Neurons: Resting Membrane Potential and Action Potential PDF

Neurons Kamalini Ranasinghe MD PhD Assistant Professor of Neurology Memory and Aging Center Department of Neurology University of California San Francisco  Basic Neurophysiology Resting Membrane Potential & Action Potential  Ganong’s Review of Medical P...

Neurons Kamalini Ranasinghe MD PhD Assistant Professor of Neurology Memory and Aging Center Department of Neurology University of California San Francisco  Basic Neurophysiology Resting Membrane Potential & Action Potential  Ganong’s Review of Medical Physiology Excitable Tissue: Nerve Guyton and Hall Textbook of Medical Physiology Membrane Potentials and Action Potentials Resting Membrane Potential & Action Potential What is the resting membrane potential of a cell (neuron) ? Ganong’s Guyton and Hall -65 to -90 mv What is the mechanism that gives rise to resting membrane potential? The potential inside the neuron is 90 millivolts more negative than the potential in the extracellular fluid Inside the neuron is -90 mv is arrived by ionic negative compared to movement across the cell outside, because of membrane. negatively charged proteins. -90 mv Protein anions What is the mechanism? Inside the neuron is -90 mv is arrived by ionic negative compared to movement across the cell outside, because of membrane. negatively charged proteins. -90 mv Protein anions What is the mechanism? The distribution of ions across the membrane Concentration Concentration Ion inside outside K+ 140 4 ➡ K+more concentrated inside Na+ 14 142 ➡ Na+ more concentrated outside K+ K+ Na+ Na+ Na+ Na+ Equilibrium potential for K+: No net movement of ions when separated by a phospholipid membrane What is meant by ‘permeability’ K+ There are channels that allows the passage of K+ across the neuronal membrane. “Leaky K+ channels” Fact: at rest, neuronal membrane has two types of leaky channels K+ Na+ Leaky K+ channels Leaky Na+ channels Fact: There are many more leaky K+ channels than leaky Na+ channels K+ K+ K+ Na+ K+ Therefore, neuronal membrane is more permeable to K+ than to Na+  K+ K+ K+ Na+ K+ So this is our situation …. Now lets take each ion at a Equilibrium potential for K+: No net movement of ions when separated by a phospholipid membrane Equilibrium potential (electromotive force; EMF) Nernst equation i o 61 Nernst potential for K+ Concentration Concentration Ion inside outside K+ 140 4 Na+ 14 142 = -61x log10 (140/4) = -61 x 1.54 = -93.94 = -94 If the cell is ONLY permeable to K+ the RMP is -94 mv Nernst potential for K+ Concentration Concentration Ion inside outside K+ 140 4 Na+ 14 142 = -61x log10 (140/4) = -61 x 1.54 = -93.94 = -94 -90 mv Nernst potential for Na+ Concentration Concentration Ion inside outside K+ 140 4 Na+ 14 142 = -61x log10 (14/142) = -61 x -1.006 = 61.37 = 61 If the cell is ONLY permeable to Na+ the RMP is 61 mv  2 ions ! Now what ? Goldman equation Goldman equation Relative Permeability Membrane is far more permeable to K+ than Na+ Relative permeability of K+ to Na+ is 100 to 1 = -61x log10 ( 14 x1 + 140 x 100 ) 142 x 1 + 4 x 100 Concentration Concentration Ion inside outside K+ 140 4 Na+ 14 142 = -61 x log10 ( 14 + 14000 ) 142 + 400 = -61 x log10 ( 14014 ) 542 = -61 x 1.412. = -86.1 ~ -86mv -90 mv  -90 mv Leaky K+ channels Leaky Na+ channels Outside -86 mv Inside Mechanisms that give rise to resting membrane potential? 1.Protein Anions 2.leaky K+ channels 3.leaky Na+ channels 4.Na+/K+ pump  Relative Goldman Permeability Ion Concentration inside Concentration outside equation K+ Na+ 140 14 142 410 K+ K+ K+ K+ K+ K+ = -61x log10 ( 14 x1 + 140 x 100 ) = -61x log10 ( 14 x1 + 140 x 100 ) 142 x 1 + 4 x 100 142 x 1 + 10 x 100 = -61 x log10 ( 14 + 14000 ) = -61 x log10 ( 14 + 14000 ) 142 + 400 142 + 1000 = -61 x log10 ( 14014 ) = -61 x log10 ( 14014 ) 542 1142 = -61 x 1.412. = -86.1 ~ -86mv = -61 x 1.088 = -66.42 ~ -66mv  Relative Goldman Permeability Ion Concentration inside Concentration outside equation K+ Na+ 140 14 4 148 142 Na+ Na+ Na+ Na+ Na+ Na+ = -61x log10 ( 14 x1 + 140 x 100 ) = -61x log10 ( 14 x1 + 140 x 100 ) 142 x 1 + 4 x 100 148 x 1 + 4 x 100 = -61 x log10 ( 14 + 14000 ) = -61 x log10 ( 14 + 14000 ) 142 + 400 148 + 400 = -61 x log10 ( 14014 ) = -61 x log10 ( 14014 ) 542 548 = -61 x 1.412. = -86.1 ~ -86mv = -61 x 1.408 = -85.9 ~ -86mv Because membrane is more permeable to K+ than Na+ ………. (i) RMP is closer to K+ equilibrium potential than Na+ equilibrium -90 mv potential (ii) Small change in extracellular K+ makes BIG changes in RMP -68 mv -90mv (iii) Hyperkalemia makes neuronal membrane less polarized (depolarize)  Nerve Action Potential Rapid changes in neuronal membrane potential that spread along the nerve. Nerve Action Potential Membrane potential (mv) Depolarization Overshoot Repolarization 0 After-hyperpolarization -90 RMP 0 1 2 3 4 Time (ms) Threshold potential (~15 mv)  Who are the players ? Extracellular K+ Na+ Na+ K+ Na+ Na+ Na+ K+ Na+ Na+ Na+ Leaky K+ Leaky Na+ Na+/K+ pump K+ Na+ K+ Na+ K+ Na+ Voltage-gated K+ K+ Voltage-gated K+ K+ K+ Na+ channel K+ channel Intracellular RMP 1. Voltage gated: Open after a depolarizing threshold (~15 mv) 2. Voltage gated Na+ open first 3. Voltage gated K+ open next  Voltage gated Na+ ✓ Three stages + + + + + + + + + + + + ✓ Fast dynamics (open fast, + + + + + + inactivate and close fast) Closed Open Inactivated (resting) Voltage sensor Voltage gated K+ + + + + ✓ Two stages + + + + + + + + ✓ Slow dynamics (open slow, and close slow) Closed Open (resting)  Extracellular Resting membrane potential Intracellular Voltage gated Na+ channels open; Na comes gushing in; membrane potential becomes positive very fast; Channels become inactivated and then close very fast; Voltage gated K+ channels open; K+ move out from the cell; membrane potential becomes less positive (towards negative); Channels become close Dynamics of K+ and Na+ voyage gated channels Voltage gated Na+ Voltage gated K+ ✓ Fast dynamics (open fast, ✓ Slow dynamics (open inactivate and close fast) slow and close slow)  Conductance (permeability) of K+ and Na+ during action potential Voltage gated Na+ ✓ Fast dynamics (open fast, inactivate and close fast) Voltage gated K+ ✓ Slow dynamics (open slow and close slow) Conductance (permeability) redrawn (normalized to RMP value) 30 K+ 20 Conductance 10 0  Membrane potential (mv) -90 0 Ek ENa 0 10 20 30 Ionic conductance (normalized) Na+ channels Na+ channels ‘inactivated’ ‘closed' Normalized to baseline values A few more facts…. Action potential feedback cycles ✓ Feedback control in voltage- gated ion channels in the membrane Resting potential Action potential Restoration ✓ Na+/K+ pump restores the membrane to resting state ionic concentrations -55 -75 -70 -90 Anything that makes RMP higher (depolarized) will increase excitability  Relative Goldman Permeability Ion Concentration inside Concentration outside equation K+ Na+ 140 14 142 4 10 K+ K+ K+ K+ K+ K+ = -61x log10 ( 14 x1 + 140 x 100 ) = -61x log10 ( 14 x1 + 140 x 100 ) 142 x 1 + 4 x 100 142 x 1 + 10 x 100 = -61 x log10 ( 14 + 14000 ) = -61 x log10 ( 14 + 14000 ) 142 + 400 142 + 1000 = -61 x log10 ( 14014 ) = -61 x log10 ( 14014 ) 542 1042 = -61 x 1.412. = -86.1 ~ -86mv = -61 x 1.128 = -68.8 ~ -69mv -75 -90 Anything that makes RMP higher (depolarized) will increase excitability Hyperkaleamia  Excitability Excitability -75 -90 Anything that elevates the threshold will reduce excitability High K+ Low K+ Hypercalceamia Voltage sensor + + + + + + + + + + + + + + + + + + Closed Open Inactivated Ca++ Changes the voltage sensor; makes it less sensitive. Therefore gates do not open easily  Excitability Excitability Excitability Excitability -75 -90 High K+ Low K+ High Ca++ Low Ca++ Therapeutic highlights - Rx of hyperkalemia Therapeutic highlights - Local anesthetics + + + + + + + + + + + + + + + + + + Closed Open Inactivated Local anesthetics reversibly block the voltage gated LA Na+ channels at peripheral nerve endings Action potential propagation Nodes of Ranvier and saltatory conduction Axon initial segment (axon hillock) 3 (main) types of glia Microglia Oligodendrocytes 1. Astrocyte 2. Myelinating glia (oligodendrocyte/Schwann) 3. Microglia Astrocytes  Clinical condition Physiological relevance The resting membrane potential of skeletal muscle in affected individuals shifts from a normal value of −90 mV Hyperkalemic periodic paralysis to a value of −60 mV which inactivates Na+ channels and prevents action potential generation Cushing syndrome Electrolyte imbalance (be sure to follow this when you learn renal physiology), gives rise to hypokalemia Motor nerves are most vulnerable to pressure. Sleeping on your arm may give rise to a temporary paralysis of Saturday night paralysis skeletal muscles. Myelin protein zero (P0) and a hydrophobic protein PMP22 are components of the myelin sheath in the Guillain–Barré syndrome peripheral nervous system. Autoimmune reactions to these proteins cause a peripheral demyelinating neuropathy. Mutations in myelin protein genes cause peripheral neuropathies that disrupt myelin and cause axonal Charcot-Marie-Tooth disease degeneration. Antibodies and white blood cells in the immune system attack myelin, causing inflammation and injury to the Multiple sclerosis sheath and eventually the nerves that it surrounds. Loss of myelin leads to leakage of K+ through voltage-gated channels, hyperpolarization, and failure to conduct action potentials. Thank you for listening…… questions ?  A medical student was working in a neurophysiology lab and was learning factors that determine the resting membrane potential of a neuron. Which of the following statements correctly explains how a change in concentration of an ion inside or outside of the neuron would change its resting membrane potential? A. A decrease in extracellular Ca2+ concentration would stabilize the membrane and reduce its excitability. B. A decrease in the extracellular Na+ concentration would reduce the size of the resting membrane potential. C. A decrease in the extracellular K+ concentration increases the gradient for K+ to leak out of the neuron, making the cell more hyperpolarized. D. A decrease in intracellular Na+ concentration would make the resting membrane potential more negative. E. An increase in the extracellular K+ concentration would move the resting membrane potential from a normal value of −90 mV to −70 mV. Which of the following ionic changes is correctly matched with a component of the action potential? A. Opening of voltage-gated K+ channels: After-hyperpolarization B. A decrease in extracellular Ca2+: Repolarization C. Opening of voltage-gated Na+ channels: Depolarization D. Rapid closure of voltage-gated Na+ channels: Resting membrane potential E. Rapid closure of voltage-gated K+ channels: Relative refractory period What is meant by the action potential threshold? Choose the correct option. A) Critical level of depolarization required to trigger an action potential B) Critical level of hyperpolarization required to trigger an action potential C) The action potential threshold is the same as the generator potential. D) Critical level at which electrical current is injected through a microelectrode  What role do voltage-gated potassium channels play in the action potential? Choose the correct option. A) Voltage-gated potassium channels maintain the resting membrane potential. B) Voltage-gated potassium channels help depolarize the membrane toward the threshold for an action potential. C) Voltage-gated potassium channels interfere with sodium conductance. D) Voltage-gated potassium channels restore negative membrane potential after the spike. Resting membrane potential is closer to EK because the membrane is more permeable to cations than anions. True or false? A) True B) False A Scientist reads the following ionic measurements (see table below) from inside and outside a neuron at body temperature (37 oC) with a resting membrane potential of -65 mv. Choose the correct statement about this experiment. A) If the cell membrane is made slightly more permeable to Na+ the resting membrane potential will become more positive compared to -65 mv B) If the cell membrane is made permeable to K+ ions only the resting membrane potential will be -80 mv C) If the cell membrane is made permeable only to Cl- ions there will be no change in resting membrane potential D) All of the above