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Y1 s1 membrane potentials 2013


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Y1 s1 membrane potentials 2013

  1. 1. Excitable Tissues,Resting MembranePotential & ActionPotentialProf. Vajira WeerasingheProfessor of PhysiologyDepartment of PhysiologyFaculty of
  2. 2. Objectives1. Explain why some membranes are excitable2. Describe the electrochemical basis of restingmembrane potential3. Describe the mechanism of generation andpropagation of action potential4. Explain the differences in action potentials ofskeletal, smooth and cardiac muscles
  3. 3. Excitable Tissues• Tissues which are capable of generation andtransmission of electrochemical impulses alongthe membraneNerve
  4. 4. Excitable tissuesexcitable Non-excitableRed cellGITneuronmuscle•RBC•Intestinal cells•Fibroblasts•Adipocytes•Nerve•Muscle•Skeletal•Cardiac•Smooth
  5. 5. Membrane potential• A potential difference exists across all cellmembranes• This is called– Resting Membrane Potential (RMP)
  6. 6. Membrane potential– Inside is negative with respect to the outside– This is measured using microelectrodes andoscilloscope– This is about -70 to -90 mV
  7. 7. Excitable tissues• Excitable tissues have morenegative RMP( - 70 mV to - 90 mV)excitable Non-excitableRed cellGITneuronmuscle• Non-excitable tissueshave less negative RMP-53 mV epithelial cells-8.4 mV RBC-20 to -30 mV fibroblasts-58 mV adipocytes
  8. 8. Resting Membrane Potential• This depends on following factors– Ionic distribution across the membrane– Membrane permeability– Other factors• Na+/K+pump
  9. 9. Ionic distribution• Major ions– Extracellular ions• Sodium, Chloride– Intracellular ions• Potassium, ProteinateK+Pr-Na+Cl-
  10. 10. Ionic distributionIon Intracellular ExtracellularNa+10 142K+140 4Cl-4 103Ca2+0 2.4HCO3-10 28
  11. 11. Gibbs Donnan Equilibrium• When two solutionscontaining ions areseparated by membranethat is permeable to someof the ions and not to othersan electrochemicalequilibrium is established• Electrical and chemicalenergies on either side ofthe membrane are equaland opposite to each other
  12. 12. Flow of Potassium• Potassium concentration intracellular is more• Membrane is freely permeable to K+• There is an efflux of K+K+K+K+K+K+ K+K+K+K+K+
  13. 13. Flow of Potassium• Entry of positive ions in to the extracellular fluidcreates positivity outside and negativity insideK+K+K+K+K+ K+K+K+K+K+
  14. 14. Flow of Potassium• Outside positivity resists efflux of K+• (since K+is a positive ion)• At a certain voltage an equilibrium is reachedand K+efflux stopsK+K+K+K+K+ K+K+K+K+K+
  15. 15. Nernst potential (Equilibrium potential)• The potential level across the membrane thatwill exactly prevent net diffusion of an ion• Nernst equation determines this potential
  16. 16. Nernst potential (Equilibrium potential)• The potential level across the membrane thatwill exactly prevent net diffusion of an ionIon Intracellular Extracellular NernstpotentialNa+10 142 +60K+140 4 -90Cl-4 103 -89Ca2+0 2.4 +129HCO3-10 28 -23(mmol/l)
  17. 17. Goldman Equation• When the membrane is permeable to several ions theequilibrium potential that develops depends on– Polarity of each ion– Membrane permeability– Ionic conc• This is calculated using Goldman Equation (or GHKEquation)• In the resting state– K+ permeability is 50-100 times more than that of Na+
  18. 18. Ionic channels• Leaky channels (leak channels)– Allow free flow of ions– K+ channels (large number)– Na+ channels (fewer in number)– Therefore membrane is more permeable to K+
  19. 19. Na/K pump• Active transport system for Na+-K+exchange using energy• It is an electrogenic pump since 3 Na+efflux coupled with 2 K+ influx• Net effect of causing negative chargeinside the membrane3 Na+2 K+ATP ADP
  20. 20. Factors contributing to RMP• One of the main factors is K+ efflux (Nernst Potential:-90mV)• Contribution of Na+ influx is little (Nernst Potential:+60mV)• Na+/K+ pump causes more negativity inside themembrane• Negatively charged protein ions remaining inside themembrane contributes to the negativity• Net result: -70 to -90 mV inside
  21. 21. Electrochemical gradient• At this electrochemical equilibrium, there is an exactbalance between two opposing forces:• Chemical driving force = ratio of concentrations on 2sides of membrane (concentration gradient)• The concentration gradient that causes K+ to move from inside tooutside taking along positive charge and• Electrical driving force = potential difference acrossmembrane• opposing electrical gradient that increasingly tends to stop K+ frommoving across the membrane• Equilibrium: when chemical driving force is balancedby electrical driving force
  22. 22. Action potential
  23. 23. Action Potential (A.P.)• When an impulse is generated– Inside becomes positive– Causes depolarisation– Nerve impulses are transmitted as AP
  24. 24. DepolarisationRepolarisation-70+30RMPHyperpolarisation
  25. 25. Inside of the membrane is• Negative– During RMP• Positive– When an AP is generated-70+30
  26. 26. • Initially membrane is slowly depolarised• Until the threshold level is reached– (This may be caused by the stimulus)-70+30Threshold level
  27. 27. • Then a suddenchange in polarisationcauses sharpupstroke(depolarisation) whichgoes beyond the zerolevel up to +35 mV-70+30
  28. 28. • Then a suddendecrease inpolarisation causesinitial sharp downstroke (repolarisation)-70+30
  29. 29. • Spike potential– Sharp upstroke anddownstroke• Time duration of AP– 1 msec-70+301 msec
  30. 30. All or none law• 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
  31. 31. All or none law• The principle that the strength by which a nerveor muscle fiber responds to a stimulus is notdependent on the strength of the stimulus• If the stimulus strength is above threshold, thenerve or muscle fiber will give a completeresponse or otherwise no response at all
  32. 32. • Sub-threshold stimulus No action potential• Threshold stimulus Action potential istriggered• Supra-threshold stimulus Action potential istriggered• Strength of the stimulus above the threshold is codedas the frequency of action potentials
  33. 33. Physiological basis of AP• When the threshold level is reached– Voltage-gated Na+ channels open up– Since Na+ conc outside is more than the inside– Na+ influx will occur– Positive ion coming inside increases the positivity of themembrane potential and causes depolarisation-70+30outsideinsideNa+Voltage-gated Na+ channel
  34. 34. Physiological basis of AP– When membrane potential reaches +30, Na+channels are inactivated– Then Voltage-gated K+ channels open up– K+ efflux occurs– Positive ion leaving the inside causes more negativity insidethe membrane– Repolarisation occurs-70+30outsideinsideAt +30K+
  35. 35. • Depolarisation– Change of polarity of the membrane• from -70 to + 30 mV• Repolarisation– Reversal of polarity of the membrane• from +30 to -70 mV-70+30-70+30
  36. 36. Hyperpolarisation• When reaching theResting level rateslows down• Can go beyond theresting level– Hyperpolarisation• (membrane becomingmore negative)-70+30
  37. 37. Role of Na+/K+ pump• Since Na+ has come in and K+ has gone out• Membrane has become negative• But ionic distribution has become unequal• Na+/K+ pump restores Na+ and K+ conc slowly– By pumping 3 Na+ ions outward and 2+ K ionsinward
  38. 38. VOLTAGE-GATED ION CHANNELS• Na+ channel– This has two gates• Activation and inactivation gatesoutsideinsideActivation gateInactivation gate
  39. 39. • 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 fastoutsideinsideoutsideinside-70 Threshold level +30Na+ Na+outsideinsideNa+m gateh gate
  40. 40. Voltage-gated Na+ channel• There is a voltagesensor• Which opens upactivation gate• Na+ influx occurs• Membrane becomesmore positive
  41. 41. • 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+ equilibriumpotential
  42. 42. VOLTAGE-GATED K+ Channel• K+ channel– This has only one gateoutsideinside
  43. 43. – 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 occursoutsideinsideoutsideinside-70 At +30K+ K+n gate
  44. 44. Basis of hyperpolarisation• After reaching the restingstill slow K+ channelsmay remain open:causing further negativityof the membrane• This is known ashyperpolarisation-70+30outsideinsideK+
  45. 45. Summary
  46. 46. Animation
  47. 47. Refractory Period• Absolute refractoryperiod– During this period nervemembrane cannot beexcited again– Because of the closureof inactivation gate-70+30outsideinside
  48. 48. Refractory Period• Relative refractoryperiod– During this period nervemembrane can beexcited by suprathreshold stimuli– At the end ofrepolarisation phaseinactivation gate opensand activation gatecloses– This can be opened bygreater stimuli strength-70+30outsideinside
  49. 49. Na+ and K+ concentrations do not change during an action potential• Although during an action potential, large changestake place in the membrane potential as a result ofNa+entry into the cell and K+exit from the cell• Actual Na+and K+concentrations inside and outside ofthe cell generally do not change• This is because compared to the total number of Na+and K+ions in the intracellular and extracellularsolutions, only a small number moves across themembrane during the action potential
  50. 50. Propagation of action potential (Basis of nerve conduction) 
  51. 51. Propagation of AP• When one area is depolarised• A potential difference exists between that siteand the adjacent membrane• A current flow is initiated• Current flow through this local circuit iscompleted by extra cellular fluid
  52. 52. Propagation of AP• This local current flow will cause opening ofvoltage-gated Na+ channel in the adjacentmembrane• Na+ influx will occur• Membrane is depolarised
  53. 53. Propagation of AP• Then the previous area become repolarised• This process continue to work• Resulting in propagation of AP
  54. 54. Propagation of AP
  55. 55. Propagation of AP
  56. 56. Propagation of AP
  57. 57. Propagation of AP
  58. 58. Propagation of AP
  59. 59. Propagation of AP
  60. 60. Propagation of AP
  61. 61. Propagation of AP
  62. 62. Animation 
  63. 63. AP propagation along myelinated nerves• Na+ channels are concaround nodes• Therefore depolarisationmainly occurs at nodes
  64. 64. Distribution of Na+ channels • Number of Na+ channels persquare micrometer of membranein mammalian neurons50 to 75 in the cell body350 – 500 in the initialsegment< 25 on the surfaceof myelin2000 – 12,000 at the nodes ofRanvier20 – 75 at the axonterminal
  65. 65. AP propagation along myelinated nerves• Local current will flow from one node to another• Thus propagation of action potential and therefore nerveconduction through myelinated fibres is faster thanunmyelinated fibre– Conduction velocity of thick myelinated A alpha fibres isabout 70-100 m/s whereas in unmyelinated fibres it is about1-2 m/s
  66. 66. Saltatory conduction • This fast conduction through myelinated fibresis called “saltatory conduction”• Saltatory word means “jumping”• This serves many purposes– By causing depolarisation process to jump at longintervals it increases the conduction velocity– It conserves energy for the axon because less lossof ions due to action potential occurring only at thenodes
  67. 67. Animation 
  68. 68. Na+/K+ pump• Re-establishment of Na+ & K+ concentrationafter action potential– Na+/K+ Pump is responsible for this– Energy is consumed– Turnover rate of Na+/K+ is pump is much slowerthan the Na+, K+ diffusion through channels3 Na+2 K+ATP ADP
  69. 69. Clinical importance • Local anaesthetics (eg. procaine) block voltagegated sodium channels in pain nerve fibres• Thereby pain signal transmission is blocked
  70. 70. Clinical importance• Demyelinating diseases– In certain diseases antibodies would form against myelinand demyelination occurs– Nerve conduction slows down drastically• eg. Guillain-Barre Syndrome (a patient suddenly find difficult to walk,weakness rapidly progress to upper limbs and respiratory difficultywill also occur)
  71. 71. Muscle action potentials• Skeletal muscle• Cardiac muscle• Smooth muscle
  72. 72. Skeletal muscle• Skeletal muscle is supplied bysomatic nerve• When there is a signal to themuscle it contracts and relaxes• Thus there are two events in theskeletal muscle– Electrical - action potential– Mechanical - contraction
  73. 73. Muscle contraction• Excitation - contraction coupling– Excitation : electrical event– Contraction : mechanical eventMechanical event follows electrical event
  74. 74. Skeletal muscle• Electrical event in a skeletal muscle membraneis exactly similar to nerve action potential• Same duration = 1 msec• Same voltage difference = from -70 to +30 mV
  75. 75. Cardiac muscle• Innervated by autonomic nerves (sympatheticand parasympathetic)• Similar to skeletal muscle– Electrical event - action potential– Mechanical event – muscle contraction• However cardiac muscle action potential iscompletely different to that of skeletal muscle
  76. 76. Cardiac muscle action potentialPhases• 0: depolarisation• 1: short repolarisation• 2: plateau phase• 3: repolarisation• 4: restingDuration is about 200 to 300 msec
  77. 77. Cardiac muscle action potentialPhases• 0: depolarisation(Na+ influx through fast Na+channels)• 1: short repolarisation(K+ efflux through K+channels, Cl- influx as well)• 2: plateau phase(Ca2+ influx through slowCa2+ channels)• 3: repolarisation(K+ efflux through K+channels)• 4: resting
  78. 78. Differences• Prolonged plateau phase• Due to opening of slow Ca2+ channels• Which causes Ca2+ influx• Membrane is not repolarised immediately• Mechanical event occurs together with theelectrical eventExcitation : electrical eventContraction : mechanical event
  79. 79. Refractory period• Cardiac muscle refractory period is about 200msec• Equal to the period of depolarisation, plateauphase & part of repolarisation phases• The reason for this is that the fast sodiumchannels are not fully reactivated and thereforecannot reopen to normal depolarizing stimuli
  80. 80. Smooth muscle• eg. gut wall, bronchi, uterus• Controlled by nerve supply (autonomic nerves)or hormonal control
  81. 81. Smooth muscle• Resting membrane potential may be about -55mV• There are different types of action potentials• Spikes– Slow waves - duration 10-50 msvoltage from -55 to 0 mV– Plateau waves - similar to cardiac muscles• Ca2+ influx is more important that Na+ influx
  82. 82. Pacemaker cells• Cardiac – SA node• Spontaneous action potentials• RMP = -40 mV
  83. 83. Depolarisation• Activation of nerve membrane• Membrane potential becomes positive• Due to influx of Na+ or Ca++
  84. 84. Hyperpolarisation• Inhibition of nerve membrane• Membrane potential becomes more negative• Due to efflux of K+ or influx of Cl-
  85. 85. Channel blockers• Tetrodotoxin (TTX) is a naturally-found poisonthat inhibits the voltage-gated Na+channels• Tetraethyl ammonium (TEA), a quaternaryammonium cation, is an agent that inhibits thevoltage-gated K+channels
  86. 86. Other substances• Oubain– Plant poison which blocks Na+/K+ pump• Digitalis– Drug used in cardiac conditions– blocks Na+/K+ pump
  87. 87. Effect of serum hypocalcaemia• Concentration of calcium in ECF has aprofound effect on voltage level at which Na+channels activated• Hypocalcaemia causes hyperexcitability of themembrane• When there is a deficit of Ca2+ (50% belownormal) sodium channels open (activated) by asmall increase in the membrane potential fromits normal level– Ca2+ ions binds to the Na+ channel and alters thevoltage sensor
  88. 88. Effect of serum hypocalcaemia• Therefore membrane becomes hyperexcitable• Sometimes discharging spontaneouslyrepetitively–tetany occurs• This is the reason for hypocalcaemia causingtetany
  89. 89. Carpopedal spasms
  90. 90. Membrane stabilisers• Membrane stabilisers (these decreaseexcitability)• Increased serum Ca++– Hypocalcaemia causes membrane instability andspontaneous activation of nerve membrane– Reduced Ca level facilitates Na entry– Spontaneous activation• Decreased serum K+• Local anaesthetics• Acidosis• Hypoxia
  91. 91. Membrane stabilisers• Membrane destabilisers (these increaseexcitability)•Decreased serum Ca++•Increased serum K+•Alkalosis