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20 Cards in this Set
- Front
- Back
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Structure
Intro Unique Mechanism Drugs Disorders of NMJfunction |
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intro Where and what is the junction? |
· Peripheral chemical synapse
· Junction between a-motorneuone axons andskeletal muscle fibres |
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Diagram |
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Where is AChE located? |
AChE sits within invaginations – post-junctionalfolds (motor end plate with nAChRs – 10,000 receptors/um2
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What makes it unique? |
· No inhibitory inputs – transmission is alwaysexcitatory
· EPP always sufficient to trigger AP (cf. CNS) · Everything to excess – ensures transmission. Excess Ach release, receptor density, eppexceeds threshold for AP generation · No AP – miniature EPP (mepp’s). ACh vesiclesspontaneously leak into NMJ – v. small depolarisation (0.5mV) – oneACh-containing vesicle. |
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Mechanism: overview |
1. AP activates voltage-dependent Ca channels– Ca enters neuron. 2. Influx ofCa ions – Ca2+ bind to sensor proteins (synaptotagmin) on synapticvesicles – triggers vesicle docking and fusion with cell membrane through SNARE proteins. 3. Exocytosis – empties vesicle contents incleft. 4. AChdiffuses across cleft (30 nm) and binds to nicotinic ACh receptors on membraneof muscle fibres (sarcolemma) 5. OpensNa channels to open – AP travels down myofibril – muscle contraction 6. Vesiclesare recycled. |
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Explain vesicles |
· Quanta – one vesicle full of ACh. 200 in NMJ EPP– 5-10,000 molecules of ACh and ATP · Vesicles – large dense core vesicles –neuropeptides and large nts synthesised in curones transported via fast axonaltransport; small clear core vesicles – small nts – synthesised in presynapticterminals |
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Explain SNARE proteins |
· Membrane fusion – v-SNARE and t-SNARE proteinson separate membranes combine to form a trans-SNARE complex. |
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Explain ACh receptors |
· Ionotropicreceptors – serve as ligand-gated ion channels and do not use second messengers(as metabotropic do). · 16different subunits [Greek] a(9); b (4); g; d; e · Muscle type – pentameric (aabde), selectiveagonist/antagonist; neuronal –pentameric but diverse |
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How are vesicles recycled? |
AChE in endplate membrane close toreceptors.
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What is NM block used for? |
adjunctto anaesthesia |
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Non-depolarising blockers. mechanism |
· Competitive antagonists (curare – poison, usedmedically to impose paralysis for surgery) to binding of ACh to its receptors. Alsodirectly block ionotropic activity of ACh receptors. Can be reversed by AChEinhibitors. |
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Non-depolarising blockers. side effects |
· hypotension due to its effect of increasinghistamine, a vasodilator. Cause tetany fade – muscles fail to maintain afused tetany at sufficiently high frequencies of electrical stimulation,perhaps as affects presynaptic receptors |
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Depolarising blockers. Mechanism |
· Depolarise the sarcolemma of the skeletal musclefiber - persistent depolarisation makes the muscle fiber resistant to further stimulationby ACh - desensitised. |
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How are Depolarising blockers removed? |
· Agonist removed by phosphorylation by the activationof second messenger-dependent protein kinases – agonist-induced conformationalchange in receptor – receptor desensitisation. Revert to prolonged open statewhen agonist is bound in presence of positive allosteric modulator. |
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e.g. of Depolarising blockers |
succinylcholine |
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Compare types |
Depolarising blockers:
Agents are more resistant to AChE sopersistently depolarise muscle fibres. |
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Two types of Disordersof NMJ function |
Myasthenia Gravis Duchenne muscular dystrophy |
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Myasthenia Gravis Cause Symptoms Treatment |
· Autoimmune. 80% Ab produced to target alphachain of nicotinc AChR (80%). –Alsocause internalisation of the AChreceptor with subsequent degradation · Muscleweakness, fatigue, ptosis (lack of eye control) · Treatment– anticholinesterases |
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DMD - cause |
· X-linked, absence of dystrophin at NMJ. |
