The Cyprus International Institute for the Environment and Public Health In collaboration with the Harvard School of Public Health Somatic Nervous System Lecture 5 • Consists of axons of motor neurons • Originate in spinal cord or brain stem and end on skeletal muscle • Motor neuron releases neurotransmitter, ACh Neuromuscular Physiology • Stimulates muscle contraction (240-249, 253-267,270-286,288-297) • Motor neurons = final common pathway • Various regions of CNS exert control over skeletal muscle activity Excluded: muscle length, tension, contraction and velocity, • Spinal cord, motor regions of cortex, basal phosphorylation of myosin nuclei, cerebellum, and brain stem • Pathologies • Polio virus destroys the cell bodies of motor neurons • Amyotrophic Lateral Sclerosis (ALS) Constantinos Pitris, MD, PhD • A.k.a. Lou Gehrig’s Disease • Most common motor neuron disease Assistant Professor, University of Cyprus • Gradual degeneration of motor neurons [email protected] • Unknown cause http://www.eng.ucy.ac.cy/cpitris/courses/CIIPhys/ 2 Somatic Nervous System Muscle • Comprises largest group of tissues in body • Skeletal (30-40% BW), smooth and cardiac (10% BW) Striated Unstriated • Controlled muscle contraction allows muscle muscle • Purposeful movement of the whole body or parts of the body • Manipulation of external objects • Propulsion of contents through various hollow internal organs • Emptying of contents of certain organs to external environment Skeletal Cardiac Smooth • Three types of muscle muscle muscle muscle • Skeletal muscle • Make up muscular system • Cardiac muscle • Found only in the heart • Smooth muscle • Appears throughout the body systems as Voluntary Involuntary components of hollow organs and tubes muscle muscle • Classified in two different ways • Striated or unstriated • Voluntary or involuntary 3 4 Structure of Skeletal Muscle Neuromuscular Junction • Muscle consists a number of • Axon terminal of motor Tendon muscle fibers lying parallel to Muscle neuron forms one another and held together Connective neuromuscular junction tissue by connective tissue Muscle fiber with a single muscle cell (a single • Single skeletal muscle cell is muscle cell) • Terminal button (of neuron) known as a muscle fiber • Motor End Plate (of muscle • Multinucleated cell) • Large, elongated, and cylindrically shaped • Fibers usually extend entire length of muscle Muscle fiber Dark A band Light I band Myofibril 5 6 Neuromuscular Junction Neuromuscular Junction • Signals are passed between • Acetylcholinesterase nerve terminal and muscle fiber by means of neurotransmitter Action potential • On the chemically-gated cation propagation ACh Myelin sheath in motor neuron channels of the end plate • AP in motor neuron reaches Voltage-gated • Inactivates ACh (as ACh terminal calcium channel Axon 2+ terminal • Voltage-gated Ca channels open Vesicle of acetylcholine molecules attaches and • ACh is released by exocytosis detaches from the receptors) Terminal button • ACh diffuses across the space and • Ends end-plate potential and the binds to receptor sites on motor end Action potential propagation action potential plate of muscle cell membrane in muscle fiber • Binding triggers opening of cation • Ensures prompt termination of channels in motor end plate contraction •Na+ movements (larger than K+ movements) depolarize motor end Voltage-gated plate, producing end-plate potential Na+ channel • Local current flow between depolarized end plate and adjacent Acetycholinesterase Motor end plate muscle cell membrane brings Acetylcholine adjacent areas to threshold receptor site Contractile elements • Action potential is initiated and Chemically gated within muscle fiber propagated throughout muscle fiber cation channel 7 8 Neuromuscular Junction Structure of Skeletal Muscle Z line A band I band • Neuromuscular junction is vulnerable to chemical agents and diseases • Myofibrils Portion • Black widow spider venom • Contractile elements of muscle fiber of myofibril • Causes explosive release of ACh • Viewed microscopically myofibril • Prolonged depolarization keeps Na+ channels at inactive state displays alternating dark (the A M line H zone • Respiratory failure from diaphragm paralysis bands) and light bands (the I bands) Thick filament Sarcomere • Botulism toxin giving appearance of striations Thin filament A band I band • From food infected with Clostridium Botulinum Æ Botulism • Blocks release of ACh • Regular arrangement of thick and • Respiratory failure from inability to contract diaphragm thin filaments • Thick filaments – myosin (protein) • Curare Cross M line H zone Z line • Poisonous arrowheads • Thin filaments – actin (protein) bridges • Binds at ACh receptor sites but has no activity and is not degrated • Organophosphates • Sarcomere • Pesticide and military nerve gases • Functional unit of skeletal muscle • Prevent inactivation of Ach by inhibiting AChE Myosin Actin • Found between two Z lines • Effect similar to Black widow spider venom Thick filament Thin filament • Z lines connect thin filaments of two • Myasthenia gravis inactivates ACh receptor sites Cross bridge adjoining sarcomeres • Autoimmune condition (Antibodies against ACh receptors) • ACh is degraded before it can act. • Antidote is neostigmine (inhibits AChE and prolongs ACh action) Thick filament 9 10 Thin filament Structure of Skeletal Muscle Myosin Z line A band I band • Titin • Component of thick filament Myosin molecule Portion • Several hundred of them • Giant, highly elastic protein of myofibril Actin binding site • Protein molecule consisting of Myosin ATPase site • Largest protein in body M line H zone two identical subunits shaped Heads • Extends in both directions from Thick filament Sarcomere somewhat like a golf club Tail along length of thick filament to Thin filament A band I band • Tail ends are intertwined around Z lines at opposite ends of each other sarcomere • Globular heads project out at one end • Two important roles: Cross M line H zone Z line • Tails oriented toward center of bridges Thick filament • Helps stabilize position of thick filament and globular heads filaments in relation to thin protrude outward at regular Cross bridge filaments intervals Myosin molecule • Greatly augments muscle’s Myosin Actin • Heads form cross bridges between elasticity by acting like a spring Thick filament Thin filament thick and thin filaments • Cross bridge has two important sites Cross bridge critical to contractile process • An actin-binding site • A myosin ATPase (ATP-splitting) site Thick filament 11 Thin filament 12 Actin Tropomyosin and Troponin • Primary structural component of • Often called regulatory thin filaments proteins • Spherical in shape Binding site for Binding site for attachment • Tropomyosin attachment • Thin filament also has two other with myosin with myosin proteins Actin molecules cross bridge • Thread-like molecules that lie Actin molecules cross bridge • Tropomyosin and troponin end to end alongside groove of • Each actin molecule has special actin spiral binding site for attachment with Actin helix • In this position, covers actin Actin helix myosin cross bridge sites blocking interaction that + + • Binding results in contraction of leads to muscle contraction muscle fiber • Troponin • Actin and myosin are often called contractile proteins. Neither Tropomyosin Troponin • Made of three polypeptide units Tropomyosin Troponin actually contracts. • One binds to tropomyosin • Actin and myosin are not unique • One binds to actin to muscle cells, but are more • One can bind with Ca2+ abundant and more highly organized in muscle cells. Thin filament Thin filament 13 14 Tropomyosin and Troponin Sliding Filament Mechanism • Troponin • Thin filaments on each side of • When not bound to Ca2+, sarcomere slide inward troponin stabilizes tropomyosin Thin filament • Over stationary thick filaments in blocking position over actin’s • Toward center of A band Tropomyosin cross-bridge binding sites Cross-bridge binding sites • They pull Z lines closer together Actin • When Ca2+ binds to troponin, • Sarcomere shortens Relaxed tropomyosin moves away from Cross-bridge binding site • All sarcomeres throughout muscle Tropomyosin blocking position Actin binding site fiber’s length shorten simultaneously Myosin cross bridge Excited Sarcomere • Contraction is accomplished by thin A band • With tropomyosin out of way, Z line H zone I band Z line actin and myosin bind, interact Troponin filaments from opposite sides of each sarcomere sliding closer Relaxed at cross-bridges together between thick filaments • Cross-bridge interaction 2+ • Ca plays a key role A band H zone I band same between actin and myosin 2+ shorter shorter • Increase in Ca starts filament width brings about muscle contraction sliding by means of the sliding filament • Decrease in Ca2+ turns off sliding Contracted mechanism process 15 16 Sarcomere shorter Thick filament Thin filament Power Stroke Power Stroke • Activated cross bridge bends • Contraction toward center of thick filament, continues if ATP is 2+ “rowing” in thin filament to which available and Ca it is attached level in sarcoplasm is high • Sarcoplasmic reticulum releases Ca2+ into sarcoplasm • Myosin head remains Energized Resting • Myosin heads bind to actin attached until ATP • Myosin heads swivel toward center binds Æ rigor mortis of sarcomere (power stroke) •Ca2+ released • ADP released • ATP quickly depleted Detachment Binding • ATP binds to myosin head and • Onset in a few hours detaches it from actin • Can last 1-2