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Nerve & Muscle Physiology
• Jeff Ericksen, MD– VCU Health Systems PM&R
Topics *
• Relevant anatomy• Cell functions for signal
transmission– Transport, resting potential, action
potential generation & propagation– Neuromuscular transmission– Muscle transduction
• Volume Conductor theory
Acknowledgements
• Electrodiagnostic Medicine by Daniel Dumitru, MD– Chapter 1: Nerve and Muscle
Anatomy and Physiology
• Superb text covering all aspects of EMG/NCS
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
Cell membrane
• Provides structure for cell• Modulates cell interaction with
environment– Mechanical, hormone-receptor
• Controls material flow into/out of cell – Nutrition/waste management
3 Key Membrane Components
• Lipids 45-49%– phospholipids, cholesterol &
glycolipids = amphipathic molecules• Polar = hydrophilic vs. nonpolar =
hydrophobic
• Proteins 45-49%• Carbohydrates 2-10%
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
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
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
Proteins
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
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
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
Membrane transportCarrier proteins
Energy
Channel protein
Simple diffusion Facilitateddiffusion
Diffusion Active transport
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
Active transport
• Transmembrane carrier protein uses ATP energy to pump ions against concentration gradient to develop transmembrane resting potential
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
Resting membrane potential created by semi-permeable membrane and
ions• Intracellular
– Na 50– K 400– Cl 52
• Extracellular
– 440– 20– 560
http://www.bioanim.com/CellTissueHumanBody6/O3channels/ionCloudPoints1ws.wrl
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
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
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
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
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!
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
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
Voltage gated channels
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
http://www.bioanim.com/CellTissueHumanBody6/O3channels/naChan1ws.wrl
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
Action potential timing
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
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
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
Nerve membrane modeling
• Resistor = direct path to current flow but with some impedance
• Nerve axon has both transmembrane resistance as well as longitudinal resistance
Current spread
• Membrane capacitor model suggests transmembrane resistance is high, hence current flows more longitudinally vs. transmembrane capacitance flow or ionic channel resistance flow
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.
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
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
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
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
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
AP generation at node
• Nodes contain high # Na channels which open with depolarization– Na influx starts process again
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
Neuromuscular junction, transducing the electrical signal to mechanical force
Multiple branches from large motor axons
What happens if varying myelin and diameter in branches?
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
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
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
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
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
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
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
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
The End!
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