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Nerve physiology

The document discusses the resting membrane potential and action potential in nerve cells. It explains that the resting membrane potential of -70 mV is established primarily due to the concentration gradients of potassium and sodium ions across the plasma membrane. Potassium ions diffuse out of the cell, while sodium ions diffuse into the cell. This creates an equilibrium potential close to the potassium equilibrium potential of -94 mV. When an excitatory stimulus is strong enough to depolarize the membrane past its threshold, voltage-gated sodium channels open, allowing rapid sodium influx and further depolarization. The membrane potential then reaches about +30 mV before sodium channels inactivate and voltage-gated potassium channels open, causing repolarization back to the resting potential.

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Nerve physiology RestingMembrane Potential & Action Potential Dr. Dina Hamdy Merzeban Lecturer of physiology Fayoum university www.facebook.com/physiology-department-fayoum-university www.youtube.com/physiology ‫فكر‬ ‫تاني‬ http://slideshare.net/merzeban
1. Leak channels or pores – always open (Resting Membrane Potential) 2. Gated channels which open and close  Chemically (or ligand)-gated channels – open with binding of a specific neurotransmitter (the ligand) (graded potential)  Mechanically-gated channels – open and close in response to physical deformation of receptors (graded potential)  Voltage-gated channels – open and close in response to changes in the membrane potential (action potential) TYPES OF PLASMA MEMBRANE ION CHANNELS
MEMBRANE POTENTIAL • Separation of opposite charges across the membrane Or • Difference in relative number of cations and anions in the ECF and ICF • Separated charges create the ability to do work • Membrane potential is measured in millivolts • 1mv = 1/1000 volts Which has the greatest membrane potential?
• Plasma membrane of all living cells has a membrane potential (polarized electrically) • Due to differences in concentration and permeability of key ions ie Na+ K+ and large intracellular proteins in ICF • Nerve and muscle cells • They are Excitable cells • Have ability to produce rapid, transient changes in their membrane potential when excited which serves as electric signals
MEMBRANE POTENTIAL – Inside is negative with respect to the outside – This is measured using microelectrodes and oscilloscope – This is about -70 to -90 mV
RESTING MEMBRANE POTENTIAL (RMP) • Constant membrane potential present in cells of non excitable tissues and excitable tissues when they are at rest (not excited) • The ions primarily responsible for the generation of resting membrane potential are Na+ &K+ • The concentration difference of Na+ and K+ are maintained by the Na+ K+ pump. TYPE OF CELL RMP SKELETAL MUSCLE - 90 mvs SMOOTH MUSCLE - 60mvs CARDIAC MUSCLE - 85 to - 90 mvs NERVE CELL - 70 mvs
GIBBS DONNAN EQUILIBRIUM  When two solutions containing ions are separated by semipermeable membrane  Electrical and chemical energies on either side of the membrane are equal and opposite to each other
Key point • Concentration gradient for K is towards outside and for Na is towards inside • but the electric gradient for both of these ions is towards the negatively charged side of the membrane
MORE PERMEABILITY OF K+ AS COMPARED TO NA+ IN RESTING STATE •The plasma membrane is more permeable to K+ in resting state than Na+ because the membrane has got 100 times more leak channels for K+ than for Na+ •Moreover the hydrated form of K+ is smaller than the hydrated form of Na+
• Ions with highest permeability or conductance at rest will make the greatest contributions to the resting membrane potential • K is more permeable at rest so highest contribution by K and least by Na.
CAUSES OF GENERATION OF RMP 1. Only 20% of the RMP is directly generated by Na K pump 1. 80% of the RMP is caused by the passive diffusion of Na and K down the concentration gradient through leak channels
The potential at which no further net diffusion of ion occurs down the concentration gradient due to equal and opposite electrical gradient is called Nernst potential or equilibriumpotential NERNST POTENTIAL (EQUILIBRIUM POTENTIAL)
Plasma membrane ECF ICF Concentration gradient for K+ Electrical gradient for K+ EK+ = –94mV Effect of movement of K+ alone on RMP (K+ equilibrium potential)
EMF = ± 61 x log (Cin / Cout) Where 61 is constant & is = RT / z F Where R= Universal Gas constant T = Absolute temperature z = ion Valence F = Faraday, an electrical Constant. NERNST POTENTIAL (EQUILIBRIUM POTENTIAL) • The potential level across the membrane that will prevent net diffusion of an ion • Nernst equation determines this potential E = ± 61 x log (Cin / Cout) Where 61 is constant & is = RT / z F the sign of the potential is positive (+) if the ion diffusing is a negative ion, and it is negative (-) if the ion is positive.
EMF = ± 61 x log (Cin / Cout) Where 61 is constant & is = RT / z F Where R= Universal Gas constant T = Absolute temperature z = ion Valence F = Faraday, an electrical Constant. Conc K+ ions inside =140 mEq/l Conc K+ ions outside = 4 mEq/l E = ± 61 x log (Cin / Cout) E (mv)= - 61 log 140 4 = -61 log 35 = - 94mv So , if potassium ions were the only factor causing the resting potential, the resting potential would be equal to -94 mv . EQUILIBRIUM (NERNST) POTENTIAL FOR K+
Plasma membrane ECF ICF Concentration gradient for Na+ Electrical gradient for Na+ ENa+ = +61 mV Effect of movement of Na+ alone on RMP (Na+ equilibrium potential)
EMF = ± 61 x log (Cin / Cout) Where 61 is constant & is = RT / z F Where R= Universal Gas constant T = Absolute temperature z = ion Valence F = Faraday, an electrical Constant. Conc of Na+ ions inside the cell=14 mEq/l Conc of Na+ ions outside the cell= 142 mEq/l E = ± 61 x log (Cin / Cout) E = -61 log 14 = - 61 log 0.1 140 = -61X-1 = +61 mv Therefore, if Na ions were the only factor causing the resting potential, the resting EQUILIBRIUM (NERNST) POTENTIAL FOR NA+
GOLDMAN EQUATION • When the membrane is permeable to several ions the equilibrium potential is calculated using Goldman Equation (or GHK Equation) • that develops depends on –Polarity of each ion –Membrane permeability –Ionic conc • In the resting state – K+ permeability is 50-100 times more than that ofNa+
GOLDMAN EQUATION • In the resting state – K+ permeability is 50-100 times more than that ofNa+ E (mv)= -61 X log CNa+ in PNa+ + CK+ in PK+ + CCl- out PCl- CNa+ out PNa+ + CK+ out PK+ + CCl- in PCl- Where ‘C’=Concentration & P= Permeability the Goldman equation gives a potential inside the membrane of -86 mv, which is near the potassium potential. Nernst potential for Potassium -94mv. Nernst potential for Sodium +61mv
RESTING MEMBRANE POTENTIAL IN NERVES IS -90 MV SO , -86MV IS DUE TO THE EQUILIBRIUM POTENTIAL OF SEVERAL IONS AS CALCULATED BY GOLDMAN EQUATION WHICH IS NEARER TO K+ DIFFUSING POTENTIAL AND - 4MV IS PROVIDED BY NA- K PUMP
Role of Na-K Atpase in creating & maintaining the RMP • Two contributions of this pump 1. Direct electrogenic contribution of Na K pump by pumping 3 Na out and 2 K in since more +ve ions move outside so causes negativity of -4 mvs on inside (creating) 2. Indirect contribution is in maintaining the concentration gradient for K across the cell membrane, which is then responsible for the K diffusion potential that derives the membrane potential toward the K equilibrium potential.
Nerve physiology RestingMembrane Potential & Action Potential Dr. Dina Hamdy Merzeban Lecturer of physiology Fayoum university www.facebook.com/physiology-department-fayoum-university www.youtube.com/physiology ‫فكر‬ ‫تاني‬ http://slideshare.net/merzeban
EXCITABLE TISSUES • Excitability is the ability of living cells to respond to changes in their environment (stimulus) • ( i.e. generation and transmission of electrochemical impulses along the membrane) Nerve
EXCITABLE TISSUES excitable Non-excitable Red cell GIT •RBC •Intestinal cells •Fibroblasts •Adipocytes neuron muscle •Nerve •Muscle •Skeletal •Cardiac •Smooth
EXCITABILITY •TYPES OF STIMULI: 1. ELECTRICAL 2. CHEMICAL 3. MECHANICAL 4. THERMAL
THE STIMULUS: It is an external force or event which when applied to an excitable tissue produces a characteristic response. Examples of various types of stimuli are: 1)Electrical: use to produce an action potential in neurons . 2)Hormonal: hormones are released i.e. adrenaline act on heart to increases its rate 3)Thermal: stimulation of thermal receptors in skin by hot or cold objects. 4)Electromagnetic receptor: stimulation of rods & cone of retina by light. 5)Chemical: stimulation of taste receptors on the tongue 6)Sound: stimulation of auditory hair cells
FACTORS AFFECTING DEGREE OF RESPONSE TO THE STIMULUS -STRENGTH. -DURATION. -RATE OF APPLICATION.
2- STRENGTH-DURATION CURVE Utilization Time Chronaxie Minimal time
1- RATE OF APPLICATION  SUDDENLY APPLIED STIMULUS OF CERTAIN INTENSITY IS MORE EFFECTIVE THAN IF A WEAKER STIMULUS APPLIED AND GRADUALLY INCREASED TO THE SAME INTENSITY • SLOW CHANGES >>> ADAPTATION ( ↓ RESPONSE BY CONTINUOUS STIMULATION)
ELECTRICAL SIGNALS ARE PRODUCED BY CHANGES IN ION MOVEMENT ACROSS THE PLASMA MEMBRANE • Triggering agent (stimulus) • Change in membrane permeability • Alter ion flow by opening and closing of gates • Membrane potential fluctuates •Two types of electrical signal generated ie graded potential and action potential
ELECTRICAL SIGNALS: GRADED POTENTIAL AND ACTION POTENTIAL • In excitable cells changes in ion movement in turn are brought about by changes in membrane permeability in response to a triggering agent or a stimuli
ION CHANNELS • Non-gated • Always open • Gated • Open or close in response to stimuli • Chemical (ligand) • Electrical (voltage) • Mechanical • When gated channels are open: • Ions move quickly across the membrane • Movement is along their electrochemical gradients • An electrical current is created • Voltage changes across the membrane Leaky channels Gated channels
• Three parts • Cell Body or Soma: contains the nucleus & is the metabolic center of neuron • Dendrites: receptive regions; transmit impulse to cell body • Axon: transmit impulses away from cell body STRUCTURE OF NEURON
Terminologies Associated with Changes in Membrane Potential • Polarization- other than 0 • Depolarization- membrane potential less negative than RMP. • Overshoot- when the inside of the cell becomes +ve due to the reversal of the membrane potential polarity. • Repolarization- returning to the RMP . • Hyperpolarization- membrane potential more negative than RMP.
ACTION POTENTIAL (A.P.) • When an impulse is generated – Inside becomes positive – Causes depolarisation – Nerve impulses are transmitted as AP
+30 RMP -70 Hyperpolarisation
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
PARTS OF A NEURON: AXON • Initial Segment: Initial 50-100 um area after axon hillock is most excitable part; rich in Voltage gated Na channels; site where AP generates so called trigger zone • Once AP generated it always propagates towards axon terminals • Branches at its distal end into many axons terminals at end of which is an enlarged area synaptic knob or button
• Inside of the membrane is Negative – During RMP • Positive – When an AP is generated -70 +30
• Initially membrane is slowly depolarised • Until the threshold level is reached – (This may be caused by the stimulus) +30 Threshold level -70
• Then a sudden change in polarisation causes sharp upstroke (depolarisation) which goes beyond the zero level up to +35 mV -70 +30
• Then a sudden decrease in polarisation causes initial sharp down stroke (repolarisation) -70 +30
• Spike potential – Sharp upstroke and downstroke • Time duration of AP – 1 msec -70 +30 1 msec
PHYSIOLOGICAL BASIS OF AP -70 • 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 the membrane potential and causes depolarisation +30 outside inside Na+ Voltage-gated Na+ channel
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 inside the membrane – Repolarisation occurs -70 +30 outside inside At +30 K+
• 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
HYPERPOLARISATION • When reaching the Resting level rate slows down • Can go beyond the resting level – Hyperpolarisation • (membrane becoming more negative) -70 +30
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 ions inward
VOLTAGE-GATED ION CHANNELS Activation gate outside inside Inactivation gate • Na+ channel – This has two gates • Activation and inactivation gates
• • 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 outside inside -70 Na+ THRESHOLD LEVEL NA+ outside inside +30 Na+ m gate outside inside h gate
SUMMA RY
Plasma membrane ECF ICF Concentration gradient for K+ Electrical gradient for K+ EK+ = –94mV Effect of movement of K+ alone on RMP (K+ equilibrium potential)
• 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
INITIATION OF ACTION POTENTIAL •Toinitiate 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)
VOLTAGE-GATED K+ CHANNEL • K+ channel – This has only one gate outside inside
– 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 outside inside -70 AT +30 K+ K+ n gate outside inside
BASIS OF HYPERPOLARISATION • After reaching the resting still slow K+ channels may remain open: causing further negativity of the membrane • This is known as hyperpolarisation -70 +30 outside inside K+
SUMMA RY
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
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 ADP
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
Nerve physiology Propagation of Action Potential and refractory period Dr. Dina Hamdy Merzeban Lecturer of physiology Fayoum university www.facebook.com/physiology-department-fayoum-university www.youtube.com/physiology ‫فكر‬ ‫تاني‬ http://slideshare.net/merzeban
PROPAGATION OF ACTION POTENTIALS (BASIS OF NERVE CONDUCTION) • Two types of propagation • Contiguous conduction • Conduction in unmyelinated fibers • Action potential spreads along every portion of the membrane • Saltatory conduction • Rapid conduction in myelinated fibers • Impulse jumps over sections of the fiber covered with insulating myelin
PROPAGATION OF AP • When one area is depolarised • A potential difference exists between that site and the adjacent membrane • A current flow is initiated • Current flow through this local circuit is completed by extra cellular fluid
PROPAGATION OF AP • This local current flow will cause opening of voltage-gated Na+ channel in the adjacent membrane • Na+ influx will occur • Membrane is depolarised
PROPAGATION OF AP • Then the previous area become repolarised • This process continue to work • Resulting in propagation of AP
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PROPAGATION OF AP
MYELIN • Myelin • Most axons are myelinated. • Primarily composed of lipids sphingomyelin • Formed by oligodendrocytes in CNS • Formed by Schwann cells in PNS • Myelin is insulating, preventing passage of ions over the membrane as it is made up of lipids so water soluble ions cannot permeate so current cannot leak out in the ECF
AP PROPAGATION ALONG MYELINATED NERVES • Na+ channels are conc around nodes • Therefore depolarisation mainly occurs at nodes
AP PROPAGATION ALONG MYELINATED NERVES • • Local current will flow from one node to another Thus propagation of action potential and therefore nerve conduction through myelinated fibres is faster than unmyelinated fibre – Conduction velocity of thick myelinated A alpha fibres is about 70-100 m/s whereas in unmyelinated fibres it is about 1-2 m/s
SALTATORY CONDUCTION • This fast conduction through myelinated fibres is called “saltatory conduction” • Saltatory word means “jumping” • This serves many purposes – By causing depolarisation process to jump at long intervals it increases the conduction velocity – It conserves energy for the axon because less loss of ions due to action potential occurring only at the nodes
•The resistance of the membrane: Large diameter axons provide a low resistance to current flow within the axon and this in turn, speeds up conduction. •Myelin sheath: which wraps around vertebrate axons prevents current leak out of the cells. Acts like an insulator, for example, plastic coating surrounding electric wires. •Nodes of Ranvier: are present at about 1 mm intervals along the length of axons . High concentration of Na+ channels are found at these nodes so AP occurs only at nodes 2 WAYS TO INCREASE AP PROPAGATION SPEED
DISTRIBUTION OF NA+ CHANNELS • Number of Na+ channels per square micrometer of membrane in mammalian neurons 50 to 75 350 – 500 < 25 2000 – 12,000 20 – 75 in the cell body in the initial segment on the surface of myelin at the nodes of Ranvier at the axon terminal
PARTS OF A NEURON: AXON • Initial Segment: Initial 50-100 um area after axon hillock is most excitable part; rich in Voltage gated Na channels; site where AP generates so called trigger zone • Once AP generated it always propagates towards axon terminals • Branches at its distal end into many axons terminals at end of which is an enlarged area synaptic knob or button
IMPORTANCE OF SALTATORY CONDUCTION • Increases conduction the velocity myelinated through nerve fiber. • Conserves energy for the axon
CLINICAL IMPORTANCE • Local anaesthetics (eg. procaine) block voltage gated sodium channels in pain nerve fibres • Thereby pain signal transmission is blocked
CLINICAL IMPORTANCE • Demyelinating diseases – In certain diseases antibodies would form against myelin and 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 difficulty will also occur)
Voltage gated channels- responsible for AP •Action potential takes place as a result of the triggered opening and subsequent closing of 2 specific types of channels Voltage gated Na+ channels Voltage gated K+ channels
VOLTAGE GATED NA+ CHANNELS • Most important channels during AP • It has two gates and 3 states • Activation gates outside & inactivation gates inside 1. At RMP activation gates are closed so no Na+ influx at RMP thru these channels 2. Activation gates open at threshold 3. 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 4. 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
K+ CHANNEL • During RMP Voltage gated K+ channels are closed • The same stimulus which open voltage 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) • These channels close when membrane potential reaches back to RMP
Phases of action potential •Depolarization •Repolarization •Hyperpolarization
PROPERTIES OF ACTION POTENTIALS 1. The All or None Principle: Action Potentials occur in all or none fashion depending on the strength of the stimulus 2. The Refractory Period: Two phases: a) Absolute refractory period b) Relative refractory period
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
ALL OR NONE LAW • 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
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 sub-threshold stimulus does not trigger the Action potential at all, but produce local response.
• Strength of the stimulus above the threshold is coded as the frequency of action potentials
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.
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.
REFRACTORY PERIOD • Absolute refractory period – During this period nerve membrane cannot be excited again – Because of the closure of inactivation gate -70 +30 outside inside