Lecture 3: Ionic-Basis-of-Action-Potential.

Ionic-Basis-of-Action-Potential.

1. Ionic Basis of Action Potential The Role of Voltage-Gated Channels in Nerve Impulse Transmission The ionic basis of action potential relies on the function of the voltage-gated sodium and potassium channels. Voltage gated channel proteins are sensitive to voltage changes which change their shape -causing opening & closing of gates. Depolarization is produced by Na+ influx and repolarization is produced by K+ efflux.

2. Voltage-Gated Sodium Channels: Structure and Gates The voltage-gated sodium channel has two gates-one near the outside of the channel called the activation gate , and another near the inside called the inactivation gate . Both gates must be open to permit passage of Na+ through the channel, and closure of either gate prevents passage.

3. VOLTAGE-GATED ION CHANNELS Activation gate outside inside Inactivation gate Na+ channel This has two gates Activation and inactivation gates

4. • • At rest: the activation gate is closed At threshold level: activation gate opens – – Na+ influx will occur Na+ permeability increases to 500 fold • • • when reaching +30, inactivation gate closes – Na influx stops Inactivation gate will not reopen until resting membrane potential is reached Na+ channel opens fast out s ide inside -70 N a+ Threshold level Na+ out s ide inside +30 Na + m gate o ut si d e inside h gate

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6. Plasma membrane ECF ICF Concentration gradient for K + Electrical gradient for K + E K + = –94mV Effect of movement of K+ alone on RMP (K+ equilibrium potential)

7. When Na+ channel opens Na+ influx will occur Membrane depolarises Rising level of voltage causes many channels to open This will cause further Na+ influx Thus there a positive feedback cycle It does not reach Na+ equilibrium potential (+60mV) Because Na+ channels inactivates after opening Voltage-gated K+ channels open This will bring membrane towards K+ equilibrium potential

8. 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 )

9. VOLTAGE-GATED K+ Channel K+ channel – This has only one gate outside i n side

10. At rest: K+ channel is closed – At +30 K+ channel open up slowly This slow activation causes K+ efflux This will cause membrane to become more negative Repolarisation occurs out s ide inside -70 At +30 K + K + n gate o ut si d e inside

11. Basis of hyperpolarisation After reaching the resting still slow K+ channels may remain open: causing further negativity of the membrane This is known as h y pe r pola r i sa t ion -70 +30 o u ts ide inside K +

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13. Role of the Sodium-Potassium Pump in action potential Repolarization restores the resting electrical conditions of the neuron, but does not restore the resting ionic conditions Ionic redistribution is accomplished by the sodium- potassium pump following repolarization

14. Na+/K+ pump 3 Na + Re-establishment of Na+ & K+ concentration after action potential Na+/K+ Pump is responsible for this Energy is consumed Turnover rate of Na+/K+ is pump is much slower than the Na+, K+ diffusion through channels 2 K + ATP AD P

15. Na + and K + concentrations do not change during an action potential Although during an action potential, large changes take place in the membrane potential as a result of Na + entry into the cell and K + exit from the cell Actual Na + and K + concentrations inside and outside of the cell generally do not change This is because compared to the total number of Na + and K + ions in the intracellular and extracellular solutions, only a small number moves across the membrane during the action potential

16. Three Configurations of the Voltage-Gated Na+ Channel 1. Closed but capable of opening (activation gate closed, inactivation gate open). 2. Open or activated (both gates open). 3. Closed and not capable to opening, or inactivated (activation gate open, inactivation gate closed).

17. Voltage-Gated Potassium Channel The voltage gated K+ channel is simpler; it has only one gate in inner side of the channel which can be either open or closed. Changes in permeability and ion movement during an action potential (ionic basis of AP): The resting state At resting potential (-90 mv), all the voltage -gated Na+ and K+ channels are closed and ions are prevented from passing through these channel. In this state, the activation gate of Na+ channel is closed, which prevents any entry of sodium ions to the interior of the fiber through these sodium channels and inactivation gates being open. In this case channels are closed but capable of opening conformation.

18. Depolarization : The Positive Feedback Cycle When a membrane start to depolarize toward threshold as a result of triggering event the activation gates of some Na+ channels open. Now both gates are open. This is called the activated state . During this state, sodium ions influx through the channel downs its electro-concentration gradient, increasing the sodium permeability of the membrane. The inward movement of positively charged Na+ depolarizes the membrane further. This allows rapid inflow of sodium ions, which causes a further rise in the membrane potential, thus opening still more voltage-gated sodium channels and allowing more streaming of sodium ions to the interior of the fiber.

19. Threshold and Peak Potential This process is a positive-feedback cycle that, once the feedback is strong enough, continues until all the voltage-gated sodium channels have become activated (opened), when the threshold potential is reached (- 65). Further inward movement of Na+ reverses the potential, with the inside becoming positive and the outside becoming negative as the action potential peaks (+35). Therefore, a sudden increase in the membrane potential in a large nerve fiber from -90 millivolts up to about -65 millivolts usually causes the explosive development of an action potential. This level of -65 millivolts is said to be the threshold for stimulation .

20. Repolarization : Restoring the Potential At the peak of action potential, the Na+ inactivation gates begin to close and the K+ gates open. Because of the slight delay in opening of the potassium channels they open just at the same time that the sodium channels are beginning to close by inactivation gate. Na+ Inactivation If Na+ channel inactivation did not occur, the repolarization would be slowed. Speeding the Process Thus, the decrease in sodium entry to the cell and the simultaneous increase in potassium exit from the cell combine to speed the repolarization process. Restoring RMP Continued outward movement of K+ restores the resting membrane potential, with the potential reversing back.

21. Hyperpolarization (Undershoot) Further outward movement of K+ through the still open K+ gates briefly hyperpolarized the membrane. Then the K+ gates close and the membrane returns to resting potential. The After-Hyperpolarization The voltage gated K+ channels are slow to close. As a result of this persistent increased permeability to K+ , more K+ may leave than is necessary to bring the potential to resting. This slight excessive K+ efflux makes the interior of the cell transiently even more negative than resting potential, causing the after hyperpolarization.

22. Role of Inward Rectifier K+ Channels and Na+ Channel Recovery Inward Rectifier K+ Channels They are non- gated (leakage) channels, they tend to drive the membrane potential from the hyperpolarized state to the resting level as they drive K+ ions inward the nerve only in cases of hyper-polarization. Na+ Channel Recovery Another important characteristic of the sodium channel inactivation process is that the inactivation gate will not reopen until the membrane potential returns to the original resting membrane potential level. Therefore, it is usually not possible for the sodium channels to open again without first repolarize the nerve fiber. As the potential returns to resting, the changing voltage shifts the Na+ channels to their closed but capable of opening conformation , now the channel is rest, ready to respond to another stimulus.

23. The Na+-K+ Pump: Restoring Concentration Gradients The Na+-K+ pump gradually restores the concentration gradients disrupted by AP: At the completion of AP, the membrane potential has been restored to its resting level, but the ion distribution has been altered slightly. Na+ has entered the cell during depolarization and K+ has left during repolarization. The Na+ -K+ pump restores these ions to their original levels in the long run not after each AP.