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!