HMB200H1 Final: L4 How do Neurons Use Both Chemical and Electrical Signaling Mechanisms?

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University of Toronto St. George
Human Biology
Franco Taverna

Lecture 4 How do Neurons Use Both Chemical and Electrical Signaling Mechanisms? Kolb & Whishaw 5E: § 4.2-4.3, 5.1-5.3, 6.1, Figures 6.5 (ACh), 6.6 (GABA ), 6.8 (DA), 6.9 (5AHT) Tuesday, January 30 Lecture Outline: I. Recapitulation of Membrane Physiology Note: Please attend correct tutorial this week a. E.g., Na+ II. Two Ions Moving • Problem set pilots to prepare for midterm exam stage two III. Action Potential • Stage 2 doesn’t require preparation, simply a way of revisiting harder IV. Synapse questions on the midterm and answer them in groups to increase test V. Common Signaling Systems scores (using scratch cards) VI. Basic Pharmacology at the Synapse VII. Summation and Networking + + Imagine a neuron at rest, with Na channels open. Assume that most other channels have much higher permeability than the K leak channels. + 1. Which direction is net movement of Na , initially? How do you know? a. Outward b. Inward + • Both diffusion and electrical forces are directing Na inwards 2. Under what conditions will equilibrium be reached? Under which conditions will the net movement be 0? + • At equilibrium, the membrane potential will sit at +55mV (equilibrium potential for Na ) • Electrical gradient and concentration gradients will equally oppose one another • Concentration gradient doesn’t change in living cells 3. Equilibrium occurs when Na channels remain open. At equilibrium, net movement = 0, and concentration gradient = voltage gradient. Therefore, the electrical force must reverse, since the concentration gradients don’t change. What will the electrical force be? Solve Nernst. • In the beginning, the electrical force was inwards • As Na entered the cell, it eventually reversed and was pointing outwards o When inside of the cell became positive • To oppose diffusion force, we use Nernst to determine how positive the inside of the cell will need to be to oppose Na + Nernst Equation, Simplified 𝑅𝑇 [𝑋] 𝐸𝑋= 𝑙𝑛 𝑜𝑢𝑡𝑠𝑖𝑑𝑒 • Convert the natural logarithm to log10 and we get a relatively simple equation 𝑧𝐹 [𝑋𝑖𝑛𝑠𝑖𝑑𝑒 • For Na , we see 58/1, and with K , we see 10/1 approximately • X = ion of interest • We get approximately +55mV • R = universal gas constant • T = temperature (Kelvin) • F = Faraday’s constant • Z = valence charge on ion (e.g., Na = +1) Therefore… ln = 2.3×𝑙𝑜𝑔 10 𝑅𝑇 = 25𝑚𝑉 𝑎𝑡 20˚𝐶 𝑧𝐹 58 [𝑋]𝑜𝑢𝑡𝑠𝑖𝑑𝑒 𝐸𝑋= 𝑧 × 𝑙𝑜𝑔 [𝑋] 𝑖𝑛𝑠𝑖𝑑𝑒 • Equilibrium occurs when sodium channels remain open • Solving Nernst, Na+ = +55mV inside at equilibrium • At +55mV, the concentration gradient and electrical gradients will be equal and opposite • Always note that the diffusion (concentration gradient) is relatively constant • We need to focus on the variable electrical gradients when solving these problems + + What if both Na and K channels open? What does equilibrium look like? • If both Na and K channels are open, we have both concentration gradients and voltage gradients coming into play • Given the ions equilibrium potentials, we can use the Goldman equations • If both channels open and permeabilities of those channels are the same (same amount allowed to flow through both channels), we can determine the equilibrium conditions • The equilibrium conditions will sit somewhere in between the two equilibrium potentials • Ignoring the small effect of the K leak channel… • ENa+= +55mV and E =K+85mV • To solve, we can use the GHK equation iff the permeabilities are the same Nernst and Goldman Equations The Goldman-Hodgkin-Katz equation is a simple expansion of Nernst to include other ions and channels. • Adjust [out] and [in] to match our numbers • Use P slider to simulate varying permeabilities • Start with PK+ = 1 and PCl- = 1, with T = 20 • K: 1, 10, 200 • Na: 0, 100, 10 • Cl: 0, 100, 10 • Membrane potential ends up between the two (-16.3mV) 2 If both Na and K channels stay open, what does equilibrium look like? • In reality, the permeabilities of these channels aren’t always the same • If Na channel has greater permeability than K channel, we would predict the equilibrium potential to be closer to +55mV (depending on how much more permeable the channel is relative to the other) • Ignoring the small effect of the leak channel… • ENa+= +55mV and E =K+85mV • What if the permeability to Na is greater than that to K ? Summary • When more than one channel opens, you can break • Relatively permeabilities of the channels are linear multiples and factors of down the problem to the individual channels the other channels o Ions seem to move independently • Must know this in order to determine where the membrane potential will sit • Since concentration gradients don’t change, the only at equilibrium variable will be electrical gradients o Electrical gradients do have a tricky effect on the ions, because they can reverse • Must know how much (permeability of channel) of each ion is moving to solve for equilibrium conditions • Channel types are unique o Open/close stimulus and duration, same speed, permeability, probability of opening, etc. + At rest, the small K leak current is the largest current, mo EK+ E If you change the voltage, you change the current flow. • When Huxley and Hodgkin studied squid giant axon and discovered leak current, they were able to change the • At equilibrium, net flow = 0 voltage of the system and seeing what happens to the o Flow in = flow out current • For that small leak channel, it’s a linear relationship (V=IR) • At -75mV, the net current is 0 • If we increase voltage to -70mV, net flow of current will be inwards • Flow of current increases inwards as the voltage increasingly becomes more positive • Flow of current increases outwards as the voltage decreases, based on K+ 3 What did Hodgkin and Huxley actually see when they changed the voltage in the axon? + • Small K leak currents vary linearly with voltage changes through Ohm’s Law o Ohm’s Law: V = IR ▪ Voltage equals the product of current and resistance • But, when they changed the voltage to -9mV, they say a huge non-linear change in current that first depolarized the membrane, then repolarized it o This was the action potential! • Late current = out, early current = in • First they saw a large inward current, and then large outward current – not agreeing with what we had imagined with the linear relationship • What would the first graph do if just the K channels were open? • The second graph is what they saw instead o This is current flow o Convert this to voltage and the familiar action potential trace The Action Potential + • After converting to voltage, we see a non-linear effect • They deduced that the action potential was a transient rise in Na permeability • They guessed correctly that this was due to a transient rise in Na o Toward E Na+ and then back towards E K+ permeability towards +55mV, and then it returns the equilibrium membrane potential • What was the nature of the channels underlying this? o Na rushes in, and then it stops rushing in • They were half right Electrical Activity of a Membrane During the Action Potential • External stimuli activate ion channels allowing cation influx to depolarize the cell • Depolarization arrives at integration zone with high density of voltage-gated ion channels • If voltage reaches a threshold, they all start opening • This is an all or nothing activation • If it reaches the threshold, they open; if it doesn’t reach threshold, they don’t open, and the signal dies • This is a graded potential – analog signal • Recap: sensory stimuli depolarize neurons by activating ion channels o The more intense the stimulus, the more ions • Voltage changes passively move and may reach the integration zone come in, the larger the graded potential, and • Integration zone contains large numbers ofNa and K voltage-gated the more likely the action potential will be channels triggered • If voltage reaches threshold, the channels open allowing efflux of cations • The action potential is a digital signal • Note how signals are converted from graded postsynaptic potentials to all- or-none action potentials + + • Na and K voltage-gated channels are attuned to approx. - 50mV threshold (depolarized from rest) Role of Voltage-Gated Ion Channels • Both Na and K voltage-gated ion channels are attuned to the threshold voltage of about -50mV o This doesn’t include the K leak channel 4 • If the cell membrane changes to reach this voltage, both types of channels open to allow ion flow across the membrane Proposed Scheme for Voltage Gating and Opening of Central Pore (a) Closed channel (b) Open channel • One transmembrane domain has many charged amino acids on it (lysine, etc.) • It seems to be the one that responds to the voltage change by structural and conformational changes Channel Dynamics Further Defined as the Sum of All the Single Channels • Probability of an Na channel opening depends on voltage o Mean open time approx. 0.7ms o Each channel may open quickly, slowly, or not at all • Summed current reflects slow decay in probability of opening o Most open early, fewer and fewer open later • In a neuron, conductance is the sum of all open channels o The more depolarized, the more channels open o Similar for both Na and K voltage-gated channels • In any given part of the cell, there are thousands of channels • Each channel will open on average around -40mV, but each still acts independently • Each trace is a trace of a single ion channel, collected with pipette • Straight line represents closed (low or no current flowing through), little dips represent channel openings • Duration and probability of channel opening is quite variable • When you measure the whole area of that cell, with 300 channels all summed together, the current flow into the neuron from the sum of all these channels has a general area of increased current • The more depolarized you are, the more channels open, and perhaps, the more they will open repeatedly or be open for longer periods of time, and the larger the sum of the current 5 Threshold Depolarization Triggers Action Potential • Large-scale opening of voltage-gated ion channels = depolarization + • Overwhelms the small K leak channels • Na and K channels have very different kinetics • Na and K channels’ kinetics result in an action potential • Which one must open first? Next? Which one closes first? Next? waveform • First see strong and rapid depolarization with voltage shooting up to • We know that depolarization is due to Na channels opening the positive mV • Repolarization is due to closing of Na channels AND opening of K • Then it returns back to negative voltage, and in fact, it goes below channels • Undershoot phase is due to K channels remaining open resting membrane potential (in many neurons), this is the undershoot phase • Emis more positive than EK, because some Na leaks into the cell • But when the leak channels and voltage-gated K channels that • And then it relatively slowly returns back to resting membrane remain open, we get a hyperpolarization (undershoot phase) potential • This whole phase typically takes approximately 2-5ms • Huxley assumed this was due to Na channels opening, and then closing Nernst and Goldman Equations Current and Voltage Graphs The Goldman-Hodgkin-Katz equation is simply an expansion of Nernst equation to include other ions and ion channels. 1. Adjust [out] and [in] to match our numbers 2. Use P sliders to simulate varying permeabilities a. Start with PK+ = 1 and PCl- = 1 3. Try to simulate action potential 6 Understanding the Action Potential + + Separate the Na and K currents: • Na channels open first, resulting in influx of current • K channels open second, resulting in efflux of current • Convert those currents to voltages, resulting in action potential voltage trace • An action potential can be determined by looking at the two components separately • The Na channel seems to rush in first, and then the channel closes • K doesn’t seem to rush out until later, and the channels seem to stay open a much longer period of time • Red is the net effect of the action potential • Note that this shows current flow of Na and K, rather than the action potential showed by the action potential • One observation that Hodgkin and Huxley found is that if you maintain a depolarized state in the neuron (artificially), past threshold, the action potentials would exist and then another would come after a while • All or none phenomenon would repeat itself in time Check Your Understanding+ Channel Dynamics Determine Waveform 4. What happens if the K channels are faster to open? a. Wider action potential b. Narrower action potential The opening of K channels earlier will bring the membrane potential back down quicker. Action Potential Passively Diffuses, Bringing Next Group of Channels to Threshold • Sufficient voltage change opens enough Na + channels for the wave of charge change to continue • The action potential allows a temporary depolarization to occur so that it can diffuse down the membrane • If it diffuses and is strong enough to depolarize neighbouring Na channels, more action potentials occur as Na goes in and it diffuses a little bit further • This is what we measure when we measure down an axon 7 Check Your Understanding: Different Characteristics of Ion Channels 5. What opens (“gates”) the ion channels at sensory endings? • Mechanoreceptors via mechanical movements, etc. (analog) 6. What opens the ion channels in axons? • At integration zones, it’s the voltage change that opens channels 7. Which one is graded (i.e., analog)? • Opening at sensory receptors 8. Which one is all-or-none (i.e., digital)? • Opening at axons Action Potentials Move as Wave, Myelination Results in Faster and Longer Passive Phase • Diffusion is quick • The further apart the voltage-gated ion channels to regenerate the action potential, the faster it can flow • The action potential itself is slow, but the passive diffusion is quick • Myelination serves to allow diffusion to occur faster and further to speed up transmission of action potentials because it regenerates at successive nodes of Ranvier between myelin sheath • Action potential only flows in one direction though… against the law of diffusion • Saltatory conduction o Saltare = “to dance” (Latin) o Propagation of an action potential at successive nodes of Ranvier 8 Electrical Activity of a Membrane: The Action Potential Absolutely Refractory Period: • State of an axon in the repolarizing period during which a new action potential cannot be elicited (with some exceptions) because sodium channels are inactivated Relative Refractory Period • State of an axon in later phase of an action potential during which increased electrical current is required to produce another action potential (i.e., action potential is more difficult to generate, but not impossible) + • Na channels are reactivated (after brief inactivation) • K channels are still open • Refractory periods are a biophysical property of the channels themselves • Once the ion channels open, they close again very quickly • Once they close, they spend a short period of time in this state and cannot be opened (no longer voltage-dependent) o This is the absolute refractory period • ARP lasts a few milliseconds • Refractory periods limit action potential • Refractory period takes longer than it does for the diffusion of charges to the next node of Ranvier frequency and direction • Afterwards, Na channels start to reactivate again, but all at different times – all together, we have a stage when some are ready to be activated, while others are still inactivated • If enough are activated, you can fire another action potential if you depolarize strong enough – relative refractive period Check Your Understanding: Channel Dynamics Determine Waveform 9. What happens if the K channels are slower to close? a. Lower frequency action potential firing b. Higher frequency action potential firing Neurons have many different types of channels, and they can change their function. • Longer state of hyperpolarization Transmission of Signal Intensity • The stronger the stimulus at the nerve ending, we get more charges flowing in to the cell (as a graded potential) • When we hit the integration zone, it becomes an all-or-none action potential • Conversion of signal intensity is frequency • E.g., painful stimulus elicits larger graded potentials in sensory endings which are converted to action potentials • How is the intensity of the stimulus transmitted if it is converted to an all or none response? 9 Rate Law • The intensity of stimulus being transmitted in an axon is represented by the rate at which that axon fires o Higher intensity signal  higher rate of firing (more action potentials) o Lower intensity signal  lower rate of firing (fewer action potentials) • The stronger the stimulus, the more frequent the action potentials • At the integration zone, action potentials fire at faster and higher frequencies • This is the rate law Signaling is Remarkably Consistent, Given the Same Stimulus • A consistent stimulus = same frequency of action potentials, same amount of neurotransmitter release, same response (e.g., amplitude of PSPs or activation of signaling pathway) But… Signaling May Change Very Rapidly and Profoundly Plasticity is a foundational feature of the nervous system: • Changes to channels also include post- translational modification • Dynamic channel functions • Changes to the channel function through signaling (e.g., phosphorylation of channels can change their permeability or open time, or opening probability, etc.) • Different types of channel subunits • Different types of channels • Evolutionary processes (random mutations, epigenetics, etc.) Nervous System is Built to Change and Adapt • Motor neurons in frogs have multiple K channels that contribute to the action potential, most evident in the hyperpolarization phase • The one that opens very rapidly, closes early • In early part of of undershoot, the membrane potential directs up toward rest, but then plateaus again until it eventually goes up to resting membrane potential • Some neurons in guinea pigs have neurons that have increased duration with spike Hyperpolarizing afterpotentials: + trains • Frog spinal motor neurons have both slow and fast K channels that generate slow and • Subsequent spikes have longer fast afterhyperpolarization potentials afterhyperpolarization potential, and larger o Activated by Ca , and is signaling-mechanism-dependent as well • Some channels vary their function over time/activity • If each subsequent spike has a longer o E.g., guinea pig vagal neurons – size of slow afterhyperpolarization potential hyperpolarizing action potential, the rate of increases as the number of successive action potentials in the train increases frequency of signaling will decrease and be • What is the effect on signaling of these two phenomenon? inhibiting of subsequent action potentials • Have to overcome hyperpolarization to get back to threshold 10 Neurons Receive Both Excitatory and Inhibitory Inputs • Through K flow, the neuron can be hyperpolarized, the other type of common signaling that occurs o K channels causing K efflux o Cl channels causing Cl influx • The Na influx will cause EPSPs, resulting in depolarization, as an excitatory signal • When you hyperpolarize, it’s an inhibitory signal, because it takes more potential to reach threshold to fire an action potential • EPSPs: add together (depolarize), thus more likely to fire an action potential • IPSPs: subtract (hyperpolarize), thus less likely to fire an action potential • Temporal summation: inputs from far away sites arriving at the same time • Spatial summation: inputs from close together sites arriving at the same Summation of Inputs time • Integration zone occurs further down stream, except for in sensory neurons where it’s close to the nerve ending • Usually, it’s on the other side of the soma – this is where we need to depolarize, influenced by all PSPs at the synapses of the cell • They sum together • Signals can arrive at the axon hillock at the same time, even though they occur at different times • Signals can arrive at the same or adjacent synapses at the same time and summate • It takes quite a few PSPs to depolarize the neuron enough to fire an action potential Summation is a property of both EPSPs and IPSPs in any combination, such that ion influx and efflux are being summed. • Influx of Na accompanying one EPSP is added to the influx of Na accompanying a second EPSP if the two occur close together in time and space • If the two influxes are remote in time or space, or in both, no summation is possible • When efflux of K occurs close together in time and space, they sum; when they’re far apart in either or both ways, there’s no summation + + • For an EPSP and IPSP, influx of Na associated with EPSP is added to efflux of K associated with IPSP, and difference between them is recorded as long as they’re spatially and temporally close together o If they’re widely separated in time or space, or in both, they don’t interact and Summary there’s no summation • Neuron with thousands of inputs responds no differently from one with only a few inputs – • Signal inputs (e.g., sensory) activate neurons, it democratically sums all inputs that are close together in time and space • Cell body membrane always indicates the summed influences of multiple temporal and typically by depolarization • Waves of graded potentials (voltage changes) special inputs travel passively o Neuron can be said to analyze its inputs before deciding what to do at the initial • Excitatory and inhibitory inputs are integrated segment (summed) Unlike the cell body, the axon is rich in voltage-sensitive channels, beginning at the initial • Graded potentials (summed voltage changes) segment, with actual threshold voltages that vary with the type of neuron. can reach threshold to trigger action potentials o Firing rate indicates stimulus intensity • To produce an action potential, the summed graded potentials – IPSPs and EPSPs – on the cell body membrane must depolarize the membrane at the initial segment to -50mV • Action potentials actively renewed o Voltage changes rapidly move down • If threshold voltage is obtained only briefly, voltage-sensitive channels open, and just one axons or a few action potentials may occur • Refractory periods create directionality and limit • If threshold level is maintained for longer period, action potentials will follow one another in rapid succession, just as quickly as gates on voltage-sensitive channels reset frequency of action potentials • Depolarization is the excitatory response, • Each action potential is then repeatedly propagated to produce a nerve impulse that travels hyperpolarization is the inhibitory response from initial segment down the length of the axon • Many neurons have extensive dendritic trees, but those don’t have many voltage-sensitive channels and ordinarily don’t produce action potentials • Distant branches of dendrites may have less influence in producing action potentials initiated at the initial segment than do the more proximal branches of the dendrites • Inputs close to the initial segment are usually much more influential than those occurring some distance away, while distant inputs usually have a modulating effect 11 Structure of Synapses 1. Chemical synapses: junction where messenger molecules are released from one neuron to interact with the next neuron • Synaptic vesicles: round granular substances in the axon terminal that contain neurotransmitter • Dark patches on axon terminal membrane are proteins that serve largely as ion channels to signal the release of the transmitters or as pumps to recapture the transmitter after its release • Dark patches on the dendrite consist mainly of receptor molecules also made up of proteins that receive chemical messages • Synaptic cleft: separates the axon terminal and dendrite, critical to synapse function because neurotransmitter chemicals must bridge this gap to carry a message from one neuron to the next • Synapse is sandwiched by many surrounding structures, including glial cells, other axons and dendritic processes, and other synapses o Surrounding glia contribute to chemical neurotransmission in several ways – by supplying building blocks for neurotransmitter synthesis, by confining movement of neurotransmitters to the synapse, and mopping up excess neurotransmitter molecules • Presynaptic membrane forms the axon terminal, postsynaptic membrane forms the dendritic spine, and the space between the two is the synaptic cleft o Within axon terminal are specialized structures, including mitochondria, storage granules – large compartments that hold several synaptic vesicles, and microtubules, which transport substances to terminal Chemical synapses flexibly control whether a message is passed from one neuron to the next by amplifying or diminishing a signal from one neuron to the next and they can change with experience to alter their signals and mediate learning. 2. Electrical synapse: allow neurons influence each other electrically through a gap junction where cell membranes of two neurons come into direct contact • Ion channels in one cell membrane connect to ion channels in the other membrane, forming a pore that allows ions to pass from one neuron to the other in both directions • Fusion eliminates brief delay in information flow (5ms) of chemical transmission • Gap junctions allow groups of interneurons to synchronize their firing rhythmically and allow glial cells and neurons to exchange substances At the Synapse, Action Potentials Result in Chemical Message Neurotransmission in Four Steps Step 1: Neurotransmitter synthesis and storage Step 2: Neurotransmitter release • At the synapse, we have synaptic transmission where electrical signal is Step 3: Neurotransmitter binds to receptors and activates them converted to chemical signal Step 4: Deactivation of the neurotransmitter • Chemical signal occurs in four steps • Neurotransmitter is the chemical message What is a Neurotransmitter? • NT must be synthesized or present in neurons, in particular at the axon terminals (end feet) o Transmitter neurons will have enzymes to convert precursors • When released, NT must produce some signal on the postsynaptic neuron • If added to another neuron, the response should be mimicked • Must be a method to remove the NT from the synapse after the signaling is done • Tyrosine hydroxylase is a good marker for DA neurons
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