lecture04
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ackman678
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Note:
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So, how do neurons convey information over long distances that results in information transfer to other neurons at synaptic connections? It through electrical signaling that neurons are able to generate and transmit information. And this electrical signaling is possible because of a combination of…
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So, how do neurons convey information over long distances that results in information transfer to other neurons at synaptic connections? It is through electrical signaling that neurons are able to generate and transmit information. And this electrical signaling is possible because of a combination of…
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- voltage-dependent membrane permeability
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- which in turn requires special membrane proteins called ion channels and transporters
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@@ -41,9 +39,9 @@ Note:
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To understand the basis of electrical excitability in neurons, we first need to understand that neurons, like other excitable cells, have a difference in electrical potential across the cell membrane when it is at rest.
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To learn this neuroscientists stick electrodes inside of neurons. This electrode is hooked up to a voltmeter and another electrode sits outside the cell as a ground or reference electrode to complete the circuit. The difference in voltage between the inside of the cell and the outside of the cell is monitored over time and displayed on an oscilloscope.
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To learn this physiologists stick electrodes inside of cells, including neurons. This electrode is hooked up to a voltmeter and another electrode sits outside the cell as a ground or reference electrode to complete the circuit. The difference in voltage between the inside of the cell and the outside of the cell is monitored over time and displayed on an oscilloscope.
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When you do this, one finds a negative resting membrane potential of the neuron with respect to the outside. You can see in this plot at the bottom right that we’ve inserted the electrode and then over time we measure a negative membrane potential of about -70 mV. Recall that volts are a unit of electrical potential energy —>
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When you do this such as with this model neuron shown here, one finds a negative resting membrane potential of the neuron with respect to the outside of approximately -70 mV.Recall that volts are a unit of electrical potential energy, where 1 Volt is defined as the amount of energy that will drive 1 coulomb of elementary charge or 6x10^18 electrons or protons through a resistance of 1 ohm in 1 second —>
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---
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@@ -70,38 +68,54 @@ Flow rate ~ Current (amperes) = `I`
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Note:
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And voltage is related to the resistance and current in an electrical circuit as described by Ohm’s law. This analogy of a water pump/water wheel circuit helps us understand these relationships better.
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And recall from physics that voltage is related to the resistance and current in an electrical circuit as described by Ohm’s law. This analogy of a water pump/water wheel circuit helps us understand these relationships better.
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Voltage = is the potential difference, or electromotive force measured across the conductor in units of volts. Imagine a hand pump that you use to do some work and introduce pressure in a water system, that pressure or potential difference is the voltage.
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Voltage
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: is the potential difference, or electromotive force measured across the conductor in units of volts.
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: So imagine a hand pump that you use to do some work and introduce pressure in a water system, that pressure or potential difference is the voltage.
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* - Volt is defined as the difference in electric potential between two points of a conducting wire when an electric current of one ampere dissipates one watt of power between those points
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* - voltmeter, ammeter
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*Volt is defined as the difference in electric potential between two points of a conducting wire when an electric current of one ampere dissipates one watt of power between those points*
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*voltmeter, ammeter*
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Current
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: measured in amperes is the flow of electric charge across a surface at the rate of one coulomb per second. Used to express the flow rate of electric charge.
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: So imagine the rate of water flow in this water pump as the the flow of electric charge across a cell membrane. What is the charge that is moving for a cell? Monovalent and divalent atoms like Na⁺, K⁺, Cl⁻, and Ca²⁺.
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*1A equivalent to one coulomb (roughly 6.241×10^18 times the elementary charge) per second*
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*coulomb = charge (symbol: Q or q) transported by a constant current of one ampere in one second. 1C equivalent to a charge of approximately 6.242×10^18 protons or electrons.*
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*elementary positive charge: This charge has a measured value of approximately 1.6021766208×10^−19 coulombs*
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Resistance
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: is the difficulty to pass a current through a conductor measured in ohms.
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: Image the diameter of a pipe or a valve that you can regulate to be the resistance
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: inverse of resistance is conducance *g* measured in siemens (S)
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: for studying neuronal excitability rewriting Ohm's law as I = g(Vm-Ex) is most useful. g = conductance, no. of open channels. (Vm-Ex) = driving force causing either positive or negative current.
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Current: measured in amperes is the flow of electric charge across a surface at the rate of one coulomb per second. Used to express the flow rate of electric charge. Imagine the rate of water flow in this water pump as the the flow of electric charge across a cell membrane. What is the charge that is moving for a cell? Monovalent and divalent atoms like Na⁺, K⁺, Cl⁻, and Ca²⁺.
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**Ohm’s law** from physics class relates these quantities together as V = IR, and rearranging this equation and reading it as I = V/R or Current = Voltage divided by Resistance gives you a better intuitive feel for these relations. **Notice that when you have 0 voltage or potential difference you have no current.**
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* - 1A equivalent to one coulomb (roughly 6.241×10^18 times the elementary charge) per second
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* - coulomb = charge (symbol: Q or q) transported by a constant current of one ampere in one second. 1C equivalent to a charge of approximately 6.242×10^18 protons or electrons.
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* - elementary positive charge: This charge has a measured value of approximately 1.6021766208×10^−19 coulombs
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Avogadro constant
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: (symbols: L, NA)
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: is the number of constituent particles, usually atoms or molecules, that are contained in the amount of substance given by one mole.
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: Avogadro’s constant = 6.022×10^23 and is dimensionless.
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* Resistance: is the difficulty to pass a current through a conductor measured in ohms. Image the diameter of a pipe or a valve that you can regulate to be the resistance
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* Ohm’s law from physics class relates these quantities together as V = IR, and rearranging this equation and reading it as I = V/R or Current = Voltage divided by Resistance gives you a better intuitive feel for these relations. Notice that when you have 0 voltage or potential difference you have no current.
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* Avogadro constant (symbols: L, NA) is the number of constituent particles, usually atoms or molecules, that are contained in the amount of substance given by one mole. Avogadro’s constant = 6.022×10^23 and is dimensionless.
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* mole = It is defined as the amount of any chemical substance that contains as many elementary entities, e.g., atoms, molecules, ions, electrons, or photons, as there are atoms in 12 grams of pure carbon-12 (12C). This number is expressed by the Avogadro constant
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mole
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: it is defined as the amount of any chemical substance that contains as many elementary entities, e.g., atoms, molecules, ions, electrons, or photons, as there are atoms in 12 grams of pure carbon-12 (12C).
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: this number is expressed by the Avogadro constant
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---
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## Electrical signals
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* Can be generated by changing the resting potential of the neuron
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* Can be generated by changing the membrane potential of the neuron
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* Receptor potentials can be generated from the activation of sensory receptors, from touch, light, sound, and heat
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* Synaptic potentials are transmitted from one neuron to another at the synapse
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* Action potentials are the booster system to propagate electrical signals a long distance
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Note:
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Signals in neurons can be generated by changing the resting membrane potential.
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Signals in neurons can be generated by changing the membrane potential.
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This includes receptor potentials inside your body’s sensory neurons for touch, heat, light, and sound.
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@@ -124,9 +138,9 @@ This figure shows these 3 types of neuronal signals.
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- Here is a synaptic potential recorded in a postsynaptic neuron.
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- Here is an action potential in a motor neuron. Look as the y-axes here— the action potential has a much larger amplitude change than receptor or synaptic potentials.
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- Here is an action potential in a motor neuron. **Look as the y-axes here**— the action potential has a much larger amplitude change than receptor or synaptic potentials.
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To understand the basis of these electrical signals we first need to learn about how this baseline membrane potential is generated, which is the neurons membrane potential while it is at rest. We will spend most of today's class learning about the neurons resting membrane potential and which will lead into how the action potential is generated that we'll continue with next class.
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---
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@@ -148,11 +162,11 @@ This figure shows these 3 types of neuronal signals.
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Note:
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I said that the resting membrane potential is more negative on the intracellularly than extracellularly– this is because of the lipid bilayer and its transmembrane proteins which together make a functional cell membrane
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I said that the resting membrane potential is more negative inside the neuron with respect to its extracellular space– this is because of the lipid bilayer and its transmembrane proteins which together make a functional cell membrane
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We can that the cell, a bit like American politics, is polarized with one side more negative and the other being more positive
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We can think of the cell, a bit like American politics, is polarized with one side more negative and the other being more positive
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This polarization results in a potential difference across the membrane (remember our water pump example) of about -70 mV
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This polarization of the cell results in a potential difference across the membrane (remember our water pump example) of about -70 mV
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And its there is a concentration gradient in ions (which are charged atoms like sodium, potassium, and chloride) that results in this difference in distribution of charge across the neuron’s membrane
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So we insert the microelectrode into the cell and find that this neuron is resting at -65 mV.
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Then we inject a small amount of negative current (less than 1 nA) so that we hyperpolarize the cell and we see that the membrane responds passively, meaning that the membrane potential changes and recovers with an exponential relationship.
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* 1-(1/e) = 63% Vm and 1/e (37%) of Vm
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* 1-(1/e) = 63% (rise) Vm and 1/e (37%) (decat) of Vm
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If we depolarize the cell membrane from rest by injecting pulses of positive current we get corresponding passive responses with exponential rises and decays of membrane potential– **unless that cell is a neuron and we’ve exceeded the threshold potential (shown by the red dotted line) for generating an action potential in that neuron.
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Notice if we inject stronger current pulses, we get more action potentials, also known as a higher spiking or firing rate, rather than different action potential amplitudes. If the depolarization is sufficient to generate an AP, that AP amplitude stays largely the same within each individual neuron.
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We will go over more detail each of these components later on...
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---
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@@ -231,7 +245,7 @@ Notice if we inject stronger current pulses, we get more action potentials, also
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Note:
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All electrical signals are the due to the flow of charge, positive or negative. In this case of neurons we the charge is due to the movement cations such as Na and K and anions such as Cl and neuronal membranes are selectively permeable to some of these ions giving the rise to the flow of charge or current across the cell membrane.
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All electrical signals are the due to the flow of charge, positive or negative. In this case of neurons the charge is due to the movement cations such as Na and K and anions such as Cl and neuronal membranes are selectively permeable to some of these ions giving rise to the flow of charge or current across the cell membrane.
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---
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Note:
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How do ions get across the lipid cell membrane bilayer? Remember there are proteins in the cell membrane. Some of these are selective ion transporters, remember the Na-K ATPase from cell biology. These work to create concentration gradients.
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So how do ions get across the lipid cell membrane bilayer? Remember there are proteins in the cell membrane. Some of these are selective ion transporters, remember the Na-K ATPase from cell biology. These work to create concentration gradients.
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There are also ion channels that form pores in the cell membrane that are selectively permeable for certain kinds of ions to cross the membrane. These allow ions move across the membrane
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Note:
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Ion channels span the membrane and act as pores. They can open and close, often in a voltage-dependent fashion as we will learn thursday. They show selectively such that there are different types of Na, K channels as well as others.
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Ion channels span the membrane and act as pores. They can open and close, often in a voltage-dependent fashion as we will learn thursday. And ion channels even show selectively such that there are different types of Na, K channels as well as others.
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And they can be additionally regulated or ‘gated’ by different mechanisms including voltage or binding of ligands such as neurotransmitters as we will learn in subsequent classes.
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And they can be additionally regulated or ‘gated’ by different mechanisms including voltage or binding of ligands such as neurotransmitters. We will learn much more about the selectivity and function of ion channels a couple lectures from now.
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---
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@@ -306,7 +318,7 @@ So again there are active ion transporters like the Na-K ATPase and there are io
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Note:
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We actually can predict what the resting membrane potential by knowing the concentrations of ions inside and outside the cell and knowing the relative permeability of these ions to move across the cell membrane.
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We actually can predict what the resting membrane potential is by knowing the concentrations of ions inside and outside the cell and knowing the relative permeability of these ions to move across the cell membrane.
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If a cell membrane is largely permeable to just one ion species, we can use the Nernst equation to predict the membrane potential for all kinds of cells.
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We will come back to these in a minute.
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*Walther Nernst (1864-1941)*
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*Walther Nernst (1864-1941), West Prussia, 1920 Nobel Prize in chemistry*
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---
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## Electrochemical equilibrium
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<figure><figcaption class="big">orange dots K⁺, green dots Cl⁻</figcaption><img src="figs/Neuroscience5e-Fig-02.05-1R-2_163131c.png" height="500px"><figcaption>Neuroscience 5e Fig. 2.5</figcaption></figure>
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<figure><figcaption class="big">orange dots K⁺, green dots Cl⁻. This simulated membrane is only permeable to K⁺</figcaption><img src="figs/Neuroscience5e-Fig-02.05-1R-2_163131c.png" height="500px"><figcaption>Neuroscience 5e Fig. 2.5</figcaption></figure>
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@@ -334,7 +346,7 @@ Imagine the following experiment. We have a cell and record intracellular membra
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If this membrane is only permeable to K⁺, and KCl concentration is the same inside and outside the cell, there is no net flux of K⁺
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If KCl is more concentrated inside the cell, initially there is a net flux of positively charged K⁺ from inside to outside the cell due to the chemical concentration driving force leaving the membrane hyperpolarized until the this chemical force is balanced by the electrical driving force from the positively charged K⁺ being repelled by the more positive environment now outside the cell. This is called electrochemical equilibrium, and the potential at which this occurs is called the equilibrium potential for that ion.
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If KCl is more concentrated inside the cell, initially there is a net flux of positively charged K⁺ from inside to outside the cell due to the chemical concentration driving force which leaves the membrane hyperpolarized because of the net movement of postive charge to the outside until the this chemical force is balanced by the electrical driving force from the positively charged K⁺ being repelled by the more positive environment now outside the cell. This is called electrochemical equilibrium, and the potential at which this occurs is called the equilibrium potential for that ion.
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---
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@@ -395,8 +407,7 @@ So I stated that the Nernst equation is how we can calculate the equilibrium pot
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And here is the Nernst equation is:
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Where Ex is:
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Where Ex is...
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Gas constant R
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@@ -453,10 +464,14 @@ T = 20+273
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==>58.26427
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<figure><img src="figs/Screen_Shot_2016-09-29_at_5.15.39_AM_6d8392d.png" height="100px"><figcaption></figcaption></figure>
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<figure><img src="figs/Screen_Shot_2016-09-29_at_5.15.43_AM_5c77e27.png" height="100px"><figcaption></figcaption></figure>
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---
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## Examples
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* Calculate the following equilibrium potentials at room temperature:
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* Outside 10 mM KCl, Inside 1 mM KCl membrane only permeable to K⁺ ?
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* E<sub>K+</sub> = <span class= "fragment fade-in">(58/1)log10(10/1) ==> +58</span>
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* Outside 1 mM KCl, Inside 100 mM KCl membrane only permeable to K⁺ ? <!-- .element: class="fragment fade-in"-->
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@@ -479,8 +494,6 @@ Since the Nernst equation is really just a linear equation of the form y = mx, y
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## Electrochemical equilibrium
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<div><img src="figs/Neuroscience5e-Fig-02.05-2R_c30075c.png" height="500px"><figcaption>Neuroscience 5e Fig. 2.5</figcaption></div>
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@@ -521,7 +534,7 @@ Note:
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## Membrane potential influences ion fluxes
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<figure><img src="figs/Neuroscience5e-Fig-02.06-1R_5d1ff2f.png" height="500px"><figcaption>Neuroscience 5e Fig. 2.6</figcaption></figure>
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<div><figcaption class="big">Simulated cell at room temperature</figcaption><img src="figs/Neuroscience5e-Fig-02.06-1R_5d1ff2f.png" height="400px"><figcaption>Neuroscience 5e Fig. 2.6</figcaption></div>
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Note:
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@@ -535,7 +548,6 @@ If our hypothetical battery holds the membrane at -58 mV, the equilbrium potenti
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At more negative membrane potentials than the nernst equilbrium potential we get net inward flow due to the stronger electrical driving force which in the case of potassium here is causing it to move against its chemical gradient.
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---
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## Membrane potential influences ion fluxes
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@@ -564,9 +576,9 @@ Note:
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So to summarize, remember that both the direction (inward vs outward) and magnitude of charge flow or current depends on membrane potential.
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Just remember Ohm’s law, I = V/R
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Just remember Ohm’s law, I = V/R and rewrite it as Ix = (Vm - Ex)/R
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And we can experimentally vary...
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And we as scientists can experimentally vary...
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---
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@@ -624,7 +636,7 @@ For a typical neuron at rest, pK : pNa : pCl = 1 : 0.05 : 0.45. Note that becaus
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Note:
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And as we will soon learn, the resting membrane potential and action potential voltage is mostly due to changes in K permeability and Na permeability across the neuronal membrane. As you can see in this figure, the resting membrane potential for a neuron is close to the EK eq potential due to much greater permeability for K. During an action potential Na permeability initially increases, until the Vm approaches the ENa and then Na permeability decreases until the Vm again approaches the resting membrane potential and Pk increases.
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And as we will soon lecarn, the resting membrane potential and action potential voltage is mostly due to changes in K permeability and Na permeability across the neuronal membrane. As you can see in this figure, the resting membrane potential for a neuron is close to the EK eq potential due to much greater permeability for K. During an action potential Na permeability initially increases, until the Vm approaches the ENa and then Na permeability decreases until the Vm again approaches the resting membrane potential and Pk increases.
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---
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@@ -745,7 +757,7 @@ To answer this Hodgkin and and Katz measured the membrane potential while induci
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They observed that the Vm approached ENa during an AP...
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They reason they hypothesized is that during an AP...
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They reasoned that during an AP...
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Their experiment was to lower Na concentrations in the extracellular medium—
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@@ -793,6 +805,8 @@ As you can see on the left here changing extracellular [Na] changes the action p
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* During depolarization membrane becomes super permeable to Na⁺
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* There must be Na⁺ channels that are closed during rest but become open during an action potential, and closed again at the end of an action potential
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<figure><img src="figs/Neuroscience5e-Fig-02.07-0_caebcb8.png" height="200px"><figcaption>Neuroscience 5e Fig. 2.7</figcaption></figure>
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Note:
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So a summary of the Hodgkin and Katz experiment conclusions...
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