THE ACTION POTENTIAL

1. THE ACTION POTENTIAL

2. Properties of the Action Potential • The Ups and Downs of an Action Potential • Oscilloscope to visualize an AP • Rising phase : rapid depolarization to reach the peak of 40mV • Overshoot : part where inside neurons are more positive than outside (> 0mV) • Falling phase : rapid repolarization • Undershoot : after-hyperpolarization

3. Properties of the Action Potential • The Generation of an Action Potential • Caused by depolarization of membrane beyond threshold - generator potential • “All-or-none” - conversion of analog into digital • Chain of events that lead to the generation of action potential in the thumbtack response • The thumbtack press the skin • The membrane of nerve fibers is stretched • Na+ -permeable channels that are gated by mechanical stimulation open • Na+ influx depolarizes the membrane • The depolarization reaches the threshold • Action potential

4. Properties of the Action Potential • The Generation of Multiple Action Potentials • Continuous depolarizing current injection can cause multiple action potential generation

5. Properties of the Action Potential • The Generation of Multiple Action Potentials • Firing frequency reflects the magnitude of the depolarizing current • One way that stimulation intensity is encoded • There is a limit! • Maximum firing frequency ~ 1000 Hz • Absolute refractory period : time required to initiate the next AP once an AP is initiated ~ 1 msec • Relative refractory period : for a few miliseconds after the end of absolute refractory period, current needed to reach threshold is above normal

6. The Action Potential, In Theory • Ideal cell has Na+-K+ pumps, K+-channels, and Na+-channels. • Channels are closed (gK=0) and Vm=0 mV • Potassium channels are open (gK>0) • Outward current of K+ • IK (net movement of K+) >0 until Vm reaches EK • Eventually Vm reaches EK, making driving force (Vm - E) equals zero

7. The Action Potential, In Theory • Rising phase • At -80 mV, driving force for Na+ is (Vm-ENa = -80 mV - 62 mV = - 142 mV) • When many Na+ channels open (gNa >> 0) at once because membrane is depolarized to threshold, the inward sodium current (INa)) is large - quickly brings Vm toward Ena (62 mV) assuming Na+ permeability is now far greater than K+ permeability • Falling phase • Sodium channels quickly close and potassium channels remains open • Dominant membrane permeability switches back to potassium • K+ flows out to bring Vm back to EK • The speed of falling phase depends on the size of gK

8. The Action Potential, In Reality • The Generation of an Action Potential • gNa increases at the threshold and gK transiently increases during falling phase in reality? • Hodgkin and Huxley proved it experimentally (1950) using • Voltage Clamp method • “Clamp” membrane potential at any chosen value then deduce the changes in membrane conductance by measuring currents • They proposed that the transient increase in gNa is possible due to • Existence of sodium “gates” in the axonal membrane • Gates are activated by depol. Over threshold • Gates are inactivated by a positive membrane potential • Gates are deinactivated only after membrane potential returns to a negative value

9. The Action Potential, In Reality • The Voltage-Gated Sodium Channel • A single polypeptide • Four distinct domains • Each domain contains 6 transmembrane alpha helices (S1-S6) and ion-selective pore loop • They clump together to form a pore • Selectivity filter deals with hydrated ions

10. The Action Potential, In Reality • The Voltage-Gated Sodium Channel • S4 has the voltage sensor in which positively charged amino acids are regularly spaced along the coils of helix • Depolarization can twists S4 by electric repulsion • Conformational change causes the gate to open

11. The Action Potential, In Reality • The Voltage-Gated Sodium Channel : Functional Properties • Patch-clamp method (Erwin Neher and Bert Sakmann) was developed in the mid-1970s • Small patch of membrane seals the tip of an electrode • The membrane is torn apart from the neuron • Ion current can be measured at any clamped membrane potential

12. The Action Potential, In Reality • Functional Properties of the Sodium Channel • Open with little delay • Stay open for about 1 msec • Cannot be opened again by depolarization until the membrane potential returns to a negative value near thresholod • Absolute refractory period • Channels are inactivated by the second gate • It is a slow one to act and needs to be replaced by the fast gate (deinactivation) • Explains many properties of AP

13. The Action Potential, In Reality • The Voltage-Gated Sodium Channel • Generalized epilepsy with febrile seizures (channelopathy) • Caused by a single amino acid change in the extracellular region of one sodium channel (out of many) • Slowed inactivation prolongs action potential • Toxins as experimental tools • Puffer fish toxin: Tetrodotoxin (TTX) • Toshio Narahashi • Clogs Na+ permeable pore by binding tightly • Blocks all sodium-dependent action potentials • Red Tide toxin: Saxitoxin • Na+ Channel-blocking toxin • Produced by marine protozoa, Gonyaulax dinoflagellate, typical shellfish prey • Occasional blooming of the dinoflagellates cause red tide • Structural studies and physiological studies

14. The Action Potential, In Reality • Voltage-Gated Potassium Channels • According to Hodgkin and Huxley’s experiments, falling phase cannot be explained solely by the inactivation of gNa • Existence of potassium gate was also proposed • open in response to depolarization • Potassium gates open slowly (need about 1msec after depol.) • Delayed rectifier • Potassium conductance serves to rectify or reset membrane potential • Function to diminish any further depolarization • Four separate polypeptide subunits join to form a pore

15. The Action Potential, In Reality • Key Properties of the Action Potential • Threshold • Rising phase • Overshoot • Falling phase • Undershoot • Absolute refractory period • sodium channel deinactivation • Relative refractory period - potassium channel closure (hyperpolarization)

17. Action Potential Conduction • Propagation • Depolarized to threshold • Sodium channels open • Influx of Na+ • Positive charges coming in depolarize the membrane just ahead to threshold • Next population of sodium channels open

18. Action Potential Conduction • Propagation of the action potential • Orthodromic • Action potential travels in one direction - down axon to the axon terminal • Antidromic (experimental) • Backward propagation is possible if the initiation of AP occurs in the middle of axon • Cannot turn back on itself • Refractory (inactivated sodium channels) • Typical conduction velocity: 10 m/sec

19. Action Potential Conduction • Factors Influencing Conduction Velocity • Depends on how far the depolarization ahead of the action potential spreads • The spread depends on resistance of space • Path of the positive charge • Down the inside of the axon • Across the axonal membrane - leakage • Axonal excitability • Axonal diameter (bigger = faster) • Number of voltage-gated channels • Neural pathway that are specially important for survival have evolved unusually large axons - squid giant axon

20. Action Potential Conduction • Factors Influencing Conduction Velocity • Layers of myelin sheath insulate the leakage of charges and facilitate current flow down the inside of axon • Nodes of Ranvier • Every 0.2-2.0 mm • Place of AP generation • Place of voltage-gated sodium channels • Saltatory conduction • AP travels by leaping

21. Action Potential Conduction • Multiple sclerosis • Demyelinating disease • Marked slowing of conduction • CNS version of Guillian- Barre syndrome

22. Action Potentials, Axons, and Dendrites • Spike-initiation zone • Only membrane that contains voltage-gated sodium channels are capable of generating AP • Axon hillock • Sensory nerve endings • Differences in the type and density of membrane ion channels can account for the characteristic electrical properties of different types of neuron

23. Bursting Tonic Adaptation