Neuromuscular Transmission & Myasthenia Gravis PDF

Neuromuscular transmission Dr. Hader I. Sakr Associate professor, Medical Physiology Learning objectives: Physiology of skeletal muscles. Neuromuscular transmission as regard: Definition. Properties. Characters. Myasthenia gravis. Physiology of skeletal muscles  Physiology of skele...

Neuromuscular transmission Dr. Hader I. Sakr Associate professor, Medical Physiology Learning objectives: Physiology of skeletal muscles. Neuromuscular transmission as regard: Definition. Properties. Characters. Myasthenia gravis. Physiology of skeletal muscles  Physiology of skeletal muscles - Muscle is a tissue that shortens and develops tension so that movement is brought about. - Approximately 40 % of the body is skeletal muscles, and almost another 10 % is smooth and cardiac muscles. Skeletal Muscles: - The skeletal muscles are attached to the bones. - The human body contains over 400 voluntary skeletal muscles; their contraction depends upon their nerve supply.  Physiology of skeletal muscles - Skeletal muscle performs four major functions: 1. Static force production for maintaining posture and stabilizing joints. 2. Kinetic force production for locomotion and breathing. 3. Heat production. 4. Help venous drainage. Physiology of skeletal muscles  Physiology of skeletal muscles The Muscle Proteins; A) Myosin Protein: - These heads contain an actin-binding site, ATP binding site, and a catalytic site that hydrolyzes ATP (myosin ATPase). - Also, part of the helix extends to the side with the head to form an arm (neck). - The arms and heads are called together cross-bridges.  Physiology of skeletal muscles - The cross-bridges are believed to be flexible at two points called hinges: one hinge where the arm leaves the body of the myosin filament, and the second where the two heads attach to the arm.  Physiology of skeletal muscles B) The Thin Filament Proteins: - Each thin filament contains 300-400 actin molecules. - Each actin molecule has a specific myosin cross-bridge binding site [active sites], ATP binding site, and a catalytic site that hydrolyzes ATP (actomyosin ATPase)  Physiology of skeletal muscles - Tropomyosin molecules (40-60/filament) are long filaments located in the groove between the 2 chains of actin. - The tropomyosin strands cover the active sites on the actin under resting conditions → combination between the actin and myosin cannot take place to cause muscular contraction. - Troponin molecules are small globular units located at intervals along the tropomyosin molecules. Troponin molecule is formed of three globular protein molecules: 1- Troponin-I has a strong affinity for actin and binds with it to inhibit actomyosin ATPase activity. 2- Troponin-T has a strong affinity for tropomyosin and binds with it. 3- Troponin-C has strong affinity to Ca2+.  Physiology of skeletal muscles Tubular System: Two tubular networks are present in skeletal muscle fibers. 1) The Transverse (T) Tubule is formed as an invagination of the surface of the sarcolemma. - In mammalian skeletal muscle, the T tubules are located at the junction of the A and I bands. - An AP spreading over the surface of the sarcolemma is propagated into the network of T tubules. - The space of the T tubules contains ECF.  Physiology of skeletal muscles Tubular System:  Physiology of skeletal muscles 2) The Sarcoplasmic Reticulum (SR): is the ER of the muscle fiber that surrounds each myofibril & run parallel with it. - The SR has a high [Ca+2], which is used to initiate muscle contraction when the muscle is stimulated. - The ends of the SR expand to form terminal cisternae (TC), which make specialized contacts with T tubules on either side of sarcomere, at the junction between A and I bands (triad). - Small projections (foot processes) span the 200 Ao separating the two tubular membranes. - The SR membrane contains a protein called the ryanodine receptor that contains the foot process and a Ca+2 release channel. - The T-tubule membrane contains a voltage - sensitive dihydropyridine (DHP) receptor that opens the ryanodine Ca2+ release channel on the SR. Neuromuscular junction  Neuromuscular junction - A contraction of the whole muscle is produced by large numbers of muscle fibers undergoing the contractile process at the same time. - An action potential spreading throughout the membrane of the muscle fiber normally results from a nerve impulse arriving at the neuromuscular junction. Neuromuscular Transmission (NMT): This means transmission of impulses from alpha motor neuron (αMN, LMN) to the skeletal muscle fibers.  Neuromuscular junction Physiologic Anatomy of Neuromuscular Junction - The αMN branches as it approaches the muscle, sending axon terminals (end feet) to several skeletal muscle fibers. - Each skeletal muscle fiber receives only one axon terminal containing acetylcholine (Ach) vesicles. - The nerve ending fits into depression in the muscle membrane that is thickened and called motor end plate (MEP).  Neuromuscular junction Physiologic Anatomy of Neuromuscular Junction - MEP is rich in Ach receptors and contains numerous junctional folds (depressions in the MEP). - An average human MEP contains about 15 to 40 million ACh receptors. - The extracellular space between the nerve terminals & muscle membrane is called Synaptic cleft and is occupied by connective tissue called basal lamina, to which the enzyme acetylcholinestrase (ACHEase) is bound.  Neuromuscular junction Sequence of Events During Neuromuscular Transmission: - AP reaches the nerve ending → opening of voltage-gated Ca+2 channels. - Ca+2 influx into the nerve terminals → binds to Calmodulin → activates CaM kinases (I & II) → the ACh vesicles fuse with the membrane → empty their contents by exocytosis - Each nerve impulse releases A.Ch from about 60 synaptic vesicles (each vesicle contains 2000 to10,000 A.Ch molecules). - The ACh diffuses to the muscle→ binds to its receptor in the MEP (ligand – gated) channels.  Neuromuscular junction Sequence of Events During Neuromuscular Transmission: - Channels opening increases Na+ and K+ conductance of the membrane. - The amount of Na+ entering the cell exceeds the amount of K+ leaving the cell → the cell depolarizes → end-plate potential (EPP). - The EPP is a graded, non -propagated response → depolarizes the adjacent muscle membrane to its firing level → APs are generated on either side of the MEP → conducted away in both directions along the muscle fiber → initiate muscle, contraction. - ACh is degraded rapidly after binding to the ACh receptor by AChEase in the synaptic cleft. - Degradation of ACh is necessary to prevent it from causing multiple muscle contractions. Properties of Neuromuscular Transmission  Neuromuscular junction Physiologic Anatomy of Neuromuscular Junction - MEP is rich in Ach receptors and contains numerous junctional folds (depressions in the MEP). - An average human MEP contains about 15 to 40 million ACh receptors. - The extracellular space between the nerve terminals & muscle membrane is called Synaptic cleft and is occupied by connective tissue called basal lamina, to which the enzyme acetylcholinestrase (ACHEase) is bound. Properties of Neuromuscular Transmission 1.It is unidirectional. 2.There is a delay of about 0.5 msec. 3.Easily fatiguedas a result of repeated stimulation due to exhaustion of ACh vesicles and depletion of the NT. 4.Effect of Ions. 5.Effect of drugs.  Properties of Neuromuscular Transmission 5. Effect of drugs. a) Drugs that stimulate muscle fiber by acetylcholine-like action. These drugs are not destroyed by cholinesterase → their action persists for many minutes to several hours e.g. methacholine, carbachol, and nicotine in small dose. b) Drugs that block neuromuscular transmission (curariform drugs): can prevent passage of impulses at MEP. Curare competes with ACh for the receptor sites on the membrane, so that ACh cannot increase the permeability of ACh channels sufficiently to initiate a depolarization wave. c) Drugs which stimulate neuromuscular transmission by inactivating cholinesterase e.g. neostigmine, physostigmine, and diisopropyl-fluorophosphate. Thus, extreme amounts of ACh can accumulate and then repetitively stimulate the muscle fiber. Myasthenia gravis  Myasthenia gravis - It is a serious and sometimes fatal disease in which skeletal muscles are weak and tire easily. - Worsen with repetitive stimulation, due to gradual decline in quantal release of A.Ch. - If the disease is intense enough, the patient dies of paralysis, particularly of respiratory muscles. - Have a bimodal distribution, with peak occurrences in 20s (women) and 60s (men). - Autoantibodies (Type-II hypersensitivity) against A.Ch NM receptors causing a 70–90% decrease in theirvnumber per endplate by either destroying some of the receptors or binding them to neighboring receptors, triggering their endocytosis.  Myasthenia gravis - It could be either ocular, affecting the extra-ocular muscles, bulbar or generalized. - About 30% of patients with myasthenia gravis have a maternal relative with an autoimmune disorder (genetic predisposition). - A greater tendency to have RA, SLE, and polymyositis (other autoimmune diseases). - The thymus may play a role by supplying sensitized Th cells against thymic proteins cross- reacting with A.Ch receptors. - More than 75% of MG patients have thymic abnormalities (e.g., hyperplastic); and 10–15% has a thymoma (tumor).  Myasthenia gravis - Treatment: 1. CT scan of the chest: is indicated in all patients with newly-diagnosed MG to rule out Thmoma. 2. The disease can be ameliorated by administration of anticholine-estrase drugs, such as physostegmine and neostigmine, to allows accumulation of adequate amounts of ACh to induce normal muscular activity. 3. Thymectomy is indicated especially if a thymoma is suspected. Even without thymoma, thymectomy induces remission in 35% and improves symptoms in 45% of patients. 4. Immunosuppressive (e.g., prednisone, azathioprine, or cyclosporine) can suppress antibody production and shown to improve muscle strength in some patients. Conclusion The junction between alpha motor neurons and skeletal muscle is called nueromuscular junction. Neuromuscular transmission (NMT) occurs through release of acetyl choline. NMT is characterized by being unidirectional, fatigued, delayed and affected by drugs and ions. Myasthenia gravis may be fatal autoimmune disease. References Guyton and Hall, 13th edition. Unit II(7); 89-93. Ganong’s review of medical physiology 25th ed. Section I(6); 130-2. Thank You