Joseph Erlanger(1874-1965) andHerbert Spencer Gasser (1888-1963) 1944 Joseph Erlanger and Herbert Spencer Gasser "for their discoveries relating to the highly differentiated functions of single nerve fibres
Joseph Erlanger and Herbert Spencer Gasser Joseph Erlanger was an American physiologist Herbert Spencer Gasser was an American physiologist, and recipient of the Nobel Prize for Physiology or Medicine in 1944 for his work with action potentials in nerve fibers while on the faculty of Washington University. Erlanger and his student Gasser were interested in developing tools that could measure impulses fired through nerve cells, and they turned to the cathode-ray oscilloscope – an instrument that allows electrical currents to be visualized as a moving two- dimensional graph on a phosphorescent screen. After its invention by Ferdinand Braun, the oscilloscope soon became the most effective tool for detecting rapid changes in electrical voltage, but still it was not sensitive enough to measure the weak and rapid electrical impulses that are fired along nerve cells
Eccles, Hodgkin and HuxleyThe Nobel Prize in Physiology or Medicine 1963 was awarded jointly to Sir John CarewEccles, Alan Lloyd Hodgkin and Andrew Fielding Huxley "for their discoveries concerning theionic mechanisms involved in excitation and inhibition in the peripheral and central portions ofthe nerve cell membrane".
Eccles, Hodgkin and HuxleySir Alan Lloyd Hodgkin British physiologist and biophysicistSir John Carew Eccles , Australian neurophysiologistSir Andrew Fielding Huxley English physiologist and biophysicist, Huxley evidenced the existence of saltatory conduction in myelinated nerve fibres. By showing how these impulses are generated and transmitted, the three scientists who receivedan equal share of the 1963 Nobel Prize in Physiology or Medicine revealed the key triggers thatspark the nervous systems in-built electrical system into life.Seeking ways of measuring electrical currents inside nerves, Alan Hodgkin and his studentAndrew Huxley turned to giant nerve fibres in the squid, which are almost a thousand times thickerthan their human counterparts. Using tiny electrodes to record the electrical difference between the inside and outside of thesenerves, they were surprised to find that the polarity did not drop from negative to zero during thetransmission of an impulse as predicted, but in fact reversed, becoming electrically positive. By carrying out a series of measurements and using complex mathematical models to interpretthe findings, Hodgkin and Huxley formulated a theory to propose how impulses are formed.Changes in the permeability of the cell membrane allow charged atoms to flow in and out of anerve fibre, creating waves of electric charge that constitute the nerve impulse
Erwin Neher, Bert Sakmann The Nobel Prize in Physiology or Medicine 1991 was awarded jointly to Erwin Neher and Bert Sakmann "for their discoveries concerning the function of single ion channels in cells"
Erwin Neher, Bert Sakmann The two German cell physologisists Erwin Neher and Bert Sakmann have together developed a technique that allows the registration of the incredibly small electrical current (amounting to a picoampere- 10-12A) that passes through a single ion channel. The technique is unique in that it records how a single channel molecule alters its shape and in that way controls the flow of current within a time frame of a few millionths of a second. They have demonstrated what happens during the opening or closure of an ion channel with a diameter corresponding to that of a single sodium or chloride ion.
The neurone Nodes of RanvierDendrites Schwann cell Nucleus of Schwann cell Myelin sheath Axon Terminal dendrites
Ionic basis of Em NaK- ATPase pumps 3Na+ out for 2 K+ pumped in. Some of the K+ leaks back out, making the interior of the cell
Gated channels: ligand-gated
Gated channels: voltage-gated
Characteristics of the NerveImpulse An electrochemical event that occurs in nerve cells following proper stimulation. An all-or-none process which is fast acting and quick to recover. An event that is described by a voltage curve that is called an action potential. The nerve impulse can be conducted the entire length of a nerve cell without diminishment (“domino effect”).
Characteristics of a NerveImpulse Continued: The nerve impulse serves as the primary information signal used by the nervous system to provide communication about stimuli, nerve cell activity, neurotransmitter release and to generate various output responses (motor action, glandular secretion, etc.). Typically initiated by graded or generator potentials from a stimulus.
Graded potentialA change in potential that decreases withdistance Localized depolarization or hyperpolarization
Nernst EquationBy the end of the 19th century, it wasknown that the cytoplasm was high in K+and that [Na+] was very low--and that thisrelationship was reversed outside the cell.The assumption was made that the cellmembrane was permiable to K+ but not toNa+.
Goldman equationwas derived to solvefor transmembranepotential using all ionsinvolvedsimultaneously.
Resting PotentialOutside of cell Sodium/Potassium pump continuously and actively pumps (3) Na+ out of the cell and (2) K+ into the cell. Na+ channels are closed so Na+ are not able to move into the cell. K+ channels are open so K+ can diffuse out of the cell. This generates a separation of charges so that the inside of the cell is relatively – and the outside is relatively +. The cell will remain in this state (at rest) until it is stimulated.Inside of cell
Action PotentialAppears when region of excitablemembrane depolarizes to thresholdSteps involved Membrane depolarization and sodium channel activation Sodium channel inactivation Potassium channel activation Return to normal permeability
The Action Potential Key Properties of the Action Potential Threshold Rising phase Overshoot Falling phase Undershoot Absolute refractory period Relative refractory period
Introduction Action Potential in the Nervous System Conveys information over distances Action potential Spike Nerve impulse Discharge
AP Characteristics Voltage-gated channels All or none Slow Non-decremental Self Propagated
Properties of the ActionPotential The Ups and Downs of an Action Potential Oscilloscope to visualize an AP Rising phase, overshoot, falling phase, and undershoot
Properties of the ActionPotential The Generation of an Action Potential “All-or-none”: Cross threshold value for action potential Chain reaction Opens Na+-permeable channels Na+ influx depolarized membrane reaches threshold action potential
Properties of the ActionPotential Firing frequency reflects the magnitude of the depolarizing current
The Generation of an ActionPotential Figure 2.16.1
Characteristics of actionpotentials Generation of action potential follows all-or-none principle Refractory period lasts from time action potential begins until normal resting potential returns Continuous propagation spread of action potential across entire membrane in series of small steps Saltatory propagation action potential spreads from node to node, skipping internodal membrane
The Generation of an Action Potential
Induction of an action potential
Induction of an action potential
Action potential propagation When the V-G Na+ channels open, they cause a depolarization of the neighboring membrane. This causes the Na+ and K+ channels in that piece of membrane to be activated
AP propagation cont. The V_G chanels in the neighboring membrane then open, causing that membrane to depolarize. That depolarizes the next piece of membrane, etc. It takes a while for the Na+ channels to return to their voltage-sensitive state. Until then, they won’t respond to a second depolarization.
Propagation of an Action Potentialalong an Unmyelinated Axon
Saltatory Propagation along aMyelinated Axon
Saltatory Propagation along aMyelinated Axon
Action Potential Conduction Propagation of the action potential Down axon to the axon terminal Orthodromic: Action potential travels in one direction Antidromic (experimental): Backward propagation Typical conduction velocity: 10 m/sec Length of action potential: 2 msec
Action Potential Conduction Factors Influencing Conduction Velocity Spread of action potential along membrane Dependent upon axon structure Path of the positive charge Inside of the axon (faster) Across the axonal membrane (slower) Axonal excitability Axonal diameter (bigger = faster) Number of voltage-gated channels
Action Potential Conduction Factors Influencing Conduction Velocity Myelin: Facilitates current flow Layers of myelin sheath Myelinating cells Schwann cells in the PNS Oligodendroglia in CNS
All-or-None PrincipleThroughout depolarisation, the Na+ continues to rush inside until the action potential reaches its peak and the sodium gates close.If the depolarisation is not great enough to reach threshold, then an action potential and hence an impulse are not produced.This is called the All-or-None Principle.
Repolarization1. The sodium/potassiumpumps return the cell to aresting state by activelypumping (3) Na+ out ofthe cell and (2) K+ intothe cell.2. The K+ continues todiffuse out of the cell.
Refractory Period after AP won’t fire again relative & absolute Relative during after hyperpolarization requires greater depolarization ~
Refractory PeriodThere are two types of refractory period:Absolute Refractory Period – Na+ channels are inactivated and no matter what stimulus is applied they will not re- open to allow Na+ in & depolarise the membrane to the threshold of an action potential.Relative Refractory Period - Some of the Na+ channels have re-opened but thethreshold is higher than normal making it more difficult for the activated Na+channels to raise the membrane potential to the threshold of excitation.
Absolute refractory period Na+ channels deactivate will not trigger AP must reset
Anti-seizure Medications Seizures caused by hyperactive brain areas Multiple chemical classes of drugs All have same approach Decrease propagation of action potentials ⇓ Na+, Ca++ influx (delay depolarization/prolong repolarization) ⇑ Cl- influx (hyperpolarize membrane)
Clinical Correlation It is the rate of action potential propagation that determines neurologic function. Determined by frequency of action potentials. What is a seizure? What is a seizure? What would be the What would be the effect on the membrane effect on the membrane of ⇑ Cl- -influx of ⇑ Cl influx during a seizure? during a seizure? Hyperpolarization & … ⇓ seizure activity!