Neuromuscular System I PDF

Neuromuscular System I P T 8 2 0 2 , A P P L I E D P H Y S I O LO GY Objectives Membrane potentials and action potentials Skeletal muscle structure and contraction Neuromuscular Domains Fiber Types...

Neuromuscular System I P T 8 2 0 2 , A P P L I E D P H Y S I O LO GY Objectives Membrane potentials and action potentials Skeletal muscle structure and contraction Neuromuscular Domains Fiber Types EC Motor Couplin Units g Neuromuscul ar Health/Functi on Force Structu Generatio re n Bioenergetic Signaling s properties Membrane Potentials and Action Potentials Review….. Net diffusion rate depends on: Membrane permeability Concentration gradient: From higher to lower concentration Electrical potential gradient: Away from like charge, toward opposite charge Pressure gradient Membrane Potentials Electrical potentials exist across the membranes of virtually all cells of the body Some cells generate rapidly changing electrochemical impulses at their membranes These impulses are used to transmit signals along the nerve or muscle membranes The potential difference between the inside and outside is the diffusion potential The diffusion potential across a membrane that exactly opposes the net diffusion of a particular ion through the membrane is called the Nernst potential for that ion Magnitude of Nernst is determined by ratio of specific ions on two sides of membrane – bigger the ratio more likely you will have movement Don’t worry about any calculations Diffusion Potentials Membrane potentials are caused by [ion] differences (i.e., concentration gradient) across selectively permeable membranes Concentration of potassium [K+] is greater inside nerve cell vs outside Concentration of sodium [Na+] is greater outside nerve cell vs inside Diffusion Potentials – K+ Let us assume that the membrane in this case is permeable to the potassium ions but not to any other ions Large [K+] gradient from the inside toward the outside, there is a strong tendency for potassium ions to diffuse outward through the membrane They carry positive electrical charges to the outside, thus creating electro-positivity outside the membrane and electronegativity inside the membrane The potential difference between the inside and outside, called the diffusion potential, becomes great enough to block further net potassium diffusion to the exterior The potential difference is about -94 millivolts, with negativity inside the fiber membrane Diffusion Potentials – Na+ Let us assume that the membrane in this case is permeable to the Na ions but not to any other ions Large [Na+] gradient from the outside toward the inside, there is a strong tendency for Na ions to diffuse inward through the membrane They carry positive electrical charges to the inside, thus creating electropositivity inside the membrane and electronegativity outside the membrane The potential difference is about 61 millivolts, with negativity outside the fiber membrane Resting membrane potential Concentration difference of ions across a selectively permeable membrane can, under appropriate conditions, create a membrane potential Many of the rapid changes in membrane potentials observed during nerve and muscle impulse transmission result from rapidly changing diffusion potentials There is a period of dormancy in which a resting membrane potential can be measured Resting membrane potential changes in response to various stimuli which alters activities for various ion transporters, ion channels, and membrane permeability for sodium, potassium, calcium, and chloride ions Only a brief transient state for many cells  Resting membrane potential The resting membrane potential varies depending on the cell type Maintaining resting membrane potential is dependent on Potassium diffusion – potassium is highly permeable (100 times greater than sodium) Sodium diffusion Sodium-Potassium Pump Additional contributions from chloride ions Resting membrane potential There is 100× more K+ leak channels compared to Na+ leak channels – simple diffusion along the gradient The sodium potassium pump -the pumping of more sodium ions out of the cell then potassium ions into the cell causes a continual loss of positive charge from inside the membrane So how does resting membrane potential change? Action potentials The means by which nerve signals are transmitted Rapid changes of membrane potential that propagates along the nerve fiber membrane to the end Each action potential begins with a sudden change from the normal resting negative membrane potential to a positive potential and ends with an almost equally rapid change back to the negative potential Action potentials Stages Resting stage: the resting membrane potential before the action potential begins Depolarization stage: rapid increase in permeability to Na+ from outside to inside, which may overshoot neutral (zero) in select nerve fibers -the potential rising rapidly in the positive direction Repolorization stage: Na+ channels close and K+ channels increase opening, allowing K+ to rapidly diffuse out to reestablish resting potential Voltage-gated sodium and potassium channels heavily influence this change in polarity during depolarization & repolarization  Voltage-Gated Channels - Sodium Voltage-gate sodium channels have 2 gates and 3 separate states: Activation gate closed at resting potential During activation (approx. -55mV) conformational change opens activation gate ↑ permeability of Na+ into the cell (500- 5,000x) Conformational change closes inactivation gate Inactivation gate remains closed until membrane returns to/near resting potential Voltage-Gated Channels - Potassium Slow activation gate closed at resting potential During depolarization, undergoes conformational change, opens slow activation gate ↑ permeability of K+ Voltage-Gated Channels Potassium conductance increases only about 30- fold during the latter stages of the action potential and for a short period thereafter Sodium conductance increases several thousand–fold during the early stages of the action potential Resting state: Conductance for K+ is 50-100x as great as conductance for Na+ Depolarization: Sodium channels instantaneously activate (open) Repolarization: Sodium channels inactivate (close) and voltage gated potassium channels open. Once the membrane potential has returned to -90 mV, potassium channels close. hieving and propagating an action potential May be initiated by mechanical, chemical, or electrical stimulus! Requires that depolarization (e.g., Na+ influx > K+ outflow) reaches a certain threshold (e.g., 15-30 mV) to set the sodium channel positive feedback cycle in motion Once achieved in one location, adjacent positions on the membrane usually follow Depoloraization continues in an all-or-nothing fashion along the length of the axon (nerve impulse), unless sufficient voltage is not achieved at some point Following impulse transmission, the resting potential is re-established via the sodium-potassium pump, which ↑ activity when intracellular [Na+] ↑ Propagating an action potential An AP elicited in one location, means adjacent positions on the membrane usually follow Current flows from the depolarized area of the membrane to the adjacent areas Positive charges are carried by inward-diffusing sodium ions through the membrane and then for several millimeters in both directions These positive charges increase the voltage for a distance of 1 to 3 millimeters inside large myelinated fibers to above the voltage threshold Therefore, sodium channels in these new areas immediately open and the AP spreads The trigger for an action potential can differ in different cells…  Refractory Period A refractory period occurs when a new action potential cannot be elicited because the membrane is still depolarized from the prior AP Resting potential must be re-established to allow for re-opening of the inactivation gate of the sodium channels that closed due to depolarization - Refractory periods limit the maximum frequency of APs An absolute refractory (ARP) period is when another AP cannot be elicited regardless of stimulus magnitude (e.g., 1/2,500th sec) Relative refractory period (RRP)— greater than normal stimulus required to  Signal Transmission Schwann cells surround the nerve axon forming a myelin sheath Multiple layers of cell membrane with lipid substance sphingomyelin to insulate Saltatory conduction occurs as the impulse is transmitted node to node – node of Ranvier Can incease conduction velocity by 5-50x and reduce demand for re-establishing resting potential Saltatory Conduction Saltatory conduction: APs are conducted from node to node. This has 2 main benefits: Increases the velocity of nerve transmission 5 to 50-fold. Conserves energy Conduction Velocity Clinical Application – Multiple Sclerosis MS is an immune-mediated inflammatory demyelinating disease of the CNS Patients have a difficult time describing their symptoms Patients may present with paresthesias of a hand that resolves, followed in a couple of months by weakness in a leg or visual disturbances Impacts function and strength over time Skeletal Muscle Structure Skeletal Muscle Structure Entire muscle Surrounded by epimysium Consists of many bundles (fasciculi) Fasciculi Surrounded by perimysium Consists of individual muscle cells (muscle fibers) Muscle fiber Surrounded by endomysium Consists of myofibrils divided into sarcomeres (German for small boxes!) Skeletal Muscle Structure Fibers usually extend the length of the muscle Fibers range from approximately 10- 80 micrometers (diameter) Fibers usually interface with a single nerve ending (middle of the muscle) Every muscle is composed of muscle fibers Each muscle fiber is composed of 100s to 1000s of myofibrils Structure of a Single Muscle Fiber Myofibrils Myofibrils Muscle  fasciculi  muscle fiber  myofibril Contractile element of skeletal muscle threadlike structures that contain contractile proteins; myosin & actin give the muscle cell a striated appearance - myofibrils have light and dark bands I bands (light): contain only actin A bands (dark): contain myosin and ends of actin Sarcoplasm The many myofibrils of each muscle fiber are suspended side by side in the muscle fiber. The spaces between the myofibrils are filled with intracellular fluid called sarcoplasm Sarcoplasmic reticulum longitudinal network of channels surrounding myofibril storage sites for calcium Transverse tubules (T tubules) run perpendicular through the muscle fiber Permit nervous impulse to penetrate to myofibrils Terminal cisternae Enlarged portions of the sarcoplasmic reticulum T tubules pass between two terminal cisternae Sarcomere The smallest functional unit of a muscle fiber Each myofibril composed of numerous sarcomeres joined end to end at z lines Each sarcomere includes An I band (light zone) An A band (dark zone) An H zone (in the middle of the A band and contains no actin) An M line (bisects the H zone and delineates the center of the sarcomere Sarcomere sarcomere Titin The side-by-side relationship between actin and myosin filaments is maintained by titin, a filamentous molecule. The springy titin molecules act as a framework that holds myosin and actin filaments in place, so the contractile machinery of the sarcomere will work Sarcomere: Protein Filaments Used for muscle contraction Myosin Thick filament Comprises about 60% of muscle protein Approximately 1500 myosin filaments in each myofibril Appears dark on scope Actin Thin filament Approximately 3,000 actin filaments per myofibril Also contains two additional proteins: troponin and tropomyosin Appears lighter on scope Myosin (Thick Filaments) Each myosin molecule is composed of 6 polypeptide chains: 2 heavy chains and four light chains Two intertwined filaments with globular heads Globular heads The myosin filament is twisted so each successive pair of cross-bridges is axially displaced from the previous pair by 120° Will interact with actin filaments for contraction Actin (Thin Filaments) Actually composed of different proteins F-Actin molecule: composed of G-actin molecules Actin filament: comprised of double-stranded F-actin molecule base inserted into Z-disks Tropomyosin: wrapped spirally around sides of F-actin helix at rest, lie on active sites of actin strands (inactive) tropomyosin structural change uncovers the active sites (active) Troponin: protein complex of 3 subunits, each with a role; troponin I: strong affinity for actin troponin T: strong affinity for tropomyosin troponin C: strong affinity for Ca2+ ions Actin & Myosin Relationship Sliding Filament Mechanism Muscle contraction occurs by a sliding filament mechanism. Relaxed: Ends of the actin filaments extending from two successive Z disks barely overlap Contracted: actin filaments have been pulled inward along the myosin filaments, so their ends overlap one another. The Z disks have been pulled by the actin filaments up to the ends of the myosin filaments Forces generated by cross bridges cause the actin filaments to slide inward among the myosin filaments. When an AP travels along the muscle fiber, the sarcoplasmic reticulum releases calcium ions that surround the myofibrils The calcium ions activate the forces between the actin and myosin filaments and contraction begins Energy, in the form of ATP is required for the contractile process Skeletal muscle structure: sliding filament mechanism (walk-along theory, ratchet theory) “Before contraction can take place, the inhibitory effect of the troponin-tropomyosin complex must itself be inhibited.” 1. Head of crossbridge binds with ATP 2. ATP-ase activity of the head cleaves ATP (leaves products attached) 3. Conformational change extends head toward actin 4. Ca2+ attachment to troponin C 5. Leading to troponin complex conformational change 6. Exposing actin active sites tropomyosin moves out of way 7. Myosin head attaches to active site 8. Change in intramolecular forces 9. Head tilts toward the arm, pulling actin filament (power stroke) via energy earlier stored by ATP cleavage 10.Head tilt frees earlier cleavage products (ADP + Pi) 11.Head binds new ATP molecule, causing The Sliding Filament Model  8. Myosin head reattaches to a different actin- myosin binding site 7. An ATP molecule binds to the myosin head, providing enough energy to break the bond 6. Actin is pulled past the myosin, This is called power stroke 3. Actin-myosin binding sites 4. Myosin heads 5. Head tilt frees 1. An action are exposed. The calcium earlier cleavage 2. Calcium bind with the ions bind to a protein potential crosses channels on tropomyosin, changing actin-myosin products (ADP + Pi) the neuromuscular open the shape of the protein binding sites junction moves the tropomyosin and exposes the binding sites And breath….. S E E YOU ON FR IDAY QU IZ C LOS E S T ODAY – ON C E S TA RT E D ON LY 15 M IN U T E S T O F I N IS H