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9/23/16 - W3D4H3 Neurons and Action Potentials Why This Topic? Action potentials are the basic unit of signaling in the central nervous system (CNS). All information our brain receives about the sensory world, and likewise all the sensations, emotions, thoughts and dreams generated in the brain, are conveyed via action potentials. Emergent properties are any unique property that "emerges" when component objects are joined together in constraining relations to "construct" a higher-level aggregate object, a novel property that unpredictably comes from a combination of two simpler constituents Learning Objectives 1. Explain the ionic basis of the action potential. 2. Explain the concept of threshold in terms of the underlying ion channel activity. 3. Describe the refractory period and how it is produced mechanistically. Next Week 9/27 4. Describe how changes in resting membrane potential affect the action potential. 5. Explain the propagation of an action potential down an axon and describe how the refractory period contributes to this. 6. Describe the importance of myelination for action potential propagation. A Quick Review Ion gradients across the membrane are maintained by the Na+/K+ ATPase pump. This protein pumps three Na+ ions out of the cell and two K+ ions into the cell helping maintain the necessary concentrate gradients that we’ve studied earlier. + Na+ Na+ Na Establishing these gradients is a way to store POTENTIAL ENERGY that can be used to do work, which is a prerequisite for cell survival and cell function. For example, the concentration differences for Na+ can be used to send electrical signals (i.e., action potentials) and also in secondary active transport to move glucose and calcium against their concentration gradients. (i.e., concentrate glucose in the cell (via Na+/Glu symport) or to pump Ca2+ out of the cytosol (via Na+/Ca2+ antiport). K+ + K A Quick Review Recall that the Nernst equation can be used to describe the behavior (i.e., movement) of the four most relevant ions: Na+, K+, Cl- and Ca2+ Review: Using these values in Table 1, can you calculate the equilibrium potentials for these ions at body temperature using the Nernst equation? Table 1. Normal resting concentration of various ions Ion [Intracellular] (mM) [Extracellular] (mM) Nernst Equilibrium Potential (mV) Na+ 12 142 66 K+ 140 4 -95 Cl- 8 105 -69 Ca2+ 7.0 x 10-5 2.5 139 *mM = mmol/L Nernst equilibrium potential (mV) is: EqX = (61.5/z) Log ([Xout]/[Xin]) A Quick Review If the membrane is permeable to a single ion, the membrane potential will move towards and reach the equilibrium potential for that ion. For example: o if the membrane were only permeable to K+, then the resting membrane potential would equilibrate at -95 mV. o if the membrane were only permeable to Na+, then the resting membrane potential would equilibrate at +66 mV. o If multiple ions are permeable to varying extents this results in what? A resting membrane potential that is not equal to any one of the calculated Nernst potentials. o A typical membrane potential lies between -65 mV and -70 mV. What ions do you think are the most permeable? Changing the membrane potential does not require the movement of very many ions. For example, only 1 in every 100,000 K+ ions needs to move to change the membrane potential 1 mV. LO1: Ionic basis of the action potential: PNa and PK are the permeabilities for sodium and potassium, respectively. Knowing the basis of ion distribution and movement across the plasma membrane Hodgkin and Huxley (1939) able to explain the action potential by measuring flow of current across the membrane, shown below. During an action potential (AP) the membrane potential (V) briefly reverses, hyperpolarizes and then returns to baseline. This correlates with an increase in sodium conductance followed by an increase in potassium conductance. This was a major discovery using the “patch clamp” technique. Action Potential From: Silverthorn, D.E. Human physiology: an integrated approach (7th edition). New Jersey: Prentice Hall/Pearson. 2016. Figure 8-9 (1 of 9) Action Potential From: Silverthorn, D.E. Human physiology: an integrated approach (7th edition). New Jersey: Prentice Hall/Pearson. 2016. Figure 8-9 (2 of 9) Action Potential “rising phase” of the AP (depolarizing) From: Silverthorn, D.E. Human physiology: an integrated approach (7th edition). New Jersey: Prentice Hall/Pearson. 2016. Figure 8-9 (3 of 9) Action Potential “steep rising phase” of the AP (depolarizing) From: Silverthorn, D.E. Human physiology: an integrated approach (7th edition). New Jersey: Prentice Hall/Pearson. 2016. Figure 8-9 (4 of 9) Action Potential “overshoot” From: Silverthorn, D.E. Human physiology: an integrated approach (7th edition). New Jersey: Prentice Hall/Pearson. 2016. Figure 8-9 (5 of 9) Action Potential “falling phase” of the AP (repolarizing) From: Silverthorn, D.E. Human physiology: an integrated approach (7th edition). New Jersey: Prentice Hall/Pearson. 2016. Figure 8-9 (6 of 9) Action Potential “undershoot” (hyperpolarization) From: Silverthorn, D.E. Human physiology: an integrated approach (7th edition). New Jersey: Prentice Hall/Pearson. 2016. Figure 8-9 (7 of 9) Action Potential From: Silverthorn, D.E. Human physiology: an integrated approach (7th edition). New Jersey: Prentice Hall/Pearson. 2016. Figure 8-9 (8 of 9) Action Potential From: Silverthorn, D.E. Human physiology: an integrated approach (7th edition). New Jersey: Prentice Hall/Pearson. 2016. Figure 8-9 (9 of 9) Action Potential permeability permeability From: Silverthorn, D.E. Human physiology: an integrated approach (7th edition). New Jersey: Prentice Hall/Pearson. 2016. Figure 8-9 (bottom) Voltage-gated Na+ Channels Figure 8-10a Voltage-gated Na+ Channels Figure 8-10b Voltage-gated Na+ Channels Figure 8-10c Voltage-gated Na+ Channels Figure 8-10d Voltage-gated Na+ Channels This repolarization is caused by voltage-dependent K+ channels opening. Figure 8-10e The Hodgkin cycle Figure 8-10e LO1: Ionic basis of the action potential: PNa and PK are the permeabilities for sodium and potassium, respectively. http://tmedweb.tulane.edu/pharmwiki/doku.php/introdu ction_to_cardiac_physiology_electrophysiology LO2. Explain the concept of threshold in terms of the underlying ion channel activity. If we inject a weak, brief depolarizing current (inward movement of positive charge) into an excitable cell, we will see voltage changes that scale with the magnitude of the current that we inject (Figure 1). If we gradually increase the magnitude of the injected current, at some point something very different happens: the membrane voltage makes a large and rapid excursion in response to injected current. This is an action potential: a large, rapid and discrete change in transmembrane voltage. Action potentials are the basic unit of signaling in the central nervous system. All the information our brain receives about the sensory world, and likewise all the thoughts and dreams generated in the brain, are conveyed via action potentials The “Threshold” Hodgkin and Huxley were able to stimulate APs with small depolarizing pulses They found a depolarizing pulse of about 5 mV would result in an action potential 50 % of the time and defined this degree of depolarization threshold, that is a degree of depolarization the resulted in a Hodgkin-Huxley cycle half of the time. A stimulation less then this is less then 50 % likely to result in an AP while a greater stimulus is more likely to give rise to an AP Once an AP is initiated though, it is an all or none phenomenon. There are no half Aps. LO 3. Describe the refractory period and how it is produced mechanistically There is a theoretical maximum frequency at which APs can fire. This is because the AP is an all or none phenomenon (and you cannot trigger another AP in the middle of the upslope of a Hodgkin-Huxley cycle) and because h-gates will have to be reset before they sodium channels can reopen and initiate a new action potential. This period is called the refractory period and can be divided into: • The absolute refractory period when h-gates are shut and you cannot trigger a new AP until they are open. • The relative refractory period when some h-gates are shut and the cell is hyperpolarized an AP can be triggered but it will require more input and not be as rapid as a normal AP. A Quick Review LO1: Ionic basis of the action potential: LO2. Explain the concept of threshold in terms of the underlying ion channel activity. If we inject a weak, brief depolarizing current (inward movement of positive charge) into an excitable cell, we will see voltage changes that scale with the magnitude of the current that we inject (Figure 1). If we gradually increase the magnitude of the injected current, at some point something very different happens: the membrane voltage makes a large and rapid excursion in response to injected current. This is an action potential: a large, rapid and discrete change in transmembrane voltage. Action potentials are the basic unit of signaling in the central nervous system. All the information our brain receives about the sensory world, and likewise all the thoughts and dreams generated in the brain, are conveyed via action potentials LO 3. Describe the refractory period and how it is produced mechanistically A few words about conductance. The movement of ions across the membrane is described by conductance, which is the inverse of resistance as represented by Ohm’s law: I = V/R where I is current, V is voltage which is the driving force, and R is resistance. Conductance of current is equal to the inverse of resistance. The conductance is a direct function of the number of channels that open and allow electrical current carried by one or more ions to flow into or out of the cell. R = V/I or Conductance (G) = I/V So, conductance for Na+ is: GNa+ = INa+/VNa+ Where V is = Vm-ENa+ Do you get this? NOTE: The SI unit of measure for R is the ohm (Ω), for current (I) it is the amp (A), for voltage (V) it is the volt (V) and for conductance (G) it is the siemens (S). A few words about the reversal potential. Remember, conductance for Na+ can be calculated as: GNa+ = INa+/VNa+ Where: VNa+ is = Vm-ENa+ then substituting: GNa+ = INa+/(Vm-ENa+) And finally, rearranging to solve for current due to sodium flow we have: INa+ = GNa+(Vm-ENa+) 1. So, if all the Na+ channels are closed, GNa+ = ? What then is INa+ ? 2. Or, if channels are open but Vm = ENa+ , what is the driving force and what is INa+ ? The Vm at which no flow occurs for Na+ is called the reversal potential, and in this case = ENa+ 3. What will happen Vm is LESS than ENa+? (e.g., Vm = -70 mV) 4. What will happen if Vm is GREATER thanENa+? (e.g., +80 mV) What if the reversal potential for an ion channel that is selective for “univalent” cations so both Na+ and K+ are permeable? (e.g., the Ach muscarinic receptor in the motor end plate of skeletal muscle.) • If ACh were to open an ion channel permeable only to K+, then the reversal potential of the end plate would be at the equilibrium potential for K+, which for a muscle cell is close to -100 mV. (Would K+ flow? No) • If the ACh-activated channels were permeable only to Na+, then the reversal potential of the current would be approximately +70 mV, the Na+ equilibrium potential of muscle cells. (Would Na+ flow? YES!!!!!) • If these ACh-activated channels were permeable to both Na+ and K+, then the reversal potential of the end plate would be between +70 mV and -100 mV. • IN this case, the reversal potential is NOT equal to either EK+ or ENa+. • What actually happens in realty? A Quick Review The resting membrane potential is largely set by outward leakage of potassium, however, some inflow of sodium occurs through sodium channels. The relative degree of sodium influx can influence the resting membrane potential (RMP) Neglecting the role of Cl-, which of these cell types do you believe has the lowest permeability to sodium? Note, for the moment we are neglecting the role of chloride movement. Some cell types are freely permeable to chloride (through open channels) while others have gated chloride channels that can be opened and closed. So, be prepared in the future to consider this when discussing specific cells and tissues. Based on your review of Nernst E(Cl-) values, what influence will movement of chloride have on the membrane potential? (Assume EqCl- = -69 mV). How would calcium movement influence RMP? (Hint: based on what you know about typical Ca2+ concentrations, what direction will Ca2+ flow ?)