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Chapter 4

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Janelle Leboutillier

Chapter 4 The Action Potential Introduction  Action potential (spike, nerve impulse, discharge): a signal – created when the cytosol momentarily becomes positively charged with respect to the extracellular fluid – that shares information throughout the nervous system  Cytosol in neuron negatively charged with respect to the extracellular fluid at rest  All similar in size and duration and do not diminish as they are conducted down the axon  Neurons transfer the signal to its destination by using the frequency and pattern as a code Properties of the Action Potential  The Ups and Downs of an Action Potential ◦ Membrane potential (V ) man be determined using a microelectrode ◦ Voltmeter is used to measure electrical potential difference between the microelectrode tip inside the cell and another outside the cell ◦ At rest V m -65 mV ◦ Action potentials happen so fast that a special type of voltmeter named a oscilloscope must be used to measure the voltage changes ◦ Axon hillock impaled by two electrodes (one for measuring and one for stimulating) ◦ Figure 4.1 shows different phases of an action potential over time (~2 milliseconds)  Rising phase: rapid depolarization of membrane (mV goes up, steep incline) until peak value of ~40 mV  Overshoot: inside of neuron is positively charged with respect to the outside  Falling phase: rapid repolarisation until membrane is more negative than resting membrane potential  Undershoot (after-hyperpolarisation): gradual restoration of the resting potential  The Generation of an Action Potential + ◦ When thumbtack pierces skin, nerve fibres are stretched and gated Na channels open + ◦ Na enters fibre through channels and depolarization occurs (generator potential) ◦ Threshold: critical level of depolarization that must be crossed in order to trigger an action potential ◦ Ways depolarization can occur: entry of sodium ion through ion channels sensitive to fibre stretching, entry of sodium ions through channels sensitive to neurotransmitters released by other neurons, injection of electrical current through microelectrode ◦ “All or none” – applying increasing depolarization has no effect until it crosses threshold  The Generation of Multiple Action Potentials ◦ If continuous depolarizing currents are passed into a neuron through a microelectrode, many action potentials will arise in succession ◦ Rate of AP generation (firing frequency) depends on magnitude of continuous depolarizing currents (i.e. if current is only enough to reach threshold, rate may be around 1 Hz = 1 impulse/sec) ◦ Firing frequency increases as amount of depolarizing current increases ◦ Maximum firing frequency = 1000 Hz ◦ Absolutely refractory period: once an AP has been initiated it is impossible to initiate another one for a period of 1 msec ◦ Relative refractory period: relatively difficult to start another AP for a few milliseconds after absolute refractory period; current required to depolarize neuron to threshold is above normal The Action Potential, In Theory  Depolarization of the cell during the AP is caused by the influx of sodium ions across the membrane, and repolarisation is caused by the efflux of potassium ions  Membrane Currents and Conductances ◦ Ideal neuron: sodium-potassium pump, potassium channels, sodium channels ◦ Potassium ion concentrated twenty fold inside cell, sodium ion concentrated 10 fold outside cell ◦ At 37 degrees Celsius, E = k80 mV, E = 6NamV ◦ At rest, both potassium channels and sodium channels are closed, but if potassium + channel opens K ions will flow out of cell and down concentration gradient until V mE (kr -80mV) ◦ I ion= gion(Vm-E ionhere I (electrical current) = net movement of ions, g (electrical conductance) = number of open potassium channels ◦ At rest no potassium channels are open there g = 0 and there is no flow ◦ When gates open g > 0 and large driving force on potassium ions (because V is m not equal to E ) creates flow out of cell until V and E are equal again k m k  The Ins and Outs of an Action Potential ◦ The membrane potential becomes so negative with respect to sodium ions that there is a large driving force on sodium ions (no net current until sodium channels open) ◦ Once the gates up, g becomes high, current is generated and sodium ions are pushed in the direction that will takemV toward ENa (inward across the membrane) ◦ Influx depolarizes the neuron until V mpproaches E (6NamV) assuming that neuron permeability is far greater to sodium than potassium ◦ In theory, rising phase of the AP is explained by membrane sodium channels opening in response to depolarization of the membrane beyond threshold (until membrane potential is equal to ENa ◦ Falling phase explained as sodium ion channels close and potassium ion channels remain open cause a shift in dominant membrane ion permeability back to potassium ion and potassium keeps flowing out of the neuron until V m E agkin ◦ If g kncreases during falling phase AP would be shorter The Action Potential, In Reality  Theory is tested by measuring the conductances of sodium and potassium of the membrane during AP  Voltage clamp invented by Kenneth C. Cole was used by Hodgkins and Huxley to clamp the membrane potential of an axon at any value and deduce chances in membrane conductance at different membrane potentials by measuring currents across the membrane  Hodgkins and Huxley showed that the rising phase of the AP was caused by increase in + g Naand inf+ux of Na ions and falling phase was associated with increase in gkand an efflux of K ions  Hodgkins and Huxley hypothesized that transient changes were controlled by sodium gates in the axonal membrane that were activated when the membrane was depolarized above threshold and inactivated when the membrane had a positive membrane potential  The gates are unlocked and able to be open again only after membrane potential returns to negative value  New molecular biological techniques enable neuroscientists to determine the structure of the proteins and new neurophysiological techniques allow scientists to measure the ionic currents that pass through single ion channels  The Voltage-Gated Sodium Channel + ◦ Highly selective to Na ions; opens and closes by changes in electrical potential ◦ Sodium Channel Structure  Singly long polypeptide  Four distinct domains (I-IV) with six transmembrane alpha helices (S1- S6)  Domains clump with pore in middle; closed at negative +otential (rest)  Depolarization to threshold twists molecule to allow Na through  12 times more permeable to sodium ions than potassium ions  As sodium ion passes into channel, sodium ions stripped of most water molecules; retained water then becomes chaperone for ion  Ion water complex used to selectively filter by size (sodium ion is smaller than potassium ion)  Voltage sensor in S4  S4: positively charged AA residues spaced along helix therefore a change in membrane potential (depolarization) causes a conformational change which opens the gate ◦ Functional Properties of the Sodium Channel  Patch clamp: method used to study the ionic currents passing through individual ion channels (Neher et al.)  Seal tip of electrode to small patch of neuronal membrane  Patch torn away from neuron and ionic currents measured and ionic currents measured as the membrane potential is clamped at the value that the experimenter selects  If patch contains only one channel, it’s behaviours can be studied  Voltage gated sodium channels only pop open at -40 mV  Characteristic pattern: open without delay, stay open for 1 msec and then inactivate (globular portion of protein occludes pore), cannot be opened again by depolarization until membrane potential returns to threshold value  Explaining the AP:  Channels open at -40mV = threshold  Rapid opening of channels (depolarization) explains steep rising phase of AP  AP happens so quickly because channels only stay open for 1 msec  Another AP cannot be generated until the channels are deinactivated = absolute refractory period  Generalized epilepsy with febrile seizures: caused by AA mutation in extracellular regions of one sodium channel  Epilepsy is the result of a lot of synchronous electrical activity in the brain  In this disorder – seizures due to fever  3 months – age 5  Slow inactivation of sodium channel (longer AP)  Channelopathy: genetic disease caused by alterations in structure and function of ion channels ◦ The Effects of Toxins on the Sodium Channel  Tetrodoxin (TTX) – hormone of ovaries in pufferfish that blocks sodium channels (selectively) by binding to a site on the outside of the channel  Fatal if ingested  Saxitoxin: channel blocking to
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