1. Action Potential Excitable tissue – Nerve,muscle contd…..

2. Learning objectives Genesis of Action potential Properties of action potential and accommodation Nerve conduction Conduction velocity of action potential with saltatory conduction Synapse and neuromuscular transmission Types of synaptic arrangement EPSP and IPSP

4. Action potential  The sequence of rapid changes in the membrane potential that spread rapidly along the nerve fiber when a threshold stimulus is applied following its restoration to the resting level is called action potential Three stages 1. Resting stage 2. Depolarization stage 3. Repolarization stage

5. Terminology The usual resting membrane potential is oriented with the cell interior negative. Depolarization: it’s the process of making the membrane potential LESS NEGATIVE Depolarization makes the interior of the cell less negative, or it may even cause the cell interior to be positive. Hyperpolarization: is the process of making the membrane potential more negative

6. Threshold potential : it’s the membrane potential at which occurrence of the AP is inevitable. The threshold potential is less negative than the resting membrane potential (an inward current is needed for this to happen) At threshold potential, the net inward current becomes larger than the net outward current to sustain the threshold.

7. Overshoot: that portion of the AP where the membrane potential is positive (cell interior positive) Undershoot: is that portion of the AP, following re- polarization where the membrane potential is more negative than at rest.

10. Action Potentials PHASES: threshold excitation (depolarisation) rising phase falling phase (Repolarisation) undershoot (hyperpolarisation )

12. Membrane Conductance Definition Membrane conductance refers to the number of channels that are open in a membrane. For example, Na+ conductance is proportional to the number of open channels that will allow the Na+ to pass through the membrane. General properties If conductance is increasing, channels are opening, and if conductance is decreasing, channels are closing. The rate at which ions move across a membrane depends on the number of open channels and the net force. When ions flow through channels, the cell’s membrane potential changes. However, under physiologic conditions, too few ions flow to produce a significant effect on the ion’s extracellular concentration or the concentration gradient across the membrane.

16. VOLTAGE GATED Na ⁺ AND K ⁺ CHANNELS 1. Voltage gated Na⁺ channels ↙↘ Activation gate (outside) Inactivation gate( inside ) Delayed 10,000 of a sec. close at R M P. Conformationalchange increases permeability by 500–5000 times 2. Voltage gated K⁺ channels Opening corresponds with the closure of Na⁺ gates 3. Other ions : Ca⁺ Ca⁺pump acts along with Na⁺ pump in heart and smooth muscle Voltage gated Ca⁺ channel – slow

18. VOLTAGE GATED NA AND K CHANNELS

19. Generation of Action Potential

20. Tetrodotoxin (TTX) and lidocaine block these voltage-sensitive Na+ channels and abolish action potentials.

21. Electrical properties of Smooth Muscle 1.RMP (-50mv). It is Unstable leading to spontaneous excitation. 2.Depolarisation due to the entry of Ca ++ mainly and Na + to a lesser extent. Repolarisation due to delayed K + efflux & closure of Ca ++ channels. 3. Sinusoidal waves (Basal electric rhythm) can be recorded from the longitudinal muscles of stomach and intestine. This decides the frequency of peristalsis.

22. Membrane potential (mV) -50 -45 0 200 msec Action potential K + efflux Ca 2+ influx Threshold of VOC’s

23. Electrical properties of SM – contd. 4. Action potentials - Spike potentials * appears either on the up going or down going wave of sinusoidal wave * decides the intensity of peristaltic wave - Pacemaker potentials * are generated in multiple foci that shift from place to place * responsible for spontaneous excitation - Plateau type * significance not known

25. Characteristics of an AP Stereotypical size and shape Propagation All or none response Refractory period

26. Stereotypical size and shape Stereotypical size and shape: Each normal action potential for a given cell type looks identical, depolarizes to the same potential, and repolarizes back to the same resting potential.

27. ACTIONPOTENTIAL

28. Types & duration of AP 1.Spike potential (Nerve fibre,skeletal muscle ) – 10 to 50m sec 2.Plateau type (Myocardial cell & smooth muscle cell ) – 250 to 350m sec 3.Pace maker type (Conducting system of heart & smooth muscle fibres ) – 100 to 150m sec

29. Propagation: Propagation: An action potential at one site causes depolarization at adjacent sites, bringing those adjacent sites to threshold. Propagation of action potentials from one site to the next is nondecremental.

30. Initiation & propagation of AP

31. All or none response--- Either the AP occurs or does not occur. All-or-none response: An action potential either occurs or does not occur. If an excitable cell is depolarized to threshold in a normal manner, then the occurrence of an action potential is inevitable. If the membrane potential has not reached the threshold, no action potential can occur.

32. Refractory period Refractory period: the period during which another normal action potential cannot be elicited in an excitable cell. Refractory periods can be absolute or relative.

33. Refractory period Absolute refractory period (functional refractory period)-- The absolute refractory period is that period during which no matter how strong the stimulus, it cannot induce a second action potential Relative refractory period--The relative refractory period is that period during which a greater than normal stimulus is required to induce a second action potential.

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35. Accommodation When a nerve or muscle cell is depolarized slowly or is held at a depolarized level, the usual threshold potential may pass without an action potential having been fired called accommodation. occurs because depolarization closes inactivation gates on the Na+ channels and if depolarization occurs slowly enough, the Na+ channels close and remain closed. Example: hyperkalemia which causes sustained depolarisation of the resting membrane.

36. Interrupting the Positive Feedback Loop: Voltage- Gated Sodium Channels Inactivate The rising phase of the action potential ends when the positive feedback loop is interrupted. Two processes break the loop: 1. the inactivation of the voltage-gated sodium channels. 2. the opening of the voltage-gated potassium channels. The voltage-gated sodium channels have two gates: 1. A voltage-sensitive gate opens as the cell is depolarized. 2. A second, time-sensitive inactivation gate stops the movement of sodium through the channel after the channel has been open for a certain time. At the resting membrane potential, the voltage sensitive gate is closed. As the neuron is depolarized, the voltage-sensitive gate opens. At a certain time after the channel opens, it inactivates. At the peak of the action potential, voltage-gated sodium channels begin to inactivate. As they inactivate, the inward flow of sodium decreases, and the positive feedback loop is interrupted. voltage-sensitive gate time-sensitive gate resting depolarized inactive

37. Propagation of action potentials In Neuron

38. Interrupting the Positive Feedback Loop: Voltage-Gated Potassium Channels Open The voltage-gated potassium channels respond slowly to depolarization. They begin to open as the membrane depolarizes, but responds so slowly that they become fully activated only after the action potential reaches its peak. potassium moves out of the cell as voltage-gated potassium channels open. As potassium moves out, depolarization ends, and the positive feedback loop is broken. Both the inactivation of sodium channels and the opening of potassium channels interrupt the positive feedback loop. This ends the rising phase of the action potential.

39. Repolarization We have seen potassium leaving the cell as voltage- gated potassium channels opened. With less sodium moving into the cell and more potassium moving out, the membrane potential becomes more negative, moving toward its resting value. This process is called repolarization. Repolarization

40. Hyperpolarization In many neurons, the slow voltage-gated potassium channels remain open after the cell has repolarized. Potassium continues to move out of the cell, causing the membrane potential to become more negative than the resting membrane potential. This process is called hyperpolarization. By the end of the hyperpolarization, all the potassium channels are closed. Hyperpolarization

42. Factors affecting: Conduction Velocity of the Action Potential. Size of the action potential: Cell diameter: Myelin: The greater the myelination, the greater the conduction velocity. (Demyelination (e.g., multiple sclerosis, Guillain-Barre syndrome): This would decrease the amplitude of the action potential as it travels from node to node. If the action potential arrives below a certain magnitude, another action potential may not be generated and transmission is blocked.) Thus, Large myelinated fibers =fast conduction

44. Comparing nerve conduction in an unmyelinated and a myelinated axon. Myelinated axons conduct impulses upto 50 times faster than the fastest unmyelinated axon.

45. Synaptic Transmission Synapse: a site where information is transmitted from one cell to another. Two types; electrical and chemical synapses Electrical synapse – information is transmitted electrically. Gap junctions are low resistance pathways found in cardiac muscle and in some types of smooth muscle and account for the very fast conduction in these tissues. Accounts for synchronised contraction of cardiac ventricles, bladder and uterus.

46. Chemical synapse

47. Types of synaptic arrangements One to one - A single action potential in the presynaptic cell causes a single action potential in the postsynaptic cell. One to many – A single action potential in a presynaptic cell causes a burst of action potentials in many postsynaptic cells. Many-to-one synapses – the commonest arrangement; many presynaptic cells converge on a postsynaptic cell, these inputs summate, and the sum of the inputs determines whether the postsynaptic cell will fire an action potential.

48. SYNAPTIC INPUT-EXCITATORY AND INHIBITORY POSTSYNAPTIC POTENTIALS Excitatory Postsynaptic Potentials(EPSP) - synaptic inputs that depolarize the postsynaptic cell, bringing the membrane potential closer to threshold and closer to firing an action potential; produced by opening Na+ and K+ channels. Excitatory neurotransmitters include ACh, norepinephrine, epinephrine, dopamine, glutamate, and serotonin. Inhibitory Postsynaptic Potentials (IPSP) - synaptic inputs that hyperpolarize the postsynaptic cell; produced by opening of Cl- channels. Inhibitory neurotransmitters are gamma -aminobutyric acid (GABA) and glycine.

49. Summation at synapses a. Spatial summation occurs when two excitatory inputs arrive at a postsynaptic neuron simultaneously. Together, they produce greater depolarization. b. Temporal summation occurs when two excitatory inputs arrive at a postsynaptic neuron in rapid succession. Because the resulting postsynaptic depolarizations overlap in time, they add in stepwise fashion. c. Facilitation, augmentation, and post-tetanic potentiation occur after tetanic stimulation of the presynaptic neuron. In each of these, depolarization of the postsynaptic neuron is greater than expected because greater than normal amounts of neurotransmitter are released, possibly because of the accumulation of Ca 2+ in the presynaptic terminal.

50. Clinical Focus- Channelopathies Channelopathies affecting neurons include episodic and spinocerebellar ataxias, some forms of epilepsy, and familial hemiplegic migraine. Ataxias are a disruption in gait mediated by abnormalities in the cerebellum and spinal motor neurons. One of the best-known sets of channelopathies is a group of channel mutations that lead to the Long Q-T (LQT) syndrome in the heart

51. Local Anesthetics. Among the most important stabilizers are the many substances used clinically as local anesthetics, including procaine and tetracaine. Most of these act directly on the activation gates of the sodium channels, making it much more difficult for these gates to open, thereby reducing membrane excitability.

52. For a television game show, 16 contestants volunteer to be stranded on a deserted island in the middle of the South China Sea. They must rely on their own survival instincts and skills. During one of the challenges, one team wins a fishing spear. They catch a puffer fish and cook it over the open flames of their barbecue. None of them are very skilled in cooking, but they enjoy the fish anyway. One of the contestants, a worldwide traveler, comments that it tastes like Fugu. After dinner, they all develop a strange tingling around their lips and tongue. They all become weak, and their frailty progresses to paralysis. They all die. What was the cause of death? A Tetrodotoxin B Botulism C Bacillus cereus food poisoning D Tetanus E Ciguatoxin

53. A well-meaning third year medical student accidentally pushes an unknown quantity of KCl IV to a patient. If the concentration of potassium outside a neuron were to increase from 4 mEq/L to 8 mEq/L, what would you expect to happen to the minimal stimulus required for initiation of an action potential? A The minimal stimulus required for initiation of an action potential would remain the same B The minimal stimulus required for initiation of an action potential would increase C The minimal stimulus required for initiation of an action potential would decrease D The minimal stimulus required for initiation of an action potential would stay the same, but the amplitude of the peak of the action potential would increase E The minimal stimulus required for initiation of an action potential would stay the same, but the conduction velocity of the action potential down an axon would slow

54. Q : During the upstroke of the nerve action potential (A)there is net outward current and the cell interior becomes more negative (B) there is net outward current and the cell interior becomes less negative (C)there is net inward current and the cell interior becomes more negative (D) there is net inward current and the cell interior becomes less negative

56. At which point on the action potential does the Na+current exceed theK+ current? a. Point A b. Point B c. Point C d. Point D e. Point E At which point on the action potential is the membrane closest to theNa+ equilibrium potential? a. Point A b. Point B c. Point C d. Point D e. Point E