. But basically, there's going to be some sort of like shape change that now is going to cause a response in that cell And that might easily spread to other cells and the tissue. A-acceptors. Aceptors are endogenous proteins that are alternative drug binding sites. So we talked about albumin. There are other proteins like alpha-1 acid glycoprotein. Beta globulins. If our drug is floating around in the plasma and holds on to albumin It's very much like our drug floating in the plasma and then getting our effect site cell in binding to receptor. So any other substance that can kind of bind onto that protein or sorry, bind onto the drug molecule but is not our desired receptor is called an aceptor. So we consider albumin an acepter. These are different types of receptors in drawn form. We will talk about you know these will kind of mention the basic types now But as we go and start to learn more and more about different drug classes, we will revisit A lot of these receptor types Especially when we get to our anesthetics, a lot of our drugs are G protein coupled. A lot of them are ligand gated. And voltage gated. Fun fact, the G protein couple receptor crosses a membrane seven times in this kind of ribbon-like formation So anytime you see a receptor on an image and it looks like that and it crosses seven times it is g protein coupled  11/6/24 PHARMACOLOGY maker 4 PHYSIOLOGY REVIEW 5 A & P Review Answer The cell membrane is a ________________ bilayer penstein we The cell membrane is mostly impermeable to ________ – soluble substances such as ions and glucose Yeti µ Structurally, ion channels, receptors and enzymes are ________________ Oxygen and carbon dioxide move through cell membranes via this mechanism. amusion The sodium-potassium ATPase (pump) moves __(how many?)__ Na ions 3Pmmouijati.in t.IE __(in/out)__ and ___(how many?)___ K ions __(in/out)__ Ion channels transport charged ions across cell membranes causing actpornigt iEcI conduction of electrical signals, known as ____________ _____________ The endoplasmic reticulum makes proteins, lipids and metabolizes carbohydrates. The sarcoplasmic reticulum in the muscle stores and releases what important 2nd messenger? 6 2  11/6/24 THE ACTION POTENTIAL Deponanremain resit a ssw.es s 7 NEURONAL ACTION POTENTIAL 70 Resting membrane potential (slightly polarized) at -70 mV ICF relatively ________________ Negative compared to ECF sodunpotasionremiqe.is 8 30 NEURONAL ACTION POTENTIAL propagate the along membrane Stimulus (e.g., change in nearby membrane potential) initiates process Threshold at –55mV when Na+ voltage-gated channels open ________________________________ mail.EEriani neses Te egm b eeso 9 3  11/6/24 30 NEURONAL ACTION POTENTIAL Membrane potential at +30mV, time-bound Na+ channels close = inactivation K+ voltage-gated channels open as delayed response to original stimulus hiii in I ________________________________ 10 iE a Heparisation NEURONAL ACTION POTENTIAL Na+/K+ ATPase active K+ channels are slow to close transport of ions i iE _______________________________ RESTING MEMBRANE POTENTIAL mails 11 ACTION POTENTIAL ABNORMALITIES Calcium inexmanntense potential Hypocalcemia – prevents Na+ channels from closing between APsLacion ○ Sustained __________________________________ muscer deporisation (repetitive fire; e.g., tetany) Hypercalcemia – decreases cell membrane permeability to Na ○ Decreased excitability of membrane ithadtocrestactionpotential Reprovisationisagents 12 4  11/6/24 ACTION POTENTIAL ABNORMALITIES Potassium Hypokalemia – more negative RMP potential resinmansion iiiIi ○ _____________________________________, decreased membrane excitability (e.g., skeletal muscle weakness) man examsmanner Sodium Sodium channel blockade, prevents threshold potential for AP generation (e.g., decreased contractility, altered cardiac conduction) netd ens Pairst.in theseIntentitit Iii the 13 THE SYNAPSE AP from pre-synaptic membrane to post-synaptic membrane across cleft Pre-synaptic membrane viii Vesicles with neurotransmitter Reuptake pump c an aaaa.in cnn.mn Voltage-gated ca channels Receives afferent action potential https://www.dana.org/article/qa-neurotransmission-the-synapse/ 14 THE SYNAPSE i Post-synaptic membrane I I i NT binds receptors Efferent action potential iiii.it iiiiiiii Receptors & structural proteins maintain synaptic homeostasis = postsynaptic density andit manume pag.zeaests.mn https://www.dana.org/article/qa-neurotransmission-the-synapse/ 15 5  11/6/24 THE SYNAPSE presomizmanson posiS.EE 16 THE SYNAPSE Modulation Change in synaptic function Synaptic signaling, membrane potentials influence depolarization & stimulus response Delay 0.3 - 0.5 ms → NT release, diffusion, binding, ion flow barista not Fatigue to s ame cause Repetitive stimulation of excitatory synapses Reduced post-synaptic responseemanedepoisae.atepaorisaons May also be related to depletion of NT stores comes 17 THE SYNAPSE Post-Tetanic Facilitation Repetitive stimulation of presynaptic terminal Short rest period Synapse _____________________________________ go quasarepeness more than normal to subsequent stimulation ingens tore L cat 18 6  11/6/24 THE SYNAPSE Neuronal Responsiveness Changes in pH ○ Alkalosis - increased excitability ○ Acidosis - decreases __________________________________ excitability Changes in PaO2 ○ Hypoxia - decreased excitability 19 RECEPTOR PHARMACOLOGY 20 CELL MEMBRANE LIPID BILAYER 21 7