Nerve and Electrophysiology [IGCLG].pdf

NERVE & ELECTRO PHYSIOLOGY Ivy Grace C. Lim – Gueta, M.D. LECTURE OUTLINE Review of Basic Concepts Nervous System: Cells and Systems Basic Physics of Membrane Potentials Resting Membrane Potential Action Potential – Generation, Propagation and Repolarization in Nerve Cell Re-establishm...

NERVE & ELECTRO PHYSIOLOGY Ivy Grace C. Lim – Gueta, M.D. LECTURE OUTLINE Review of Basic Concepts Nervous System: Cells and Systems Basic Physics of Membrane Potentials Resting Membrane Potential Action Potential – Generation, Propagation and Repolarization in Nerve Cell Re-establishment of Na – K gradient after AP Action Potential in other cells – an overview Synaptic Transmission in Nerves  PART 1: REVIEW OF BASIC CONCEPTS “CATION” “ANION”  PART 2: BASIC PHYSICS OF MEMBRANE POTENTIALS  Electrical potentials exist across the membranes of virtually ALL CELLS in the body. DISTRIBUTION OF IONS IN HUMAN CELL DISTRIBUTION OF IONS IN HUMAN CELL Na+ K+ Cl- - - - - - - NEGATIVE ANIONS - - ECF ICF DISTRIBUTION OF IONS IN HUMAN CELL Na + Cl - K+ EXTRACELLULAR FLUID (ECF) INTRACELLULAR FLUID (ICF) Na+ Cl- - K+ NEGATIVE ANIONS DETERMINANTS OF DIFFUSION POTENTIAL Basic Rules For ION MOVEMENT 1. Concentration gradient (C) Diffusion from HIGHER to lower concentration 2. Polarity Opposite Charge ATTRACTS and Like charge REPELS. 3. Permeability of Membrane (P) Ability to cross the membrane DIFFUSION Na+ Na+ Cl- Na+ Na+ Na+ Cl- Cl- K+ Na+ Na+ Na+ Cl- Na+ Cl- EXTRACELLULAR FLUID (ECF) INTRACELLULAR FLUID (ICF) K+ K+ K+ K+ - K+ K+ Na+ Cl- K+ K+ K+ K+ NEGATIVE ANIONS K+ DIFFUSION Na+ Na+ K+ K+ Cl- K+ Na+ Na+ Cl- Cl- K+ K+ K+ Na+ EXTRACELLULAR FLUID (ECF) INTRACELLULAR FLUID (ICF) Na+ Na+ - K+ K+ Na+ Cl- Cl- K+ K+ Na+ Na+ Cl- K+ K+ NEGATIVE ANIONS DIFFUSION POTENTIAL = inside - outside Na+ Na+ Cl- 0 Na+ Na+ Na+ Cl- Cl- K+ Na+ Na+ Na+ Cl- Na+ Cl- EXTRACELLULAR FLUID (ECF) INTRACELLULAR FLUID (ICF) K+ K+ K+ K+ Na+ Cl- - NEGATIVE ANIONS K+ K+ K+ K+ K+ K+ 0 K+ DIFFUSION POTENTIAL = inside - outside Na+ Cl- -1 Na+ Na+ Na+ Cl- Cl- K+ Na+ Na+ Na+ Cl- Na+ Cl- EXTRACELLULAR FLUID (ECF) INTRACELLULAR FLUID (ICF) K+ K+ K+ K+ +1 Na+ Na+ Cl- - K+ K+ K+ K+ K+ K+ NEGATIVE ANIONS K+ DIFFUSION POTENTIAL = inside - outside Na+ Cl- Na+ Na+ Na+ Na+ Na+ Na+ Cl- Cl- Cl- Cl- EXTRACELLULAR FLUID (ECF) K+ -2 INTRACELLULAR FLUID (ICF) K+ K+ K+ K+ +2 Na+ Na+ Na+ Cl- - K+ K+ K+ K+ K+ K+ NEGATIVE ANIONS K+ DIFFUSION POTENTIAL = inside - outside Na+ Cl- Na+ Na+ Na+ Na+ Na+ Cl- Cl- Cl- Cl- EXTRACELLULAR FLUID (ECF) K+ -3 INTRACELLULAR FLUID (ICF) K+ K+ K+ K+ +3 Na+ Na+ Na+ Na+ Cl- - K+ K+ K+ K+ K+ K+ NEGATIVE ANIONS K+ DIFFUSION POTENTIAL = inside - outside Na+ Na+ Cl- 0 Na+ Na+ Na+ Cl- Cl- K+ Na+ Na+ Na+ Cl- Na+ Cl- EXTRACELLULAR FLUID (ECF) INTRACELLULAR FLUID (ICF) K+ K+ K+ K+ Na+ Cl- - NEGATIVE ANIONS K+ K+ K+ K+ K+ K+ 0 K+ DIFFUSION POTENTIAL = inside - outside Na+ Na+ Cl- +1 Na+ Na+ Na+ Cl- Cl- K+ Na+ Cl- K+ Na+ Na+ Na+ Cl- EXTRACELLULAR FLUID (ECF) INTRACELLULAR FLUID (ICF) K+ K+ K+ Na+ Cl- - NEGATIVE ANIONS K+ K+ K+ K+ K+ K+ -1 K+ DIFFUSION POTENTIAL = inside - outside Na+ Na+ Cl- K+ +2 Na+ Na+ Na+ Cl- Cl- K+ Na+ Cl- K+ Na+ Na+ Na+ Cl- EXTRACELLULAR FLUID (ECF) INTRACELLULAR FLUID (ICF) K+ K+ K+ Na+ Cl- - NEGATIVE ANIONS K+ K+ K+ K+ K+ K+ -2 DIFFUSION POTENTIAL = inside - outside Na+ Na+ K+ Cl- K+ Na+ Na+ Na+ Cl- Cl- K+ Na+ Cl- K+ Na+ Na+ Na+ Cl- EXTRACELLULAR FLUID (ECF) Diffusion potential blocks further net K+ diffusion despite concentration gradient INTRACELLULAR FLUID (ICF) K+ K+ K+ Na+ Cl- - NEGATIVE ANIONS K+ K+ K+ K+ K+ -3 NERNST EQUILIBRIUM POTENTIAL is the diffusion potential across a membrane (inside) that exactly opposes net diffusion of particular ion. aka: “REVERSAL POTENTIAL” EMF: electromotive force z: electrical charge of ion NERNST EQUILIBRIUM POTENTIAL Na + Cl - K+ EXTRACELLULAR FLUID (ECF) INTRACELLULAR FLUID (ICF) Na+ Cl- - K+ NEGATIVE ANIONS  ELECTROCHEMICAL DRIVING FORCE Vdf = Vm - Veq Electrochemical Driving force Membrane potential Equilibrium potential/ REVERSAL POTENTIAL - + ECF + - ICF Vdf DETERMINANTS OF DIFFUSION POTENTIAL Basic Rules For ION MOVEMENT 1. Concentration gradient (C) Diffusion from HIGHER to lower concentration 2. Polarity Opposite Charge ATTRACTS and Like charge REPELS. 3. Permeability of Membrane (P) Ability to cross the membrane Goldman- Hodgkin-Katz equation (GOLDMAN EQUATION) used to calculate Diffusion Potential if membrane is permeable to SEVERAL DIFFERENT IONS. KEY POINTS FROM GOLDMAN EQUATION Na, K and Cl – most important ions for membrane 1 potential. Membrane permeability determines importance of each 2 ion. Charge and direction of ions determines 3 Electronegativity/positivity of the ICF. Rapid changes in Na and K membrane permeability are 4 responsible for nerve impulse transmission.  PART 3: RESTING MEMBRANE POTENTIAL (RMP) RESTING MEMBRANE POTENTIAL OF NEURON RESTING MEMBRANE POTENTIAL Potential INSIDE the cell when resting or not transmitting signal. Large nerve fiber: - 70mV (Meaning: 70mV MORE negative inside than the ECF) DETERMINANTS OF RMP 1 K+diffusion + 2 Na diffusion + + 3 Na - K ATPase pump 1. K + Diffusion (K + ”leak” channel) ECF 100x more permeable to K than Na High concentration of K inside than outside (35:1) à passive efflux of K à Nernst Potential: - 94mV ICF 2. Na + Diffusion (Na + -K + ”leak” channel) ECF High concentration of Na outside than inside à passive influx of Na à Nernst Potential: +61mV ICF Since the membrane is 100x more permeable to K (-94mV) than Na (+61mV), diffusion of K contributes more to membrane potential (-86mV) (near K potential) 3. Na + - K + ATPase PUMP ECF Electrogenic pump Pumps 3 Na+ OUT and 2 K+ IN Net deficit: NEGATIVE POTENTIAL inside Additional - 4mV in electronegativity Causes large concentration gradient for ICF Na and K. RESTING MEMBRANE POTENTIAL OF NEURON Na -K + + leak channel - 86 mV Na+ - K+ ATPase pump - 4 mV Total RMP -90 mV  PART 4: ACTION POTENTIAL ACTION POTENTIAL aka “SPIKE” Rapid, ”all-or-none change” in membrane potential Generated by voltage dependent ion channels in plasma membrane Propagated with SAME size and shape along the axon. ACTION POTENTIAL aka “SPIKE” 1. DEPOLARIZATION ECF Opening of Voltage gated Na-channel à sudden increase in Na+ permeability à Na+ influx à LESS negative inner membrane potential “DE – POLARIZATION” may overshoot and become POSITIVELY charged in larger nerve fibers. ICF 2. REPOLARIZATION ECF Closure of Voltage gated Na-channel and opening of voltage gated K+ channel à rapid efflux of K+à more negative inner membrane potential “RE – POLARIZATION” ICF CHANNELS CONTRIBUTING TO ACTION POTENTIAL 1. VOLTAGE- GATED Na + CHANNEL FAST channel With 2 gates: ACTIVATION GATE Near the outside Closed at RMP (+) opens via conformational changes if voltage is at -55mV (depolarization) INACTIVATION GATE Inner side Open at RMP (+) closes with depolarization BUT is SLOWER than the activation gate. 1. VOLTAGE- GATED Na + CHANNEL 1 2 3 “CLOSED” “INACTIVATED” INITIATION OF ACTION POTENTIAL POSITIVE-FEEDBACK CYCLE Initial rise in membrane potential à (+) opening of voltage gated Na activation gate à RAPID inflow of Na à further rise in MP à (+) activation of MORE Na channel THRESHOLD POTENTIAL - 55mV: threshold for stimulation of AP Required membrane potential to create Positive feedback cycle. Na influx > K efflux hence – DEPOLARIZATION. Hence: ALL or NONE AP PROPAGATION OF ACTION POTENTIAL ALL OR NOTHING PRINCIPLE Significant amount of voltage to stimulate the next area of the membrane until it travels over the entire membrane. Ratio of Action Potential to Threshold for excitation must be >1 at ALL times If less: spread of depolarization stops. DIRECTION OF PROPAGATION Travels in ALL direction away from stimulus. Positive charges are propagated for 1-3mm distance à (+) Na channel in the next area. 1. VOLTAGE- GATED K + CHANNEL THRESHOLD POTENTIAL (-55mV) Will ALWAYS evoke a spike/ AP when reached (ALL or NONE PRINCIPLE) 1. VOLTAGE- GATED K + CHANNEL ABSOLUTE REFRACTORY PERIOD An “INACTIVATED” gate will NOT reopen despite any stimulus until the membrane returns to near THRESHOLD POTENTIAL (-55mV) original RMP Hence, cannot evoke another AP. 2. VOLTAGE- GATED K + CHANNEL With 1 gate SLOW activation 2 states Closed Resting state Open If membrane potential rises from -70mV toward ZERO But since the gate is SLOW à slight delay in opening about the same time the Na channel begins to INACTIVATE. 1. VOLTAGE- GATED K + CHANNEL SLOW VOLTAGE GATED K+ channel Opens and closes SLOWLY. (1)OPENING: about the same time of the INACTIVATION of Na-channel. (2)CLOSING: slow closing hence brings the membrane potential back to Negative à closer to the Nernst Potential for potassium (more negative than the RMP) à (3)AFTER HYPERPOLARIZATION 1. VOLTAGE- GATED K + CHANNEL RELATIVE REFRACTORY PERIOD Able to fire a 2nd AP with STRONGER than normal stimulus. THRESHOLD POTENTIAL (-55mV) STORNGER STIMULUS STIMULUS  Opening of Na 1 activation gate Influx of Na Depolarization Closure of Na Repolarization (return 2 inactivation gate Cessation of Na influx to RMP) Repolarization and 3 Opening of K gate K efflux Afterhyperpolarization 4 Closure of K gate Cessation of K efflux Return to RMP CLINICAL CORRELATION PRIMARY PERIODIC HYPERKALEMIC PARALYSIS Mutation in voltage gated Na+ channel à decreased rate of voltage inactivation à LONGER lasting AP à increased extracellular K+ à Refractory period à Paralysis CLINICAL CORRELATION SAXITOXIN POISONING (Paralytic Shellfish Poisoning) Saxitoxin: produced by reddish dinoflagellates (red tides) that are eaten by shellfish. Na+ channel blocker à no AP à life threatening paralysis with 30 minutes after consumption  PART 5: RE-ESTABLISHING GRADIENTS AFTER AP RE-ESTABLISHMENT OF NA-K GRADIENT Transmission of AP along the nerve fiber, reduces concentration differences of Na and K inside and outside the cell. RE-ESTABLISHMENT OF NA-K GRADIENT Na – K ATPase pump “Recharges” the nerve fiber by returning 3 Na OUT and 2 K IN using ATP.  PART 6: ACTION POTENTIAL IN OTHER CELLS ( A N O V E R V I E W ) HEART MUSCLE Opening of FAST Na 1 channel Influx of Na 2 2 Opening of SLOW Ca channel Influx of Ca+ ion hence, the PLATEU Opening of SLOW K 3 gate K efflux 3 1 CARDIAC CELL NERVECELL R E - E X C I T A T I O N F O R S P O N T A N E O U S R H Y T H M Y C I T Y Seen in: (1)heart (2)Intestine (peristalsis) (3)Neuron (for control of breathing) Self-induced Rhythmical Excitation Increase voltage to positive direction à 1 Na & Ca influx positive feedback mechanism Firing of Action 2 potential 3 Repolarization Then cycle repeats  PART 7: SYNAPTIC TRANSMISSION IN NERVES Nervous System is a communication and control network that allows organism to interact with its environment (internal/external) N E U R O N ( N E R V E C E L L ) 3 MAIN CELLULAR COMPARTMENTS Dendrites Branching extensions of soma Main direct recipients of signals Soma Main genetic & metabolic center and receives input from (Cell Body/Perikaryon) dendrites/other neurons Axon Extension of cell that conveys output to other neurons NEURON (NERVE CELL) Initial segment of axon where AP is first generated With HIGH density of voltage gated Na+ channel AXON HILLOCK O H M ’ S L A W O H M ’ S L A W i n P A S S I V E D O M A I N ↓ Diameter OR ↑ length ↑ Resistance ↓ Speed of Current flow Greater decay in electronic potential (lesser length constant) *similar to circuit composed of Passive elements S P E C I A L C H A R A C T E R I S T I C S O F S I G N A L T R A N S M I S S I O N I N N E R V E T R U N K S VELOCITY Small Unmyelinated 0.25m/sec Large Myelinated 100m/sec Myelin Sheath Electrical insulator that decreases flow through the membrane ~ 5000x Saltatory Conduction in Myelinated Fibers Increases Velocity to as much as 5-50 x Conserves energy since only the nodes of Ranvier depolarizes à less loss of ions à less energy expenditure for Na-K ATPase pump CLINICAL CORRELATION DEMYELINATING DISORDERS Multiple Sclerosis Diabetic Neuropathy Lost of Myelin à shorter length constant à decreasing amplitude of action potential à Propagation failure à loss of motor control and sensory deficit E X C I T A T I O N : E l i c i t i n g A c t i o n P o t e n t i a l THRESHOLD POTENTIAL (-55mV) Any factor STIMULUS (mechanical/chemical/electrical) that will cause Na INFLUX à Depolarization T H R E S H O L D F O R E X C I T A T I O N ( A P ) & A C U T E L O C A L P O T E N T I A L THRESHOLD POTENTIAL (-55mV) STIMULUS Acute Subthreshold Potentials / Acute Local Potentials Threshold Membrane Suprathreshold Membrane Potential Potential à ACTION POTENTIAL Local Potential Graded Response Decay with both TIME and Excitatory Post Synaptic SPACE/DISTANCE Potential (EPSP) Inhibitory Post synaptic (d/t re-uptake and degradation of Potential (IPSP) transmitter from synaptic cleft) Depends on which ligand gate is activated Action Potential All or none travels the entire membrane “hyperpolarizing potential” “depolarizing potential”  Multiple local potentials can summate to trigger a spike (AP) Temporal Summation local potential in rapid succession (less than their duration) “summate in TIME” Spatial Summation Local potentials generated by different distant synapse can summate “summate in SPACE” Sublinear Summation Local potentials generated by near synapse summate but at a less than linear due to SHUNTING (leaky channel) T H R E S H O L D F O R E X C I T A T I O N ( A P ) & A C U T E L O C A L P O T E N T I A L 1. VOLTAGE- GATED K + CHANNEL ABSOLUTE REFRACTORY PERIOD An “INACTIVATED” gate will NOT reopen despite any stimulus until the membrane returns to near THRESHOLD POTENTIAL (-55mV) original RMP Hence, cannot evoke another AP. 1. VOLTAGE- GATED K + CHANNEL RELATIVE REFRACTORY PERIOD Able to fire a 2nd AP with STRONGER than normal stimulus. THRESHOLD POTENTIAL (-55mV) STORNGER STIMULUS STIMULUS Axodendritic Axosomatic Axo-axonal Dendrodendritic Dendrosomatic SYNAPTIC TRANSMISSION CLASSIC SYNAPTIC TRANSMISSION 1 Arrival of AP at the active zone of presynaptic terminal 2 Opening of Voltage gated Ca+ channel à Ca influx 3 Calcium mediated fusion of vesicles with the plasma membrane 4 Release of Neurotransmitter 5 Binding of neurotransmitter to specific receptors (1)Ionotropic (2)Metabotropic 6 Changes in post synaptic membrane IONOTROPIC METABOTROPIC NERVE & ELECTRO PHYSIOLOGY Ivy Grace C. Lim – Gueta, M.D.