Exam_I_Notes - EXAM I NOTES FOR SUMMER 2009 Lecture #1 –...

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Unformatted text preview: EXAM I NOTES FOR SUMMER 2009 Lecture #1 – June 4, 2009 Why have a nervous system? It sometimes lies to you and it guesses a lot. It’s a way of sensing and responding. But mainly, it serves as a way of communication within the body Types of Communication in the Body Slow and undirected/general targets = endocrine systems (chemical) Fast and specific targets = nervous system (electro‐chemical) Neuronal Structures to Know Dendrites collect electrical signals Cell Body (aka soma) is where information is processed Axon Boutons are axon terminals Schwann Cell Myelin Sheath Nodes of Ranvier Nerves are piles/bundles of axons Synapse The decision to send a signal doesn’t occur at the cell body. It occurs in the axon hillock. What is a brain? – It is a highly dense collection of neurons. Why have a brain? What is the need for it? bilateral organisms, which send information into a particular centralized/localized area, need a brain in the area where most of the senses are sending information Information from the senses gets processed at four levels spine brain stem cerebellum cortex What are “ganglia”? “little brains” i.e. dorsal root ganglia are processing centers on the side of the spine Classic Theme Stressed in the Course = an inhibition of an inhibition is a form of excitation. Sensory neurons are constantly working. (Butt neurons and chair example) Know the Anatomy Slide shown in Lecture #1 Slides (6.04.09) Lecture #2 – June 5, 2009 Vast majority of the neural activity in your brain is reflexes. (stuff that you’re not aware of) One of the things that you are aware of is sensory systems (smell, taste, see, and hear stuff) The idea of having a sense of self is called propioception Propioception deals with senses so it’s input of information body awareness and where the limbs are oriented more importantly, tell you that these limbs are part of you if this system is damaged, you may not know that a particular limb is yours loss of propioception: think that your own limb is not your own this is distributed throughout the body Paralyzed: assume three things o can’t feel; can’t sense (no input) o can’t control; loss of motor systems (no output) o BUT it isn’t necessarily true that there’s a loss of sense of body when we anesthetize properly, we do the following… o put patient to sleep o numb the patient o “paralyze” or stop muscle control o kill body perception o give them amnesiac drug A step beyond propioception: diff between sensation and perception sensation: raw information coming in perception: how you process a sensation (persistent theme throughout the course); just because people sense something, doesn’t mean that they perceive it in the same way Motor Systems: reflex arc – first level of sense and response o spinal reflex o instantaneous response to stimuli without any thought/brain‐stem/cerebellum processes Sensory (peripheral) to Inter (central) to Motor (peripheral) All of the neurons in CNS are inter‐neurons Myotonia: lack of muscle control (get’s rigid) we know how things work by understanding how it’s broken Brain and Behavior: kind of motor system, which is basically how your perceptions are manifested (that’s what we call behavior) you can have senseand response (reflexive) with no perception involved but when you add the guess work of your brain/prior experience, that’s perception you often do things because of what you perceive and you don’t know why you did them Cerebellum: does almost all of the learned motor behavior first we’ll talk about learning in terms of motor systems then we’ll talk about learning in terms of perceptual learning (aka what you’re writing down) spine, brainstem, cerebellum and THEN brain engages You only need half of your brain. We will talk about learning, memory, sleep, and fear. Sleep is just a lack of “awakeness.” You’re turning off a system that keeps you awake. If there’s a single mutation in this system, you can fall asleep at any time (narcolepsy). The brain stem triggers this malfunction in a narcoleptic person. Chalk Talk in Lecture #2 Why would an ion enter a cell? Concentration gradient Electrical gradient Receptors can be… 1) ionotropic (channel): ions can flow through 2) metabotropic Is the pumping out of sodium required for the neuron to reset? NO! This is a myth. Membrane/Selective permeability deals with that concept of potential. Sodium‐Potassium ATPase pump: constantly running 3 Na+ out for 2 K+ going in NOT TRUE (1‐1) then, how do you establish the charge gradient? High K+ and Low Na+ = INSIDE Low K+ and High Na+ = OUTSIDE When sodium enters, it will change charge difference, making the inside go from negative to positive. Dendrites can have any number of receptors for different chemicals, inputs and other stuff. An axon, however, is defined by its structure and it’s receptors. It has something like an antenna (which is full of positive charges). If enough of the positive ion (sodium in most cases) comes in, that receptor on the axon opens, allowing more sodium into the cell. When a billion number of sodium ions flow into the cell, the cell has become more positive relatively. However, the concentration gradient has not changed at all because there is so much sodium on the outside of the cell relative to the inside. This makes the Na+ still want to come in. You tip a delicate balance in the neuron, but the ion concentration NEVER changes. You process information at the level of a neuron. The choice of whether to respond to that depends on how much sodium has to enter in order for the sodium‐gated channel in the axon to open. You can change the sensitivity of the neurons by dictating when that channel responds. If the first voltage gated sodium channel opens, then all of them down the axon will open. Calcium then flows into the axon bouton, which binds to proteins that cause vesicles to release the neurotransmitters. The neurotransmitters bind to chemoreceptors on the next neuron. Then, sodium flows into the next neuron’s dendrites. At the next axon bouton, the neurotransmitters attach to the receptors on the muscle, which allow sodium into the muscle. Axons ONLY have voltage‐gated ion channels. If we flood all that sodium in the neurons, how do we get back to the original setting? How do you reset so quickly? We have another set of channels that are also voltage gated. They let K+ out. Sodium voltage‐gated channel opens FIRST and then the K+ voltage gated opens AFTER it. The timing and order is important to reset things back to their original location. Wherever there are Na+voltage‐gated channels, there are K+ voltage gated channels a little behind. We have hundreds of voltage‐gated ion channels that process whether a signal should go down the axon and how quickly they fire. These proteins are constantly being exchanged and changed out. The nervous system is constantly changing. Sensitivity can change constantly. Neurons are more spaced out that you think. They are filled in between with glial cells. Glial cells may be involved in memory. Ligand – any thingy that binds to something (a ligand can bind to a chemo‐receptors) Once you understand how neurons work, you need to understand circuits. We have both excitatory and inhibitory. Reciprocal Inhibition: almost all of motor control is going to use at least two different kinds of neurons (sensory peripheral neuron that’s going to excite one muscle; that neuron is attached to an inhibitory interneuron, which then relaxes the corresponding muscle. These responses are simultaneous. Pulling a muscle is a failure to relax the corresponding muscle. Myotactic reflex – trying to prevent strain or too much damage Use a circle, stick, and triangle (axon buoton) to depict axon. Lecture #3 – June 8, 2009 When ions go across a membrane, it’s going to change the property of that membrane. Ions move because of gradients. There are two kinds of gradients. o Electrical gradient ‐> this CAN change o Concentration gradient ‐> this does NOT change the concentration of the ions outside and inside of the cell, for our purposes, remains the same RELATIVE concentrations don’t change A few ions flowing can change electrical gradient but DOES NOT change the RELATIVE concentration gradient V = IR V: voltage (aka potential) o Vm = membrane potential I: current (aka movement of ions) R: resistance (aka measure of the restriction of current or ion flow) Some relationships from Ohm’s Law If current (I) increases, the resistance (R) must go down for a certain constant potential (V) If I , then R when V is constant If the voltage stays the same and you see a sudden movement of ions across the membrane, then the resistance will go down. When a neuron is stimulated, sodium goes into the cell. You have a massive current coming in (I increases). Something must have let that come into the cell. This is the ion channel. When the ion channel opens, that is a change in resistance (R decreases). All of these things, how much I and R there are, establishes V. There is a charge across the membrane. The thing that establishes the relative differential of charges across the membrane is the selective permeability of the membrane. The “R” is a measure of the permeability of the neuronal membrane. Permeability and resistance are inversely related. The ability of the ions to go across the membrane (current/flow) and the concentration of those ions set the membrane potential. You have a cell with a negative concentration inside the cell and positive outside of the cell. There’s a membrane potential of 60 mV. If you add a whole bunch of chlorine ions to the outside, the membrane potential DOES NOT change. The only thing that affects the charge across the membrane is the current (the movement of ions across the membrane). The potential of the membrane is altered ONLY when there is a current. Why do ions flow? In general, it’s because of gradients In the center of the cell there is the ER (anything that’s in the ER, is outside of the cell) the most common source of Ca2+ is in the ER, or outside of the cell Reasons o Concentration gradient (diffusion) o Electrical gradient This is irrespective of the nature of the ions, just the fact that they’re there Membranes = lipid bi‐layer affects the permeability of the membrane none of the ions on the exterior of the cell can get into the cell protons, electrons, and ions cannot cross the barrier unless there is a channel channels are selectively regulating the flow if ions can’t flow across, there is no potential because there’s no potential for current Channels have certain properties o resistance o conductance channels that have almost no flow, have high resistance since they can open and close their doors, they can change their conductance channels are very specific To establish a concentration and electrochemical gradient: have been taught that it’s the sodium/potassium pump you cannot consume and generate enough energy to establish the gradients that are found on either side of the cell they are established by selective permeability of the membrane Stuff that’s happening constantly in the cell… pump driving potassium driving into the cell potassium flowing in because the cell is negative (due to DNA); there is an attraction sodium is coming out because of the pump potassium also wants to leave the cell because of concentration gradients (more potassium inside than out) For every ion, there will be some point/charge where the reason to enter the cell will be same as the force to leave the cell. This is called the EQUILIBRIUM POTENTIAL. Sodium is always going to go into the cell because of both the concentration and electrochemical gradient. At rest, your cells are completely permeable to potassium. Aka, they have leak channels. Pump is pushing the potassium out. Sodium is moving pretty slowly. Chloride is also moving. The flow of calcium is so near zero, that we have trouble measuring it. Because of the anions on the inside and the positive charge on the outside, the sodium wants to go into the cell and the potassium wants to go into the cell as well. Potassium is the most permeable ion during rest. It has the biggest I (most flow and least resistance). The potassium is the thing that’s setting the potential at rest more than anything else. At rest, the flow of potassium due to concentration is so high that it makes the sodium flow at near zero. There is also an inward flow of potassium due to charge gradient. At some point, a potassium ion is going to sit in the channel with the net force at zero (equilibrium). The Nernst Equation (Our Version) 58 [ion ]out E ion = log z [ion ]in understand this equation and understand what happens if you change one of these things if the concentration of ions change, then the equilibrium potential changes € always out over in, even for chloride z is the charge on the ion (you can have monovalent ions) The potential across the membrane is dictated by the relative concentration of the ions across the membrane. The Nernst equation is a way of calculating the equilibrium potential for each ion. Why is the equilibrium potential for sodium so positive? the internal environment has to be very positive for there to be an equal but opposite force on a sodium cation Need to be able to speak in equilibrium potentials and permeabilities. Extremely NEGATIVE equilibrium potential for potassium Extremely POSITIVE equilibrium potential for sodium (≈ 55 mV) Relative Concentrations WILL NOT CHANGE potassium is 28 more times concentrated inside than out sodium is 12 times more concentrated outside than in chlorine is 12 time more concentrated outside than in calcium is 20,000 time more concentrated outside than in Look at Diagram #2 As the conductance of a single ion increases, it’s going to push the membrane potential towards that ion’s equilibrium potential. As the permeability for an individual ion increases, it will push the membrane potential of that cell towards that ion equilibrium potential. The membrane potential is the sum of all the equilibrium potentials of the ions. Some of these dictate more than others because they have more current. Why doesn’t the calcium concentration difference push the cell voltage away from ‐60 mV to be more positive? It’s not moving very much. But, potassium is. So, there is a cell membrane potential closer towards the potassium equilibrium potential. Potassium is flowing out of the cell when you are doing nothing because it’s trying to get the membrane potential down to ‐86 mV. It’s going to try to get to this equilibrium potential. Ions will continue to flow until they reach their equilibrium potential. If you increase the potassium concentration outside of the cell, then there is no moving force for potassium to flow outside of the cell. The ions on the table have four currents at rest. Need to know where most of the concentration is relative to the outside and inside of the cell. Selective permeability establishes the membrane potential. The membrane potential is down in a negative area even though all four of the ions are flowing. Establishing Equilibrium Potential a separation of charges creates an electrical gradient = membrane potential (Vm) ions flow across the membrane this flow creates a concentration gradient flow continues until the electrical gradient “balances” the concentration gradient this Vm is the equilibrium potential Lecture #4 – June 9, 2009 Explain to him why split‐brain patients are the way they are… Recognize that they have lost the capacities of one hemispheres or the other. Explain this as one of the four sets of wires that go back and forth. (for the final) Some studies have shown that faith comes from the left hemisphere. Gradients dictate the behavior of neurons. Is a function of the electrical charges present and the concentrations of the ions relative concentrations don’t change for the most part at rest… o both gradients are driving sodium into the cell o both gradients are close to equal but opposite for potassium means that potassium is close to it’s equilibrium potential Equilibrium Potential it’s a number that we calculate that doesn’t exist in the real world it’s a theoretical potential at which point there is a flow of ions but no net current ions will continue to flow if they are not at their equilibrium potential*** See Diagram #2 How do you change currents in the neuron? channels “number of open doors and windows” that open and close at different rates there is always a flow of ions/current we are only changing the always present currents What would each ion be doing in this point in time? Talk about what/where ions flow when at a certain membrane potential. Concentration of the ion is what establishes the membrane potential. Rest of the course is about changes in the resting potential. Change it to alter how sensitive the neuron is or intentionally change it to make an action potential (which is a neuron signal). We’re interested in these changes in resting potential. Resting Potential depends on which ions are permeable at rest (in order for them to contribute to resting potential, they must permeable/have a current) the equilibrium potential of these ions (function of concentrations) the relative permeability of each ion ‐ conductance (dictates where the equilibrium potential is) The Goldman Hodgkin Katz Equation P [ Na + ]out + PK + [K + ]out + PCl − [Cl− ]in E m = 58 × log Na + + + − PNa + [ Na ]in + PK + [K ]in + PCl − [Cl ]out PNa+ = the permeability of sodium (will be something like 2 or 0.01) A neuron fires with the permeability of sodium suddenly skyrockets Why doesn’t sodium reach its equilibrium potential? There are other ions still € flowing. Driving Force Concept: as I get closer to sodium’s equilibrium potential, the driving force sitting at the doorway of the membrane gets smaller. (we’ll revisit this DYNAMIC process) Don’t forget about the negative molecules within the cell that give the cell its negativity. The cell isn’t negative because of potassium. The cell isn’t AS negative because of potassium. What controls the flow of ions in and out of cells? The channels. Sedatives, like Valium, open the chlorine channel so that it’s permeability skyrockets. It reaches it’s equilibrium potential and, therefore, the neuron cannot re‐fire and/or re‐set because every incoming sodium ion gets balanced by a exiting chloride ion. There are voltage‐gated channels and ligand‐gated channels. Calcium, glutamate, and cyclic GMP/AMP can bind and open a channel. When the channels open, we change the permeability values. It’s the change in flow that changes the membrane potential, which makes the neuron fire. When a stimulus comes in, sodium channel opens, sodium enters, changes it’s permeability, changing the membrane potential to a more positive value. Tetrodotoxin (TTX) Toxins manipulate channels It blocks all sodium channels in the cell Way to remove sodium currents is TTX, which is used in various religions, like voodoo where people are put into a state of paralysis or semi‐consciousness Derived from the puffer fish’s salivary gland, ovaries, and a couple of other parts (Fugu, which is sushi) If you cook it, the TTX is gone Concepts that we’ve had so far resting potential alters as you change the currents of ions ions are going to try to drive the cell to their equilibrium potential reason why currents change is because channels open reason why we know channels open is because we can block and open channels with drugs and toxins THEREFORE, potentials change!!! See Diagram #3 Threshold the point at which the voltage‐gated sodium channels on the axon open a value of membrane potential the first level processing is: what membrane potential value are voltage‐gated sodium channels looking for? When this membrane potential is reached, the conductance of these channels is at least a 1000 times more than the initial sodium input. It travels the length of your leg at about a hundred miles an hour. This signal (sudden change in potential) is called an action potential. It means that (at the starred point on the axon in diagram #3), we have decided to send a signal/do something. Know the Nernst Equation! Understand what it means… It’s always out over in, even with chloride (out/in). With the equilibrium potential, it doesn’t have to be monovalent. You need to make sure that the charge of the ion matches the Z. A stimulus comes in and then changes the membrane potential a little bit. A bigger stimulus comes one and then changes the membrane potential a little more. When a big stimulus comes in, the actions potential comes in. What’s enough is measured by the properties by the voltage‐gated sodium channels. They determine what’s “enough” for an action potential to fire. Action potential described as… Resting Sodium enters (rising phase) As sodium enters, potassium starts to leave because of the higher driving force Falling phase is when the membrane potential goes back down Undershoot is when you go past resting potential. A‐E is one action (look at slide from lecture #4) The properties of the receptors and channel that dictate the shape of the action potential. Exam I Question: “On your exam, I am going to change the currents such that some will greater or smaller. The time at which the channels open will be shorter or longer. He will give you a drug or toxin or a person with a low/high salt/potassium diet. Then, tell me how the shape of the action potential changes or the likelihood of the action potential. Simple concept: If you have action potentials that are really wide, you can only have so many in a period of time. If you have a flow of ions that returns to rest very quickly, that cell can return to resting potential very quickly and fire again very quickly. Potassium flowing on the left side of the action potential wave, you will never get up to threshold. Potassium flowing on the right side of the action potential allows the neuron to go back to resting potential and allows it to fire again because of another stimulus. The timing of when an ion flows dictates how fast a neuron fires. How do we know how an AP works? How did we know what the currents were? The device that did this is called the voltage clamp. What it does is the following… Sets the voltage for a neuron When you set the voltage, voltage‐gated channels open (that increases currents) Voltage clamps want to keep the cell at the same voltage Voltage clamp sets the voltage of the neuron by injecting a current to compensate for the neuron’s currents as a result of that voltage It measures currents (it DOESN’T MEASURE VOLTAGE) Analogy: o You have a bucket o Bucket has water and it leaks o You keep adding water to it to keep it at a certain level o How are you going to determine how much the bucket is leaking? o You set the water level by drawing the line at the original water level o As it leaks, you had water to keep it at the same level o You measure how much is leaking by looking at how much water you’re adding As sodium comes in, it’s going to change the voltage… every time it comes in, the VC adds a negative “thingy” to keep the same voltage During an AP, the cell is sitting at ‐60 mV… turn on the VC and set the membrane potential to 0 (the cell thinks that it went above threshold) The voltage‐gated sodium channels open at threshold Stuff going in (downwards) and stuff going out (upwards) See Diagram #3 How do you only see K+ current? Give it TTX to block sodium channels and then only see potassium current… Only sodium current looks different The currents are the channels opening and closing. The VC measures the currents. You separate the currents by blocking one or the other. Now, you look at the current and the lines are telling you that as long as you’re at 0, potassium flows. As long at you’re at 0, sodium flows briefly and then shuts off. What are these lines telling you? As long as you’re at 0, above rest, or above threshold, potassium channels stay open while sodium channels open and, even though there’s still a stimulus that says stay open, they close… Potassium and sodium channels aren’t the same (sodium open and then close while potassium stays open) Lecture #5 – June 10, 2009 Threshold (see diagram #4) is a value of membrane potential if the membrane reaches the threshold value, then “something” happens defined as the point at which the probability of voltage‐gated sodium channels in the axon will be open will increase threshold ONLY refers to sodium channels, NOT potassium (which effectively nearly always remain open) there is a lot more sodium entering the cell than the amount of potassium leaving relative permeabilities of sodium and potassium change over time Stimulatory Events (see diagram #4) input of… o sodium o calcium output of… o potassium o chloride Hyper‐Polarization: exit of K+ or input of Cl‐ In order to increase the resting potential… increase sodium into the cell decrease of potassium out of the cell can do this with cocaine or meth‐amphetamines Hyper‐excitable Neuron: somewhat depolarized, but still sub‐threshold neuron; therefore, it simply takes less stimulus to make you fire Two kinds of currents (see diagram #4) axial current: current running the distance of the axon (this is good) radial current: current that flows in any direction other than the direction of the axial current (this is bad) Neurons can be fine, but what’s wrong is the Schwann cells are missing, thinner, or less effective. Schwann cells are a kind of glial cells. This is multiple sclerosis. It is more likely, that there is something wrong with the glial cells. Why are Schwann cells critical? They prevent radial currents. These currents are a component of action potential. When there is a stimulus, there is a greater driving force of output of potassium ions, which repolarizes the cell. The stimuli must come at a fast enough rate to overcome the efflux of the potassium. If the temporal stimuli are too far apart, then the cell will re‐polarize. If you have too many potassium channels, you’re repolarizing so fast that stimuli won’t be able to fire an action potential. Graded (response proportionate to stimulus) versus action potential A‐B = depolarization A‐peak = rising phase Peak‐back to “resting” = falling phase/repolarization Getting to D = hyper‐polarization We’re going to clamp neurons at various voltages. What that will tell us is where threshold is. The voltage clamp is able to tell us about ion channels that respond to voltage. At threshold, you can see a huge current. For an action potential, there are currents. Ions are moving back and forth across the membrane. When voltage‐gated potassium channels are at zero, they will constantly stay open whereas, the sodium channels will also open, but they close on their own. Potassium channels are slow to open whereas sodium channels open very quickly. Sodium channels close relatively slowly but they still close on their own. The peak at which the action potential is defined is when the net current is zero. Capacitance: the attraction of opposite charges across a barrier current associated with this is called capacitance current you have Schwann cells to solve this problem gaps are there for channels to still exist Why wouldn’t a shorter distance between the Schwann cells increase the current? There are two types of gates: center (conformational gate) ball and chain model (occlusion gate) Sodium channels have two gates. M gate opens above threshold H gate is already opened As we depolarize, the H gate closes, determining the peak In a voltage‐gated sodium channel, the M gate is always open above threshold The height of the action potential (the amplitude) is determined by the H gate When the H gate closes, it has been inactivated Potassium channels only have an M gate open when the voltage is super high it closes later these are delayed If you alter the number of charges in the gate, you can alter the potential at which these things open. The Schwann increases the resistance to the capacitance current (increase membrane resistance). How do they do this without having resistance to the axial current? The bigger the axon, the easier it is to have an axial current. The axial/internal resistance is reduced with size increase. Therefore, it makes sense to have bigger neurons. Why don’t we want big neurons? We would always be delicate and sensitive. In general, unmyelinated cells are slower than myelinated cells. Fewer channels = currents are smaller The disease state of multiple sclerosis is that action potentials begin but they don’t make it down. There aren’t any additional channels. What would you have to change in terms of channels to increase or decrease the amount of myelin you have. During development, your node differences change. You have to alter channels to compensate for these changes. Refractory period = controlled by the H gate. Lecture #6 – June 11, 2009 Sensory Neurons are afferent (towards the CNS) Motor Neurons are efferent (away from the CNS) The information gets processed in the body of the neuron. Neurons change by changing their membranes (via membrane proteins). Threshold is determined by the voltage‐gated sodium channels at the axon hillock. Transduction: changing the type of signal (electrical gradient to a chemical gradient) Diversity of neurons is also due to neurotransmitters and receptors. See Diagram #6 to understand a little more about intermodal distance. The moment you polarize the cell with sodium, the potassium starts to leave the cell even more through already open potassium channels because the driving force for potassium has increased. Potassium channels open slower than opened sodium channels once the action potential occurs. Sodium enters through the ligand‐gated sodium channel. This causes more potassium to leave the cell through the leak channels. (This is depolarization) Just below threshold (open H gate and closed M gate) Above threshold: voltage gated sodium channel has H gate open already, but then it begins to open the M gate (rising phase) A different set of sodium channels open. These have a massive current, which means that the slope of action potential. At potentials more positive than threshold, the M gate will ALWAYS be open. Peak: voltage‐gated sodium channel closes its H gate (responsible for sharp inflection point); if some are slower to close, the inflection point becomes wider; potassium and sodium current are equal Even though the sodium channels are open longer, the action potential can be no larger (no greater magnitude.) You should know why. Falling phase: potassium is flowing out faster than sodium is flowing in; sodium channels are closed but their M gates are still open; it is a stochastic event Above threshold in falling phase, the sodium channel might be open a little and the potassium channels are open with a massive current. The high slope in falling phase = driving force goes down but the number of open channels go up when you see a neuron trying to be fast, you’re controlling neuronal transcription When you’re below the threshold value in the falling phase, the M gate is closed in the sodium voltage‐gated channel. We have more sodium channels completely closed than we would at rest. This allows us to go skittering past the resting potential, causing an undershoot. The chances of us firing again are lower and near zero. The undershoot/hyper‐ polarization is manifested as a refractory period. It prevents back propagation. Potassium channels finally close and make the main bendy point in the hyper‐polarization. The negative membrane potential causes the H gate to open. This means that you can’t have inter nodal distance that’s too long. If you add too many ion channels and make inter nodal distance twice as long. It’s going to be less capacitance because you have fewer nodes. The first incoming channels have gone past their refractory period and you have back propagation. The distance of the nodes is dictated by back propagation and enough to go down the axon. In order to change a neuron into a super neuron you have to change the refractory period. You must think about why these action potentials have the shapes that they do. Ion channels operate in many ways: leak channels o just remain open o all tissues have potassium leak channels o wouldn’t be able to see if you didn’t have potassium channels in the eyes Ligand‐gated channels Patch Clamp: voltage clamp on a single channel there are different kinds of potassium channels, we know that an individual channel will fire at different times and will be open for different lengths There are some channels that open while others close. This is a fast activating/inactivating channel. Rectifying: opens a certain membrane potential… the fact that it’s “slopey” rising phase it is a delayed rectifier (non‐inactivating) Channels that only open when you repolarize. This kind of channel is in your heart. Inward Rectifier allows potassium goes back into the cell. Calcium activated potassium channels are voltage and calcium regulated. They detect the fact that calcium has entered the axon buoton. A lot of calcium came in, we better have a bigger current. Some that respond to pH. (two‐pore) Ligand‐Gated receptors: there to shape the resting potential (in contrast, potassium channels help shape the action potential) Synapses: Example: neuro‐muscular junction o Increased surface area on muscle side (allows for more receptors) Release acetylcholine into synapse Quantal nature of neurotransmitter release o Calcium dependent release of neurotransmitters (this is true in ALL neurons) Without any stimulation whatsoever, there would be a little action potential, MEPPs Randomly, the neuron is releasing NTs in discrete packages (MEPPs = minimum package size) It isn’t true that every single MEPP is the exact same size. But, they are always a multiple discrete unit of the package worth (1 package worth produces this much current in the cell) Katz wanted to know why there were discrete quantities and why is Calcium so involved in this? Calcium dependence of NT release is what drives funding for making people look younger. Quantal nature = vesicles not all vesicles are the same size, but in neural systems they are all the same size the key to the calcium is that there are protein links between the vesicles Synapsin – vesicle loading protein; it’s where vesicles are held while you slowly fill them SNAPs – proteins that are responsible for priming/docking/arranging vesicles o Bound by a chemical Pressure (mechanical) stretch Light (electromagnetic) Temperature SNAREs – drive the fusion of the vesicles with the post‐synaptic membrane V‐SNARES Synaptotagmin – proteins attached to the vesicle; it binds calcium Synaptobrevin – forms the complex (series of proteins that look like twist ties; they pull the vesicle down); calcium affects these T‐SNARES Syntaxin: in the receiving membrane SNAP 25 (actually c‐snare because it’s cytoplasmic) Calcium with v‐snare and t‐snares will allow vesicles to bud to membrane Voltage‐gated calcium channel (VGCC): when the action potential reaches the end of the neuron, these channels open; they form a complex at synaptotagmin; calcium enters and the vesicle fuses Complex forms before the calcium enters the cell A vesicle can either come down and fuse if involved in the process “kiss and run” (faster) vs. “re‐building” (slower) it’s probably both in actuality Clostridum: bolutin toxin paralysis Clostridum tetani: tetanospasmin tetanus lives on you when big long pointy things pierce you there is a chance that this enters your body Tetanus: back spasms and most of your muscles go very rigid Botox paralyzes and tetanus causes you to go very rigid: they both attack the snares the Botox cuts your snares (destroying the vesicle loading mechanisms in my neurons) Tetanus toxin also cuts snares, but they have opposite effects… How is that possible? Paralyze: unable to send a signal to the muscle Tetanus: unable to inhibit the muscle to flex If Botox and tetanus both cut synaptobrevin at the same location, how does one cause paralysis and the other rigor? Lecture #7 – June 12, 2009 Some themes of Neurotransmitters (NTs): The way we understand what they effect is that we have toxins, drugs, or chemicals that act in a similar way to the endogenous NT in your body We understand how ion channels and receptors work by finding things that bind to them and separate distinct behaviors We often define these channels/receptors by the substance that binds to them o ie. the amino acid glutamate = #1 NT in your brain o ½ of the NTs being released in synapses in your brain are glutamaturgic an advantage of toxins is to help us to define the function of the actual channels/receptors One of the ways that we figured out that voltage‐gated sodium channels had two gates was to use toxins. there is a graded response as a result of a ligand‐gated stimuli at the beginning with incoming sodium; the more signal you give, the more sodium enters the fact that we eventually go up and then back down is a function of the fact that we have two different gates closing in a voltage‐dependent manner AND a time‐dependent manner even if you don’t reach the proper voltage, it will close when scientists make mutant forms of the voltage‐gated sodium channel without an H gate, the channel still closes => always more complex than we think to understand the difference between the gates, they poison things with scorpion toxins Scorpion toxins alpha toxin: slow and affect the inactivation gate (H gate) o slows how quickly the gate closes o results in a wider peak beta toxin: change the activation gate (M gate) properties o the sodium channel will open a little earlier than they’re supposed to o lowers the threshold to make the channels open a little earlier charybdotoxin – blocks voltage‐gated potassium channels o these channels start to open right after depolarization o if they don’t open, then threshold will be hit more quickly o the peak will be a little closer to the equilibrium potential of sodium and then plateaus TTX – blocks voltage‐gated sodium channels TEA – blocks potassium channels Black Widow Spider Venom alpha‐latrotoxin o tetramers form ion permeable pores for calcium o instantly depolarize A LOT o those neurons are releasing transmitters left and right Verapamil o Anti‐alpha‐latrotoxin treatment o calcium channel blocker (anti‐venom) o restricted to myocardial tissue and not to the somatic neurons o lesson – all of your tissues have channels that are different; calcium channels in the heart are different than those found in your fingers o introducing the notion between specificity of the channels among different tissues Calcium‐activated potassium channels are being implicated in alcohol. Alcohol effects how many calcium‐activated potassium channels there are. Also, a lot of the channels that we have we only use on occasion or some specific part of the body. When they bind, NTs can have an ionotropic effect or metabotropic effect. Many can be G‐ protein receptors. There are two general kinds of synapses Chemical (most common) o Neuro‐muscular junction is an example o NTs are released in quantum o Needed calcium to be released o Lots of proteins involved in this process o Vesicle manufacturing plant of the cell (endosome) o Kiss and run vs. endosomic pathway o Need to control these things o Synapsin coral these vesicles while they get filled o SNAPs hold them to the membrane o SNARES fuse them with the membrane o SNARES respond to calcium Electrical o Connecting two cytoplasms o Found in places like hard and smooth muscle in addition to the brain o Really aren’t gap junctions; electrical synapses have different proteins o Electrical synapses can close whereas gap junctions are open all the time o In neurons, there’s a structure called a connexon (protein called connexin) that part of these electrical synapses o Connexon can twist close and open Allows small molecules to pass Found in the heart and brain Generates a common electrical environment Changing the chemical properties of the brain Delay to pass on response is almost immeasurable VERY fast Kinds of Ligands Acetylcholine (+) o Number one NT from motor neurons to muscle (excitatory in this case) Kinds of Chemical Synapses excitatory o makes the post‐synaptic cell more depolarized inhibitory o causes the post‐synaptic cell to be less likely to have an action potential Modulatory Where does ACh come from? It’s manufactured in the synaptic terminus. It’s not transcribed/translated in the nucleus, like protein NTs. It’s made at a high rate. It’s found both in the brain and in motor systems. Acetyl CoA (comes from mitochondria, a theme) + choline = ACh ACh esterase – brakes down ACh into its parts parts get taken back into the pre‐synaptic membrane by a symport transporter you’re using the Na+ concentration gradient to drag choline back against it’s concentration gradient We’re curious about what exactly is happening at synapses. Not all cells sit at ‐60 mV Muscle cells sit at around ‐100 mV They depolarize to about ‐70 mV This isn’t an action potential The result of ACh binding quite often is only to depolarize still within the minus range Reversal potential some channels will bring in more than 1 ion when ACh binds to an ionotropic ACh receptor, it becomes permeable to more than one ion at ‐90 mV, only ion flowing is sodium at ‐50 mV, potassium starts to flow Glutamate (+) o It takes up half synapses in brain GABA (‐) and/or Glycine (‐) o Inhibitory Dopamine o Sense of well‐being o Deals with anxiety Norepinphrine/epinephrine o Alertness o Also for sense of well being o Flight or fight Seratonin o happiness histamine o pain response one point, sodium and potassium are flowing at the same current at about ‐10 mV Why is sodium the only thing flowing at ‐90 mV? It’s the only ion with a driving force because it is very close to potassium’s equilibrium potential (close to ‐90 mV) In these cells, ‐10 mV is equally distant from both equilibrium potentials because this receptor is equally permeable to both ions When we describe single ion conducting channel in terms of how much conductance it has When we have a not as selective ion channel, we describe them in terms of reversal potential (which ion is more permeable) Reversal potential = two ions have the same current rate If both ions are equally permeable, then it’s at a point equidistant from the equilibrium potentials If one ion is more permeable, the reversal potential will be closer to that ion’s equilibrium potential Final Exam: channels can be made completely from one gene product; but some can be made from multiple gene products; you have lots of different ionotropic ACh receptors; different ones can be found in different parts of the brain; it’s changed how we deal with addiction in a huge way ACh receptors just a big fat hole proteins that form a big blob/hole it has binding sites for ACh at the alpha site if you have lots of alpha, then you can bind more ACh but if you don’t have a lot, then less ACh binds you MUST have an alpha, in order to bind ACh Ionotropic ACh receptor= nicotinic (brief changes and instantaneous response) Metabotropic ACh receptor = muscarinic (slower, but changes are very profound because it goes through a G‐protein process within the cell) Agonist does what the endogenous chemical was going to do replaces whatever ACh does does the same thing as ACh nicotine is an example o binds to alpha subunit 10 times better ACh o it also crosses the blood brain barrier Antagonist prevents ACh from binding can bind somewhere completely different and reverse the effect of what ACh can do some of them block the binding site (blocking) some of them block the pore (competitive) Poisoned Dart Frogs epibatidine & alpha bungarotoxin = reversible competitive blocker for ACh Atropa belladonna – women make themselves look more interested Glutamate it’s an amino acid already everywhere in the body system since it’s in the body, why aren’t you firing? it’s only in the brain location is controlled by the blood‐brain barrier (separates CNS from rest of the body) ubiquitously excitatory precursor: glutamine (found in the glial cells) loaded into the cells via proteins (V‐gluts‐vesicle glutamate transporters‐are targets of drugs) source of the precursor comes from the mitochondria (alpha‐keto‐glutarate from krebs cycle) glial cells take up extra glutamate via transporters, convert it to glutamine and pass it backs to the cells There’s a specificity with which we load vesicles. There’s a proton‐glutamate transporter. It’s an anti‐port. In order to take up glutamate in high concentration, you have to have a high concentration of protons going the other way. You use the ATP synthesis in the opposite direction to run the protein gradient. Glutamate synapse: release glutamate from vesicles and then binds to different kinds of receptors. They can sometimes stimulate themselves. Ionotropic Glutamate Receptors: (some let sodium, calcium, and potassium into the cell) NMDA AMPA Kainate Four units Possible for K+, Na+ and Ca2+ to bind at the same time Glycine is an excitatory cofactor (that’s weird because it’s generally inhibitory) Magnesium will sometimes bind to these receptors and block it allosteric antagonist – causes receptor to do the opposite thing even though ACh is bound partial agonist/antagonist: o bind (so they’re competing) to the ACh site and they prevent ACh from doing what it’s doing o open the channel, but not enough o depolarizing blocker: causes a little bit of depolarization in the muscles, but not enough o non‐depolarizing blocker (ie curare): plugs the hole ...
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This note was uploaded on 09/28/2009 for the course BME 365R taught by Professor Rylander during the Fall '09 term at University of Texas.

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