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Nerve & Muscle Physiology
• Jeff Ericksen, MD– VCU Health Systems PM&R
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Topics *
• Relevant anatomy• Cell functions for signal
transmission– Transport, resting potential, action
potential generation & propagation– Neuromuscular transmission– Muscle transduction
• Volume Conductor theory
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Acknowledgements
• Electrodiagnostic Medicine by Daniel Dumitru, MD– Chapter 1: Nerve and Muscle
Anatomy and Physiology
• Superb text covering all aspects of EMG/NCS
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Cell membrane
• Necessary for life as we know it• Border role for cell
– Separates intracellular from extracellular milleau
• Allows ion and protein concentration gradients to exist– Creates electric charge gradients
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Cell membrane
• Provides structure for cell• Modulates cell interaction with
environment– Mechanical, hormone-receptor
• Controls material flow into/out of cell – Nutrition/waste management
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3 Key Membrane Components
• Lipids 45-49%– phospholipids, cholesterol &
glycolipids = amphipathic molecules• Polar = hydrophilic vs. nonpolar =
hydrophobic
• Proteins 45-49%• Carbohydrates 2-10%
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Lipid characteristics
• Membrane phospholipids have polar head group with 2 nonpolar tails
• In water - nonpolar tail groups form an inside excluding water
• 2 arrangements possible– Micelle = tails inside, heads face out– Bilayer
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Lipid bilayer or fluid mosaic model
• Phospholipid sheet with tails aligned in center, heads facing out for a head-tail-head sandwich– No H2O at center, 75 Angstroms
• Model as 2-D liquid with 2 degrees of freedom of motion for lipid– Long axis rotation– Lateral diffusion
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Proteins in membrane provide cell functions
• 2 membrane protein types– Transmembrane = integral - across
whole layer, amphipathic• Hydrophobic midportion acts with lipid
layer tails• Hydrophilic section faces intra/extra
environment
– Peripheral proteins - inside or outside of bilayer
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Proteins
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Membrane transport
• Lipid soluble molecules cross readily but large water soluble molecules need transport across bilayer– Transport proteins - specific for ion or
molecule to cross• Channel proteins - span bilayer, large
center, allow ion/molecule passage based on size
• Carrier proteins - binding with specific material, conformational change then crossing membrane
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Membrane transport
• Diffusion– Driven by kinetic
energy of random motion
– Thru lipids or proteins
– Follows concentration gradient
• Active transport– Needs energy
source– Fights
concentration or energy gradient
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Simple vs. Facilitated diffusion
• Simple– Crosses
membrane bilayer or channel without binding
– Increases with kinetic energy + lipid solubility + concentration gradient
– Protein channels specific for ions, often gated by cell functions
• Facilitated– Transmemb
proteins– Needs protein
binding, conformational change
– Speed of transport limited by conformational change
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Membrane transportCarrier proteins
Energy
Channel protein
Simple diffusion Facilitateddiffusion
Diffusion Active transport
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Active transport
• Acting on semi-permeable membrane allows the cell to maintain a high intracellular concentration vs. extracellular fluid
• Requires active process as diffusion would eventually equilibrate concentrations across membrane
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Active transport
• Transmembrane carrier protein uses ATP energy to pump ions against concentration gradient to develop transmembrane resting potential
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Resting membrane potential
• Excitable cells can generate and conduct action potentials over distances
• Intracellular space carries potential difference of 60-90 mV, inside with negative charge excess relative to outside
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Resting membrane potential created by semi-permeable membrane and
ions• Intracellular
– Na 50– K 400– Cl 52
• Extracellular
– 440– 20– 560
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http://www.bioanim.com/CellTissueHumanBody6/O3channels/ionCloudPoints1ws.wrl
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Nernst used thermodynamics in 1888 to determine work
done by membrane
• Work to move ion against concentration gradient is opposite to work to move against electrochemical gradient
• Can calculate contributions from different ions– K = -75 mV, Na = +55 mV
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Nomenclature
• Polarized membrane: Intracellular potential is negative relative to extracellular space
• Depolarization = less polarization of the membrane -80mV -> +20mV
• Hyperpolarization = more polarization of membrane -80mV -> -100mV
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Na influx with K efflux
• Na driven by negative charge excess inside + concentration gradient
• K driven by concentration gradient• If continued, would lose resting
potential
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Na - K ATP dependent pump
• Plasma membrane structure uses active transport
• 2 K in for 3 Na out actively• Thus 3 Na must diffuse in for 2 K
out
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Membrane potential from Goldman-Hodgkin-Katz
equation
• Resting potential mostly from K contributions
• If sudden Na permeability change, potential approaches Nernst Na potential rapidly– Action potential!
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Voltage dependent ion channels
• Ion flow across through membrane channels is initiated by membrane potential changes
• If potential exceeds a threshold, rapid increase in Na permeability followed by later K permeability increase
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Voltage dependent ion channels
• Extracellular Na activation gate with intracellular inactivation gate and slow K activation gait
• Conformational changes due to membrane potential changes influence ion permeability
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Voltage gated channels
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Channels and voltage influence
• If resting potential depolarized by 15-20 mV, then activation gate opened with 5000x increase in Na permeability followed by inactivation gate closure 1 msec later
• Slow K activation gate opens when Na inactivation gate closes to restore charge distribution, slight hyperpolarization
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http://www.bioanim.com/CellTissueHumanBody6/O3channels/naChan1ws.wrl
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Refractory periods
• Absolute = state when activation gait cannot be reopened with a strong depolarization current, the membrane potential is relatively more positive
• Relative = state when activation gait can be reopened by strong depolarizing current as membrane potential returns to equilibrium state
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Action potential timing
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Action potential propagation
• Na + charge influx spreads longtiduinally down path of least resistance to induce depolarization in adjacent membrane, some transmembrane spread
• As + charge builds up, attracts intracellular - charges and they are neutralized by new ICF + charges
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AP propagation
• Less electrochemical hold of ECF + charges which migrate and allow depolarization of membrane further
• Process is repeated down axon until end is reached
• AP is identical to AP from upstream nerve area, all or none event
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Nerve membrane modeling
• Capacitor = charge storage device, separate poles separated by a nonconducting material or dielectric– Hydrophobic center to lipid bilayer is
good dielectric, allows membrane to function well as a capacitor
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Nerve membrane modeling
• Resistor = direct path to current flow but with some impedance
• Nerve axon has both transmembrane resistance as well as longitudinal resistance
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Current spread
• Membrane capacitor model suggests transmembrane resistance is high, hence current flows more longitudinally vs. transmembrane capacitance flow or ionic channel resistance flow
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Slow process
• Longitudinal AP spread requires sequential depol. to threshold, membrane capacitor discharge and then alteration of proteins to turn on Na activation channels. This process can be slow.
• Hence unmyelinated nerve conducts slowly = 10-15 m/sec.
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Need velocity to interact with environment!
• longitudinal resistance will speed – diameter will resistance
• Eliminate need to fire all surrounding tissue will velocity of conduction– Insulate nerve to prevent leakage,
spread out the gated Na channels• Myelin & Nodes of Ranvier
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Myelin
• All peripheral nerve axons surrounded by plasma membrane of a Schwann cell– Single layer of membrane =
unmyelinated nerve, multiple layers = myelinated nerve
– Gap between Schwann cell covers = node of Ranvier
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Myelinated axons
• Outer myelin sheath + axon plasma membrane = axolemma covering axoplasm
• Schwann cell membrane has lipid sphingomyelin, highly insulating
• No Na channels under myelin, only at nodes. K channels under myelin in perinodal area
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Current conduction with myelin insulation
• AP at node, Na charge influx and current spreads longitudinally down axon
• Minimal leak between nodes, reduced by 5000 vs. unmyelinated nerve– Charge separation, reduced protein leak
channels & increased membrane resistance account for this
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Current conduction
• Circuit is closed by efflux of ionic current at node
• Na ions accumulate beneath node, reduces electrochemical pull on ECF Na above node, they migrate back to upstream node to close loop
• Above tends to increase + charge inside membrane or depolarize to give AP
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AP generation at node
• Nodes contain high # Na channels which open with depolarization– Na influx starts process again
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Myelin effects
• Conduction velocity increases• Current and action potential jumps
from node to node = saltatory conduction
• Optimal internodal length is 100x axon diameter
• Optimal myelin/axon ratio is 60/40
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Neuromuscular junction, transducing the electrical signal to mechanical force
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Multiple branches from large motor axons
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What happens if varying myelin and diameter in branches?
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NMJ anatomy
• Presynaptic– Terminal axon
sprout• Mitochodria• Synaptic vesicles =
ACH
– Presynaptic membrane
• Postsynaptic– Motor endplate
• Single muscle fiber• Mitochondria• Ribosomes• Pinocytotic vesicles• Postsynaptic
membrane– ACH receptors
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NMJ Electrochemical conduction
• Considerable slowing in smaller diam less myelinated branches
• AP depolarizes terminal axon, Na conductance increases– Calcium conductance also
dramatically increased– Influx Ca++ in terminal axon
• Possibly facilitates fusion of ACH vesicles with presynaptic membrane
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Electrochemical conduction….
• Vesicular fusion with presynaptic membrane
• Open to synaptic cleft, release quantum of ACH– 100 vesicles per AP in mammals, 10k ACH
per vesicle
• Ca++ stays in terminal axon 200 ms, keeps axon readily excitable for repeat stimulation
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ACH release• Rapid diffusion across cleft in .5
msec timing, bind receptors– Large transmembrane proteins with ACH
site and ion channel– Ligand activated vs. voltage activated
• ACH binding induces conformational change in ion channel– 1 ms opening of cation specific channel
= Na, K, Ca, repels anions with charge
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Postsynaptic ion channel opening with ACH binding
• Predominant influx is Na, K blocked by electrochem gradient, Ca concentration gradient not that large
• Na influx locally depolarizes muscle membrane= endplate potential reversal which is not propagated = EPP– Single packet of ACH from vesicle gives
MEPP
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Muscle action potential
• Generated if sufficient ACH released to cause postsynaptic membrane to reach threshold, muscle membrane depolarized and propagated impulse follows
• Muscle AP travels along muscle membrane = sarcolemma– Similar to nerve, increased Na
permeability in + feedback loop
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T-tubules• Small volume favors K
accumulation during repolarization after AP, tends to make membrane easy to depolarize again
• Penetrate into muscle to spread AP into fiber
• High surface area of T-tubules increases capacitance qualities and slows conduction in muscle
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Excitation-Contraction
• AP in T-tubule induces Ca++ release in SR terminal cisternae, exposure for 1/30 sec, then reuptake via pump
• Ca++ bind to troponin C, induces conformational change of troponin complex and influences tropomyosin to actin relationship - mechanical force
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The End!