Integration Lecture 2: Neuromuscular Diseases Contact Info: office: Ina Gittings Building, room 3A email: [email protected] phone: 621-0733 Office Hours: By appointment MJ Ramirez Human Anatomy & Physiology I (PSIO201) Fall 2015SI Integration Session on December 13th! Looking for an opportunity to practice applying and integrating the concepts that you have been learning all semester? Come join your peers at our last, final exam integration session on Sunday, December 13th, from 3:00-5:00 pm in the Javelina Room at Park Student Union for a cumulative, application-based session involving fun, collaboration with your fellow classmates and engaging group activities! We hope to see you all there & good luck with your final exams!Integration Lecture 2 Objectives 1) Apply knowledge gained in this course to physiological scenarios / problems 2) Integrate information across organ systemsVoluntary muscle movementKey Features of Neuromuscular Function • Action potential travels along axon of motor neuron to the presynaptic terminal on the muscle fiber. • Depolarization of terminal opens calcium channels to trigger release of acetylcholine (Ach). • Acetylcholine binds to nicotinic Ach receptors on muscle. Excess is destroyed by acetylcholinesterase. • Binding of Ach to receptors opens ligand gated sodium channel to cause large muscle depolarization (EPSP), which invariably triggers muscle action potential in healthy individual. • Action potential triggers calcium release from sarcoplasmic reticulum (SR), which allows sliding of actin/myosin filaments due to cross bridges. • The latter is dependent on ATP, as is subsequent sequestering of calcium back into SR.Problem #1 Preliminary diagnosis • Patient presents with muscle weakness • Difficulty standing up from seated position or lifting objects • Decreased stretch reflex • Minor atrophy (loss) of muscle tissueMajor Classes of Neuromuscular Disease • Motor neuron transmission failure (e.g. Amyotrophic Lateral Sclerosis or Multiple Sclerosis) • Efferent action potentials fail to reach synaptic terminal, either due to motor neuron degeneration or loss of myelin on axons • Neuromuscular transmission failure (e.g. Lambert Eaton Syndrome or Myasthenia Gravis) • Motor neuron action potential arrives at neuromuscular junction but fails to cause sufficient muscle excitation • Myopathies (e.g. Muscular Dystrophy or McArdle’s Myopathy) • Skeletal muscle weakness, defects in muscle proteins, loss of muscle fibers. • An inherited metabolic disorder in which genes encoding enzymes that aid in glucose metabolism are mutatedDiagnostics The conduction velocity of the nerve is within the normal range. (45-70 m/s) https://youtu.be/xTHiqR45T8YDiagnostics Interestingly, muscle contracts when fiber is stimulated directly with electric shock. https://youtu.be/lXtB_PqVHlYWhich class of neuromuscular disease is suffered by our patient? A. Motor neuron transmission failure B. Neuromuscular transmission failure C. Myopathies A. B. C.17%59%24%Motor Neuron Muscle Problem #2: What is the specific problem with patient’s neuromuscular synaptic transmission?Lambert Eaton Syndrome: • Autoimmune disorder in which the body produces antibodies against voltage-gated calcium channels in its own presynaptic terminals. • This results in decreased release of Ach from presynaptic terminals, failure to cause an action potential in the muscle fiber and, therefore, muscle weakness. Myasthenia Gravis: • Autoimmune disorder in which the body produces antibodies against nicotinic Ach receptors at its own neuromuscular junctions. • This results in failure of Ach to open enough ligand-gated channels in postsynaptic membrane, failure of muscle action potential and, therefore, muscle weakness.Diagnostics https://youtu.be/OA7gIFMzr2c• Acetylcholinesterase inhibitors are drugs such as neostigmine, physostigmine or endrophonium. • In our patient, muscle activation is restored when acetylcholinesterase is blocked by a drug. https://youtu.be/JPBCgQlrypkDoes the patient suffer from Lambert Eaton or Myasthenia Gravis? A. Lambert Eaton Syndrome B. Myasthenia Gravis A. B.66%34%Sydney Funnel Web Spider • Australia • One of the deadliest spiders in the worldCareful where you stepBased upon the initial description of symptoms, which divisions of the nervous system are being affected most by the Funnel-Web Spider (FWS) venom? A. Somatic NS and Parasympathetic B. ANS C. Enteric NS and Sympathetic D. Somatic NS, ANS, and Enteric NS E. ANS and Enteric NS A. B. C. D. E.25%11%43%13%8%Why is the answer that these symptoms reflect the output of both branches of the ANS? 1. Atracotoxin is triggering action potentials in all axons it reaches, and most tissues are innervated by both branches of the ANS. 2. Uncontrolled sympathetic output would explain excessive sweating, heart palpitations, and hypertension (high blood pressure) leading to excess fluid (edema) in the lungs. 3. Uncontrolled parasympathetic output explains excessive salivation and lacrimation (tearing).The FWS venom has only one protein target found in the nervous system. What could the protein target possibly be that it would result in such a huge variety of nervous system effects?The toxin enhances the function of a single protein. Which protein target might be a candidate for such a huge variety of nervous system effects? A. ACh-gated sodium channel B. Potassium leak channel C. Sodium-potassium ATPase D. Voltage-gated sodium channel A. B. C. D.21%42%27%10%About FWS Venom • Contains an excitatory toxin called atracotoxin or ACTX • ACTX is an excitatory toxin that binds to voltage-gated sodium channels. • In mammals, ACTX does two things: 1. Prolong the action potential by generating a plateau of depolarization lasting up to 100ms. 2. Cause spontaneous repetitive firing of action potentials, with increasing frequency (starting at ~1 per second).In 1981, was there Any Treatment for Severe Envenomation by the Australian Funnel-Web Spider? • Yes. Antivenom had just been approved for use in local hospitals, the culmination of a lifetime of work by Dr. Struan Sutherland. • After receiving 4 ampules from the very first batch of antivenom, George Wheatley was rescued from certain death. “If it hasn’t killed him, just give him some more.” These were Dr. Struan Sutherland’s instructions concerning Gordon Wheatley, the first recipient of