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Neuromuscular Junctions  LEARNING OBJECTIVES: ➢ Components of the Neuromuscular Junction (NMJ) ➢ Physiological Anatomy of NMJ

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Neuromuscular Junctions  LEARNING OBJECTIVES: ➢ Components of the Neuromuscular Junction (NMJ) ➢ Physiological Anatomy of NMJ NEUROMUSCULAR JUNCTION By:Dr.Fareeda banu A.B. Associate professor Dept of Physiology, USM-KLE IMP Neuromuscular Junctions LEARNING OBJECTIVES: ➢ Components of the neuromuscular junction (NMJ) ➢ Physiological anatomy of NMJ. ➢ Synthesis, storage and release of Ach at NMJ ➢ Events occurring during neuromuscular transmission with reference to end-plate potentials. ➢ Clinical importance of NMJ ➢ Drugs affecting NMJ transmission. ➢ Applied aspects. INTRODUCTION Movement of the body requires the interaction of a complex series of afferent and efferent neuronal signals, which result in a skeletal muscle contraction The neuromuscular junction is a specialized form of a chemical synapse comprised of an alpha motor neuron and the muscle fiber it innervates. INTRODUCTION Junctions Vrs. Synapses - NMJ is a junction between a motor neuron and a skeletal muscle. Synapse is a connection between two neurons A junction will always respond to an action potential in the presynaptic nerve. Synapses may or may not. A junction will have a safety factor, sufficient release of neurotransmitter to insure action potential generation in the effector organ, usually a thousand or so times over. MOTOR UNIT: THE NERVE-MUSCLE FUNCTIONAL UNIT ❖ Motor Unit: The Nerve-Muscle Functional Unit. A motor unit is a motor neuron and all the muscle fibers it innervate ❖ The nerve fiber forms a complex of branching nerve terminals that invaginate into the surface of the muscle fiber but lie outside the muscle fiber plasma membrane. The entire structure is called the motor end plate. NEUROMUSCULAR JUNCTION (NMJ) Defn: NMJ is a junction between the motor nerve ending and skeletal muscle fiber. Components of the NMJ: It is comprised of; Unmyelinated terminal boutons of axon supplying a skeletal muscle fiber. Pre/Post synaptic membrane: nerve membrane close to muscle membrane is Presynaptic and the muscle membrane is called Postsynaptic membrane: Junctional folds/Palisades: depressions in the motor end plate (thickened portion of muscle membrane). Synaptic space or synaptic cleft (20-30nm wide): The space between the nerve and the thickened muscle membrane. Physiological Anatomy/ Structure of the NMJ: 1. Terminal button: Axon of motor neuron branches, looses the myelin sheath and forms several axon terminals that end in small swellings (knobs) called terminal buttons or end feet, which forms a neuromuscular junction at the centre of muscle fibre Large number of Mitochondria are present in the axon terminals . It also contains nearly 3 lakhs of synaptic vesicles filled with chemical neurotransmitter, acetyl- choline (A-ch). Physiological Anatomy/ Structure of the NMJ: 2. Presynaptic membrane: This refers to the axonal membrane lining the terminal buttons of the nerve endings. 3. Post synaptic membrane: It is the thickened muscle fibre membrane (sarcolemma) in the region of NMJ. The muscle membrane in this region is depressed to form the synaptic trough in which the terminal button fits. Further, the postsynaptic membrane is thrown into large number of folds called subneural clefts or pallisades Physiological Anatomy/ Structure of the NMJ: 4. Synaptic trough: Muscle fiber membrane (postsynaptic) is specialized and is different from the sarcolemma on the rest of the muscle fiber Axon terminal and muscle fiber do not physically touch The invaginated membrane is called the synaptic gutter or synaptic trough. Physiological Anatomy/ Structure of the NMJ: 5. Subneural clefts or folds Folds of the muscle membrane at the bottom of synaptic gutter Greatly increases postsynaptic surface area, at which the synaptic transmitter (Ach) can act. Location of the majority of the acetylcholine/ Nicotinic receptors (ligand gated Na+& K+ channels) Active zone of axon terminal is located over the subneural folds. Physiological Anatomy/ Structure of the NMJ: 6. Junction is covered by Schwann cells, this insulates the junctional cleft from surrounding fluids and prevents some of the loss of neurotransmitter by diffusion from the cleft. 7. Synaptic cleft - space between axon terminal and the muscle membrane 1. 20 to 30 nm wide 2. Space filled with ECF, a gel of carbohydrate rich amorphous material and 3. A large quantities of enzyme Acetylcholinesterase (splits acetylcholine into acetylCoA and choline). Physiological Anatomy/ Structure of the NMJ: NEUROMUSCULAR JUNCTION ❖ Neurons communicate with muscle cells at neuromuscular junctions, which function much like a neural synapse. ❖ Motor axon terminal releases neurotransmitters (such as acetylcholine) which travel across a synaptic cleft and bind to receptors on a muscle fiber. ❖ This binding causes depolarization, thus possibly causing an action potential. ❖ The action potential spreads across the sarcolemma causing the muscle fiber to contract. Synthesis and Storage of Ach by the Nerve Terminals A-ch is synthesized in the mitochondria of terminal nerve boutons from Choline, Acetyl Co enzymeA, ATP and Glucose in presence of Choline Acetyl-transferase enzyme. Once formed , it is temporarily stored in minute vesicle (synaptic vesicle), each vesicle contains (a quantum) about 10,000 molecules of the neurotransmitter. When a nerve impulse reaches the neuromuscular junction, about 125 vesicles of acetylcholine are released from the terminals into the synaptic space. Neuromuscular transmission The sequence of events which causes transmission of impulse through neuromuscular junction are: 1. Release of acetylcholine by the nerve terminals 2. Effect of acetylcholine on postsynaptic membrane 3. Development of end plate potential 4. Removal of acetylcholine by cholinesterase 5. Initiation of the action potential in muscle fibre. Secretion of Acetylcholine by the Nerve Terminals • The impulse/AP arriving at the end of the motor neuron increases the permeability of its endings to Ca++. • Depolarization of the axon terminal opens voltage-gated calcium channels. • Ca 2+ enters the endings , causes Ach vesicles to fuse with the axon terminal membranes at the active sites. • Which triggers a marked increase in exocytosis of the Ach-containing synaptic vesicles. Effect of acetylcholine on the postsynaptic membrane. Each nerve impulse releases quantum of Ach from about 60 (125 Guyton) synaptic vesicles. The acetylcholine diffuses to Nicotinic cholinergic (N M ) receptors that are concentrated at the tips of the subneural cleft of the post synaptic membrane . Binding of acetylcholine to these receptors increases the Na + and K + conductance, and the resultant influx of Na+ produces a depolarizing potential; the End plate potential. NOTE: The size of the quanta of Ach released in this way varies directly with the Ca++ concentration and inversely with the Mg++concentration at the end plate. Development of End Plate Potential The RMP of skeletal muscle membrane is –90mV. The sudden insurgence of sodium ions into the muscle fiber when the Ach-gated channels open causes the electrical potential inside the fiber at the local area of the end plate to increase in the positive direction as much as 50 to 75 millivolts, creating a local potential called the End plate potential. EPP is a local graded potential EPP is analogous to an EPSP but much larger, all NMJ potentials are excitatory and cause an AP on the adjacent postsynaptic membrane every time End Plate Potential One EPP is normally more than sufficient to cause AP generation on adjacent skeletal muscle membrane When the EPP reaches a threshold of 30-40mV, it depolarizes the surface membrane of the muscle and results in generation of Action (spike) potential (120- 130mV). This spike potential in turn results in muscle contraction. AP is propagated on skeletal muscle fibers from center toward both ends so that center sarcomeres contract first (prevents excess strain on skeletal muscle fibers and produces a stronger response faster) • A,C Weakened end plate potential recorded in a curarized muscle & caused by botulinum toxin; too weak to elicit an action potential. • B Normal end plate potential eliciting a muscle action potential. Development of Action Potential The current sink created by this local potential depolarizes the adjacent muscle membrane to its firing level. Action potentials are generated on either side of the end plate and are conducted away from the end plate in both directions along the muscle fiber. The muscle action potential, in turn, initiates muscle contraction. Steps of Neuro-muscular transmission Destruction of released Ach by Acetylcholinesterase The Ach, once released into the synaptic space, continues to activate the Ach receptors as long as the Ach persists in the space. Acetylcholine is rapidly removed by two mechanisms 1. Most of the Ach is broken down by the Acetyl- cholinesterase enzyme, located in the synaptic cleft and post synaptic membrane . 2. Small amount of Ach diffuse out of the synaptic cleft into the presynaptic membrane and is then no longer available to act on the muscle fiber membrane. The rapid removal of the acetylcholine prevents continued muscle re- excitation after the muscle fiber has recovered from its initial action potential. Clinical Importance of NMJ Blocking at NMJ produces muscle relaxation, therefore Helps in surgical operation providing open fields. Reduces movement during electroconvulsive treatment of psychotic patients. Blocking at NMJ can be done by two ways: 1. By inhibiting the release of Ach from presynaptic membrane. Eg: Botulinum toxin (bacterial toxin) combines irreversibly with cholinergic motor
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