Lecture 4: The-Nerve-refractory period.

The-Nerve-refractory period.

1. The Nerve Impulse All or None Law and Nerve Fiber Properties The nerve impulse obeys all or non law. An excitable membrane either responds to a triggering event with a maximal action potential that spreads non-decrementally through the membrane, or it does not respond with an action potential at all provided that all other conditions remain constant. So;

2. Phases of action potential Depolarization Repolarization Hyperpolarization

3. Voltage gated Na+ channels Most important channels during AP It has two gates and 3 states Activation gates outside & inactivation gates inside At RMP activation gates are closed so no Na+ influx at RMP thru these channels Activation gates open at threshold The same increase in voltage that open the activation gates also closes the inactivation gates but closing of gates is a slower process than opening so large amount of Na+ influx has occurred Inactivation gate will not reopen until the membrane potential returns to or near the original RMP. Local anesthetics like lidocaine, procaine, tetracaine block voltage gated Na channels so block the occurrence of action potential

4. Voltage gated K+ channel During RMP Voltage gated K+ channels are closed Th e sam e s t i m u l u s wh i ch ope n v ol t a g e gated Na+ channels also open voltage gated K+ channel Due to slow opening of these channels they open just at the same time that the Na+ channels are beginning to close because of inactivation. So now decrease Na+ influx and simultaneous increase in K+ out flux cause membrane potential to go back to resting state (recovery of RMP) Thes e channe l s close w he n memb r ane potential reaches back to RMP

5. The Nerve Impulse Physico – chemical disturbance by a threshold stimulus (or more) and propagated as a wave along the nerve fiber. The accompanying changes : 1- Electrical changes. 2- Excitability changes. 3- Metabolic changes. 4- Thermal changes.

6. The All or None Law Sub-threshold Stimuli All sub-threshold stimuli do not produce response Threshold Stimulus Threshold (minimal) stimulus produces a maximal response. Super-threshold Stimuli Further increase in the intensity of the stimuli (super-threshold, maximal, super-maximal) do not produce any further increase in the response (as threshold stimulus already open all Na+ channels, so no more effect can produced). All or non- law is applied in the single nerve fiber and not applied in the nerve trunk.

7. Properties of Nerve Fibers Excitability It is the ability of the nerve fibers to respond to stimuli, and convert these stimuli into nerve impulses. Conductivity It is the ability of the nerve fibers to conduct nerve impulses from one site to another. Excitability Changes During Action Potential Threshold of a stimulus is commonly used as a measure of a tissue’s excitability. The higher the threshold of a stimulus, the lower the excitability, and vice versa. Hyperpolarizing responses elevate the threshold, and depolarizing potentials lower it as they move the membrane potential closer to the firing level. The closer of the membrane potential to the firing level the greater is its excitability.

8. All-or-None Principle If any portion of the membrane is depolarized to threshold an Action potential is initiated which will go to its maximum height. A supra-threshold stimulus does not produce a large Action potential. A s ub-threshold stimulus does not trigger the Action potential at all , but produce local response.

9. Properties of Action Potentials The All or No ne Principle: Action Potentials occur in all or none fashion depending on the strength of the stimulus The Refractory Period: Two phases: Absolute refractory period Relative refractory period

10. A ll o r no n e l a w Until the threshold level the potential is graded Once the threshold level is reached AP is set off and no one can stop it ! Like a gun

11. A ll o r no n e l a w The principle that the strength by which a nerve or muscle fiber responds to a stimulus is not dependent on the strength of the stimulus If the stimulus strength is above threshold, the nerve or muscle fiber will give a complete response or otherwise no response at all

12. Strength of the stimulus above the threshold is coded as the frequency of action potentials

13. Refractory period ( unresponsive or stubborn) A new action potential cannot occur in an excitable membrane as long as the membrane is still depolarized from the preceding action potential.

14. Absolute Refractory Period Membrane cannot produce another Action potential no matter how great the stimulus is. Last for almost entire duration of action potential. Cause: closure of inactivation gates of voltage gated Na channels in response to depolarization. They remain closed until the cell is repolarized back to RMP.

15. Refractory Period Absolute refractory period – During this period nerve membrane cannot be excited again – Because of the closure of inactivation gate -70 +30 o u t s ide inside

16. Relative refractory period Begins at the end of absolute refractory period & overlaps primarily with the period of hyperpolarization. Action potential can be elicited by stronger than normal stimulus. Cause: Voltage Gated K + channels are open, so more inward current is needed to bring the membrane to threshold for next action potential

17. Refractory Period Relative refractory period – During this period nerve membrane can be excited by supra threshold stimuli At the end of repolarisation phase inactivation gate opens and activation gate closes This can be opened by greater stimuli strength -70 +30 o u t s ide inside

18. Phases of Nerve Excitability The excitability of the nerve fibers passes in the following phases: 01 Temporal Rise of Excitability 02 Absolute Refractory Period (ARP) 03 Relative Refractory Period (RRP) 04 Supernormal Phase of Excitability 05 Subnormal Phase of Excitability

19. Refractory Periods During the initial depolarization up to threshold level excitability is increased (temporal rise of excitability). During the remaining part of action potential, the neuron is refractory to re-stimulation (more difficult to elicit another action potential). Refractory period is required to protect the nerve from extremely rapid repetitive stimulation. There are two refractory periods: Absolute refractory period: • Corresponding to the period from the time the firing level is reached until repolarization is about one-third complete. • During this period a second action potential cannot be elicited, even with a very strong stimulus as the excitability equal zero. Relative refractory period: • It begins from the end of initial 1/3 of repolarization to the start of after depolarization (beginning part of slow repolarization). • During this period stronger than normal stimuli can excite the nerve fiber as excitability is below normal (the membrane start to regain excitability).

20. Refractory Period: Mechanism Cause of Relative Refractory Period During this period, all Na+ channels are opened then rapidly inactivated by the inner gates, so any amount of excitatory signal applied to these channels at this point will not open the inactivation gates. The only condition that will allow them to reopen is for the membrane potential to return to or near the original resting membrane potential level. Then, within another small fraction of a second, the inactivation gates of the channels open and a new action potential can be initiated. So spike potentials cannot summate. Cause of Relative Refractory Period Some of the voltage-gated Na+ channels have returned to their resting state and are available for activation. The voltage gated K+ channels are usually wide open at this time that makes more difficult to stimulate the fiber.

21. Value of Refractory Period Forward Movement: Action potential only moves in forward direction. Backward current flow does not re-excite previously activated area. Frequency Limit: Refractory period also limits frequency of action potential. The longer the refractory period, the greater the delay before a new action potential can be initiated and the lower the frequency with which a nerve cell can respond to repeated or ongoing stimulation. Variability: Length of refractory period varies for different types of nerve fibers. Figure 31: The excitability changes that occur in after potential.

22. After Potentials and Excitability Supernormal Period It is corresponding to after-depolarization (negative after potential). It is due to reduced rate of K+ efflux caused by accumulation of +ve charge on outer side as RMP is reached. It is the period during which excitability is greater than normal. An AP can be elicited by a slightly smaller stimulus than normal (sub-threshold). Subnormal Period It is corresponding to after-hyperpolarization (positive after potential). It is due to delay closure of K+ channel causing excess efflux of K+ . It is the period during which excitability is less than normal (threshold for excitation is slightly higher than normal). Stronger stimulus is needed to excite nerve.

23. Factors Affecting Nerve Excitability: Role of Na+ Any condition that affects on Na+ permeability will affect on depolarization and nerve excitability. Membrane Stabilizers Local anesthetics as cocaine decrease Na+ influx thus decrease excitability (block voltage gated Na+ channels) thus nerve impulse fails to be produced. Hyper-calcemia Increase ionized Ca++ concentration in the ECF decreases the permeability of the membrane of nerve fiber to Na+ and decrease the excitability. Low Ionized Ca++ / Veratridine Any condition that increases the permeability of the membrane of nerve fiber to Na+ cause the nerve to be more excitable. Low ionized Ca++ concentration in the ECF and veratridine increase the permeability of the membrane to Na+ increase excitability (rapidly depolarized). Hypo-natremia Decreasing the Na+ concentration in ECF reduces the size of the action potential but has little effect on the resting membrane potential. The lack of much effect on the resting membrane potential would be predicted, since the permeability of the membrane to Na+ at rest is relatively low. Tetrodotoxin (TTX) Block Na+ channel prevent AP and decrease excitability.

24. Increased permeability of Na channels when there is deficit of Ca ions The conc. Of Ca ions in ECF has profound effect on the v ol t a g e l e v el a t which the Na channe l s be c ome activated. Ca bind to the exterior surface of the voltage gated Na channels protein molecule. S o w he n the r e is a d e fic i t o f Calci u m io n s in the E CF the voltage gated Na channels open by very little increase of membrane potential from its normal very negative level. so nerve fiber become highly excitable . Wh e n C a le v els f all 50% bel o w norma l spo n t aneous discharge occurs in some peripheral nerves causing tetany. Its lethal when respiratory muscles are involved.

25. Effect of hypokalemia on nerve and muscle Hypokalemia is decreased levels of K in blood Decreased K in blood causes the K concentration gradient between ECF & ICF to increase which leads to more negative RMP as more K leaks out of cell so hyperpolarization occurs and membrane potential is far away from threshold value so membrane is less excitable Muscle weakness and pain Irregular heart beats

26. Effect of hyperkalemia on MP Hyperkalemia is increased levels of K in blood (above 5 mmol/lit) Elevated K in blood causes the K concentration gradient between ECF & ICF to decrease which leads to less negative RMP as less K leaks out of cell so closer to threshold value so easily excitable but at the same time prevent repolarization so Na channels will not be activated so leading to muscle weakness and paralysis and cardiac arrhythmias.

27. Factors Affecting Nerve Excitability: K+ and Na+-K+ Pump Role of K+ Hypokalemia: This increase concentration gradient which increases diffusion of K+ from inside to outside the nerve fibers producing hyperpolarization and decreases excitability. This occurs in a hereditary disease known as familial periodic paralysis (the excitability of the nerves is reduced; no nerve impulses and the person become paralyzed). The condition is treated by IV administration of K+ . Hyperkalemia: Makes the resting membrane potential to depolarized (increase diffusion of K+ from outside to inside) and increase excitability. Block of K+ channels: Tetra-ethyl-ammonium (TEA) is a drug that selectively blocks only K+ channels. It prolongs repolarization but no hyperpolarization. Role Na+-K+ Pump Prolonged blockade of Na+ K+ pump would decrease in the resting membrane potential, action potential and a loss of neuronal excitability. Accommodation of Nerve Fiber Gradual increase in intensity of a sub-threshold stimulus to threshold level will give no response. As depolarization become slow and balanced with repolarization so nothing occur. Explanation: Slow opening of Na+ channels with slow entry of Na+ is balanced by: Closure of Na+ channels. Opening of K+ channels.

28. Importance of refractory period Responsible for setting up limit on the frequency of Action Potentials so prevents fatigue promotes one way propagation of action potential because the membrane just behind the ongoing action potential is refractory due to the inactivation of the sodium channels

29. Electrotonic Potentials - Anelectrotonus Hyperpol. ↓ Excitability >> nerve block. - catelectrotonus Depol. (passive) (below 7 mv) ↑ Excitability

30. Short-lived, local changes in membrane potential Decrease in intensity with distance because ions diffusing out through permeable membrane Their magnitude varies directly with the strength of the stimulus They can be summated Sufficiently strong graded potentials can initiate action potentials Graded Potentials

31. Action Potentials (APs) The AP is a brief, rapid large change in membrane potential during which potential reverses and the RMP becomes +ve & then restored back to resting state APs do not decrease in strength with distance so serve as long distance signals. Events of AP generation and transmission are the same for skeletal muscle cells and neurons

32. Summation of graded potential Graded potentials occurs at soma & dendrites & travel through the neuron and they sum up and if reach a threshold level at trigger zone they can fire action potential.

33. Graded potential has different names according to location Neuron cell body and dendrites Excitatory post synaptic potential (EPSP) Inhibitory post synaptic potential (IPSP) Motor end plate  End plate potential Receptor  Receptor potential Pace maker potential in GIT smooth muscle & heart Slow wave potential

34. Initiation of action potential To initiate an AP a triggering event causes the membrane to depolarize from the resting potential of -90 mvs to a threshold of-65 to – 55 mvs . At threshold explosive depolarization occurs. (positive feed back )

35. Strength of the stimulus above the threshold is coded as the frequency of action potentials