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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 transport Carrier proteins Channel protein Simple diffusion Diffusion Facilitated diffusion Energy 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/Cell TissueHumanBody6/O3chann els/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/Cell TissueHumanBody6/O3chann els/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!