Neuromuscular Junction and Excitation-Contraction Coupling PDF

THE NEUROMUSCULAR JUNCTION AND SKELETAL MUSCLE EXCITATION-CONTRACTION COUPLING​​ DR MUNGAI RUTH WANJIRU​​ LEARNING OUTCOMES By the end of this lesson, students should be able to: 1. Describe the connection between motor neurons and muscles (Neuromuscular junction NMJ ) 2. Explain the proc...

THE NEUROMUSCULAR JUNCTION AND SKELETAL MUSCLE EXCITATION-CONTRACTION COUPLING​​ DR MUNGAI RUTH WANJIRU​​ LEARNING OUTCOMES By the end of this lesson, students should be able to: 1. Describe the connection between motor neurons and muscles (Neuromuscular junction NMJ ) 2. Explain the process of neurotransmitter release and binding at the NMJ and generating a post synaptic electrical signal 3. Explain the process of excitation-contraction coupling 4. Clinical application describe clinical disorders associated with NMJ dysfunction (e.g., Myasthenia Gravis, Lambert-Eaton Syndrome) and use of neuro muscular blockers  The neuromuscular junction (NMJ) is one of the fastest and most efficient synapses in the human body It is capable of transmitting signals from nerves to muscles with incredible precision and speed. Within just a few milliseconds of receiving an electrical signal, the NMJ releases acetylcholine (ACh), a neurotransmitter that initiates a cascade of events leading to muscle contraction. This rapid process, known as excitation-contraction coupling, ensures that our muscles can respond almost instantaneously to stimuli, whether it's for delicate movements like typing or powerful actions like sprinting. This seamless communication between nerves and muscles is what makes complex motor functions possible, NEUROMUSCULAR Neuromuscular junction : the synapse JUNCTION between motor neuron and muscle fiber is called the neuromuscular junction Motor neurons : are the nerves that innervate muscle fibers Motor unit : single motor neuron and the muscle fibers it innervate In large muscles (e.g. the flexors of the hip or knee), each motor unit contains 1200 muscle fibers or more. In small muscles (e.g. the intrinsic muscles of the hand), each unit contains 12 muscle fibers or less. Small units contribute to the finely graded contractions used for delicate manipulations. All of these muscle fibers will be of the same type (either fast twitch or slow SKELETAL MUSCLE FIBRE Depending on their contraction speed and TYPES metabolic profile, skeletal myocytes/muscle fibres can be classified into: Type I: Slow-twitch, oxidative fibers are small, rich in mitochondria and blood capillaries (hence, red). They exert small forces and are fatigue-resistant. They are deeply placed and suited to sustained postural activities, including standing. Type IIa Intermediate (fast, oxidative– glycolytic, FOG) fibers have properties intermediate between the other two. Type IIX Fast, glycolytic (FG) fibers are large, mitochondria-poor, and capillary-poor (hence, white). They produce brief, powerful SKELETAL MUSCLE FIBRE TYPES SKELETAL MUSCLE A skeletal muscle is a collection of muscle cells, or muscle fibers(cylindrical cell with up to several hundred nuclei near the surface of the fiber) Each muscle fiber is made up of into myofibrils(muscle fibre contractile structure) surrounded by sarcolemma which form deep invaginations called transverse tubules (T-tubules) within the myofibril. Skeletal muscle fibers also contain extensive sarcoplasmic reticulum (SR) that wraps around each myofibril and consists of longitudinal tubules with NEUROTRANSMITTER RELEASE AND BINDING AT THE NMJ AND EPP action potential in motor neuron – induces release of acetylcholine into neuromuscular junction. The ACh diffuses through the basement membrane to bind with ACh receptors in the sarcolemma. Activation of the receptors leads to depolarization of the sarcolemma of the muscle cell creating an end plate potential (EPP) opening of Na+ voltage gated channels causes a muscular action potential. The action potentia is led into the interior of the muscle fiber by T tubules this causes voltage-gated Ca2+Ca2+ channels in sarcoplasmic reticulum to release Ca2+Ca2+ into cytosol which bind troponin and pull off tropomyosin The sarcoplasmic reticulum liberates Ca2+ ions that initiate contraction of the  Motor end plate contains nicotinic receptors for Ach , which are ligand gated ion channels Ach binds to the alpha subunits of nicotinic receptors and causes conformational change. When conformational changes occurs ,the central core of channels opens & permeability of motor end plate to Na + & K+ increases When the ion channel on post synaptic membrane opens both Na + & K+ flow down their concentration gradient. At resting potential net driving force for Na + is much greater than K+ ,when Ach triggers opening of these channels more Na + moves inwards than K+ out wards, depolarizing the end plate.this potential change is called end plate potential (EPP) not an action potential but it is simply depolarization of specialized motor end plate Small quanta (packets) of Ach are released randomly from nerve cell at rest, each producing smallest possible change in membrane potential of motor end plate, the MINIATURE EPP. When nerve impulse reaches the ending, the number of quanta release increases by several folds and result in large EPP. EPP than spread by local current to adjacent muscle fibers which are depolarized to threshold & fire action potential To ensure purposeful movement ,muscle cell electrical response is turned off by acetylcholinesterase (AchE), which degrade Ach to choline & acetate About 50%of choline is returned to the presynaptic terminal by Na +choline transport to be reused for Ach synthesis. Now muscle fiber can relax ,if sustained contraction is needed for the desired movement another motor neuron AP leads to release of more Ach EXCITATION CONTRACTION COUPLING AND CROSBRIDGE WATCH THE VIDEOS https://mediaspace.illinois.edu/media/t/1_cvsvl0hu https://mediaspace.illinois.edu/media/t/1_gtg69ex6 https://mediaspace.illinois.edu/media/t/1_idrhngwb https://www.youtube.com/watch? app=desktop&v=8x8H-GFtwyU  A disease involving N.M junction is characterized by the extreme muscular weakness (myasthenia=muscular & gravis=severe) It is an auto immune condition (auto immune means immunity against self) in which the body erroneously produces antibodies against its own motor end plate ach receptors. Thus not all Ach molecules can find functioning receptors site with which to bind. As a results ,AchE destroys much of Ach before it ever has a chance to interact with receptor site & contribute to EPP. Myasthenia gravis affects the voluntary muscles of the body, especially those that control the eyes, mouth, throat and limbs. The disease can strike anyone at any age, but is more frequently seen in young women (age 20 and 30) and men aged 50 and older. A myasthenia gravis crisis can involve difficulty in swallowing or breathing. The cause of myasthenia gravis is unknown and there is no cure, but early detection and prompt medical management can help people live longer, more functional lives. Treatment : it is treated with long acting anticholinesterase inhibitor  Lambert-Eaton myasthenic syndrome (LEMS) is a rare presynaptic disorder. an autoimmune disease attacks the calcium channels on nerve endings that are required to trigger the release of chemicals (acetylcholine). With fewer calcium channels, the nerve ending releases less acetylcholine. Acetylcholine is a chemical messenger that triggers muscle contraction. In people with LEMS, the lowered levels of acetylcholine are not sufficient to  Neuromuscular blockade is frequently used in anesthesia paralyze patients requiring intubation and to optimize the surgical field by inhibiting spontaneous ventilation, and causing relaxation of skeletal muscles. Depolarizing neuromuscular blockers: e.g.Succinylcholine binding to postsynaptic cholinergic receptors on the motor endplate mimic action of Ach which causes prolonged stimulation depolarization and subsequent desensitization of the receptors.used in rapid sequence induction.Usually, paralysis takes approximately 1 minute after administration and lasts approximately 7 to 12 minutes.Succinylcholine is metabolized by plasma pseudocholinesterase. If the patient has pseudocholinesterase deficiency, this can lead to prolonged neuromuscular blockade that may require postoperative mechanical ventilation. Nondepolarizing neuromuscular blockers: rocuronium,