Neuromuscular Junction (UM1010) PDF

Dr Katja Vogt Neuromuscular junctions @katjetz [email protected] BSc School of Medicine Medical Sciences 1  Dr Katja Vogt Neuromuscular ju...

Dr Katja Vogt Neuromuscular junctions @katjetz [email protected] BSc School of Medicine Medical Sciences 1  Dr Katja Vogt Neuromuscular junctions Learning objectives Discuss the anatomy of a muscle cell Identify the importance of neural cell signal transduction and transmission Explain the neuromuscular junction Recognise neuromuscular junctions in different muscle types and pathophysiological conditions @katjetz [email protected] 3 BSc Medical Sciences  Dr Katja Vogt Neuromuscular junctions @katjetz [email protected] 4 BSc Medical Sciences  Dr Katja Vogt Structure of this Sway 1. Introduction: Anatomy of a muscle cell Action potential (repeat) 2. Synapses: Structure and function of synapsis 3. Neuromuscular junctions 4. Pathophysiological conditions at the NMJ 5. Signal transduction on smooth and cardiac muscle @katjetz [email protected] 5 BSc Medical Sciences  Dr Katja Vogt Anatomy of a muscle cell = myocyte Sacrolemma Membrane of muscle cell: sarcolemma Cytoplasm: Sacroplasm Sacroplamsic reticulum, Ca+ ion pums, not ribosomes, specific form of smooth endoplasmic reticulum T-tubule - creates the folds, action potential (Na+ influx) reaches down the T-tubule T-tubule connected to sarcoplasmic reticulum by protein complex When action potential reaches critical mass —> complex (ryanodin) is triggered to release Ca+ from SR Ca+ back into the SR in 30msec @katjetz [email protected] 6 BSc Medical Sciences  Dr Katja Vogt Anatomy of a muscle cell Membrane of muscle cell: sarcolemma Cytoplasm: Sarcoplasm Sarcoplasmic reticulum: specific form of endoplasmic reticulum Ca+ ion pumps no ribosomes T-tubule: action potential reaches down the T-tubule T-tubule connected to sarcoplasmic reticulum by protein complex Protein complex triggers the release Ca+ from sarcoplasmic reticulum @katjetz [email protected] 7 BSc Medical Sciences  Dr Katja Vogt Concentration (mmol/L H2O) Resting membrane potential Ion Inside Outside Equilibrium Potential Cell Cell (mV) Every cell has a resting potential of around Na+ 15.0 150.0 60 -70mV Na+ and K+ gradients maintained across the K+ 150.0 5.5 -90 membrane by Na/K-ATPase CI- 9.0 125.0 -70 @katjetz [email protected] 8 BSc Medical Sciences  Dr Katja Vogt Ion-channels - little revision Can be very fast Cannot be coupled to energy source - passive transport only Ion selective Fluctuate between open and closed Differently-gated @katjetz [email protected] 9 BSc Medical Sciences  Dr Katja Vogt @katjetz [email protected] BSc Medical Sciences  Dr Katja Vogt Action potential Na+ into the cells All or none principle Always around 100mV K+ out of the cell A few msec Na+ channels Closed Open Closed Closed K+ channels Closed Closed Open Closed @katjetz [email protected] 11 BSc Medical Sciences  Dr Katja Vogt @katjetz [email protected] 12 BSc Medical Sciences  Dr Katja Vogt Section II Introduction: Anatomy of a muscle cell Action potential Synapses: Structure and function of synapsis Neuromuscular junctions Pathophysiological conditions at the NMJ Signal transduction on smooth and cardiac muscle @katjetz [email protected] 14 BSc Medical Sciences  Dr Katja Vogt Synapse Electrical synapse Formed by gap junction between two neurons Electrical current can flow directly Chemical synapse Signal is transmitted via neurotransmitters @katjetz [email protected] 15 BSc Medical Sciences  Dr Katja Vogt Chemical synapse - function @katjetz [email protected] 16 BSc Medical Sciences  Dr Katja Vogt Transmitter - release Some vesicles containing neurotransmitters are pre- docked to membrane Action potential arrives at the synapse Voltage-gated Ca+ channels Ca+ binds to synaptotagmin Initiates fusion with the plasma membrane @katjetz [email protected] 17 BSc Medical Sciences  Dr Katja Vogt Vesicle-Membrane fusion Facilitated by SNARE proteins Anchored membrane proteins Target of the proteolytitic botulinum and tetanus toxin  Dr Katja Vogt Vesicle-Membrane fusion Bombardier, Jeffrey P and Mary Munson. “Three steps forward, two steps back: mechanistic insights into the assembly and disasse complex.” Current opinion in chemical biology 29 (2015): 66-71. Twitter: @katjetz E-mail: [email protected] 19 BSc Medical Sciences  Dr Katja Vogt Vesicle-Membrane fusion  Dr Katja Vogt Recycling of the membrane at the synapse Membrane fusion by “kiss-and-run” mechanism (a) Membrane recycling via clathrin- mediated endocytosis (b) Pool of docked vesicles can be exchanged and are quality controlled (c) d Recycling via invagination is much slower (d) @katjetz [email protected] 21 BSc Medical Sciences  Dr Katja Vogt Synaptic cleft Typically 20nm Shielded by basal lamina from extra cellular space Can be transversed by dense filaments Neurotransmitters are released into the synaptic cleft Specialised adhesive junction 22  Dr Katja Vogt @katjetz [email protected] 24 BSc Medical Sciences  Dr Katja Vogt Section III Introduction: Anatomy of a muscle cell Action potential Synapses: Structure and function of synapsis Neuromuscular junctions Pathophysiological conditions at the NMJ Signal transduction on smooth and cardiac muscle @katjetz [email protected] 25 BSc Medical Sciences  Dr Katja Vogt Neuromuscular junction One nerve fibre per endplate Impulse arriving triggers Ca+ influx Neurotransmitter: Acetylcholine Binds to nicotinic cholinergic receptors, concentrated on the motor endplate Generation of endplate potential = muscle action potential Increase of Ca+ concentration in muscle @katjetz [email protected] 26 BSc Medical Sciences  Dr Katja Vogt Acetylcholine receptor Classed according to their pharmacological profile Nicotinic acetylcholine receptor (nAChR) Muscarinic acetylcholine receptor (mAChR) Major transmitters and their receptors transmitter-gated Na+ channel 5 subunits @katjetz [email protected] 27 BSc Medical Sciences  Dr Katja Vogt Acetylcholine receptor @katjetz [email protected] 28 BSc Medical Sciences  Dr Katja Vogt Motor endplate Made up of junctional folds, Thickened muscle membrane The synaptic cleft similar to regular synapses Receptors are concentrated on the tops of the folds Acetylcholine is cleaved by acetylcholinesterase into acetate and choline which is transported back into the presynaptic terminal  Dr Katja Vogt Muscle action potential Acetylcholine Na+ channel: influx of Na+ Ca2+ channels on sarcolemma: influx of Ca2+ Voltage gated Ca2+ channels on sarcoplasmic reticulum: influx of Ca2+  Dr Katja Vogt Muscle action potential  Dr Katja Vogt Motor action potential @katjetz [email protected] 32 BSc Medical Sciences  Dr Katja Vogt Motor action potential @katjetz [email protected] 33 BSc Medical Sciences  Dr Katja Vogt Muscle action potential Ryanodine receptor activated by voltage sensitive DHP receptor Release of Ca2+ from sarcoplasmic reticulum Influx of Ca+ Ca+ binds to Troponin and triggers myosin contraction Ca+ also acts as second messenger for cellular functions @katjetz [email protected] 34 BSc Medical Sciences  Dr Katja Vogt Section IV Introduction: Anatomy of a muscle cell Action potential Synapses: Structure and function of synapsis Neuromuscular junctions Pathophysiological conditions at the NMJ Signal transduction on smooth and cardiac muscle @katjetz [email protected] 35 BSc Medical Sciences  Dr Katja Vogt Auto @katjetz [email protected] 36 BSc Medical Sciences  Dr Katja Vogt Antibody @katjetz [email protected] 37 BSc Medical Sciences  Dr Katja Vogt Auto Antibody @katjetz [email protected] 38 BSc Medical Sciences  Dr Katja Vogt Acetylcholinesterase Voltage gated potassium channel Voltage gated calcium channel Voltage gated sodium channel Acetylcholinereceptor Acetylcholine Adaptor proteins  Dr Katja Vogt Pathophysiological conditions associated with the neuromuscular junction Autoimmune disorders Antibodies against AChR and MuSK in myasthenia gravis VGCC in Lambert–Eaton myasthenic syndrome VGKC in neuromyotonia (Isaacs’ syndrome) @katjetz [email protected] 40 BSc Medical Sciences  Dr Katja Vogt Myasthenia gravis Myasthenic fatigue @katjetz [email protected] 41 BSc Medical Sciences  Dr Katja Vogt Myasthenia gravis Achetylcholin released normal Decreased ACh receptor availability Folds on motor endplate flattened Action potential on motor end plate does not reach full potential Autoimmune disorder Most commonly caused by anti-AChR antibodies Induced receptor endocytosis Damage to membrane by activation of compliment Blockage of active side of the receptor Hyperplastic thymus, with active germinal centres @katjetz [email protected] 42 BSc Medical Sciences  Dr Katja Vogt Myasthenia gravis - clinical features Muscle weakness and fatigue, can be in crisis when with other systemic infection or disorder… Exacerbation and remission cranial muscles affected first Muscle weakness within 3 years or never Deep tendon reflexes remains Can be managed relatively well  Dr Katja Vogt Section V Introduction: Anatomy of a muscle cell Action potential Synapses: Structure and function of synapsis Neuromuscular junctions Pathophysiological conditions at the NMJ Signal transduction on smooth and cardiac muscle @katjetz [email protected] 44 BSc Medical Sciences  Dr Katja Vogt Nerve endings in smooth and cardiac muscle NO NEUROMUSCULAR JUNCTIONS! no recognisable endplates or other postsynaptic specialisations Acetylcholine, norepinephrine or epinephrine containing vesicles Nerves run along the muscle cells and “groove” them branches of neurons have enlargements (varicosities) containing synaptic vesicles up to 20,000 varicosities per neuron Transmitter probably released at each varicosity one neuron to innervate many effector cells @katjetz [email protected] 45 BSc Medical Sciences  Dr Katja Vogt Adrenergic receptors On smooth and cardiac muscle cells (in T-tubules) Bind to norepinephrine and epinephrine G-protein coupled receptors @katjetz [email protected] 46 BSc Medical Sciences  Dr Katja Vogt Neurotransmitter signalling in smooth muscle cells  Dr Katja Vogt Modulation of Smooth Muscle Activity Second Agonist Response Receptor Messenger Contractiona Norepinephrine and epinephrine from α1-AR InsP3 (predominant) sympathetic stimulation Relaxationb β2-AR cAMP Contractionc Muscarinic receptor on (direct) SMC Acetylcholine from parasympathetic stimulation Relaxationc Muscarinic receptor on (indirect) EC Angiotensin II Contractiond AT-II receptor InsP3 Vasopressin Contractiond Vasopressin receptor InsP3 Endothelin Contractiond Endothelin receptor InsP3 Adenosine Relaxatione Adenosine receptor cAMP Koeppen, Bruce M., Stanton, Bruce A. Berne and Levy Physiology E-Book.. [ClinicalKey Student].  Dr Katja Vogt Skeletal vs cardiac muscle Different membrane potential Acetylcholine binds to different receptors Pacemaker cells can fire action potentials Cardiac muscle cells rely on gap junctions to allow action potentials to proceed from one cell to the next @katjetz [email protected] 49 BSc Medical Sciences  Dr Katja Vogt Reading list Nerve and Muscle by Richard D. Keynes, David J. Aidley and Christopher L.-H. Huang, 2011 Amato AA. Myasthenia Gravis and Other Diseases of the Neuromuscular Junction. In: Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. eds. Harrison's Principles of Internal Medicine, 20e New York, NY: McGraw-Hill;. http://accessmedicine.mhmedical.com/content.aspx?bookid=21 29&sectionid=192533554 temporal and spatial coordination of exocytosis and endocytosis, Nature reviews molecular cell biology, 2003 http://www.bu.edu/histology/m/index.htm @katjetz [email protected] 50 BSc Medical Sciences  Dr Katja Vogt THANK YOU! Neuromuscular junctions MBBS Learning outcomes: Demonstrate an understanding of neural cell signal transduction and signal transmission and the neuromuscular junction @katjetz [email protected] 51 BSc Medical Sciences Dr Katja Vogt