Muscle I Pharmacology Notes

which of the 3 main types of muscle are striated? skeletal and cardiac two main functions of skeletal muscle 1. movement 2. generation of heat (shivering is an exothermic process) - connected to bones via tendons - individual multinucleated myocytes (muscle cell/muscle fibre) in the centre, myocyte membrane called the sarcolemma - covered by a layer of connective tissue called the endomysium - muscle fibres grouped into bundles called fascicles - fascicles covered in another layer of connective tissue called the perimysium - fascicles are grouped together by a sheath called the epimysium to form the muscle skeletal muscle structure structure of skeletal muscle fibre - bundles of filaments termed myofibrils - myofibrils composed of bundles of myofilaments - tunnels called T-tubules lead from the sarcolemma into the muscles interior, sarcolemma has very large SA - sarcoplasmic reticulum (ER in muscles) is wrapped around the myofibrils - terminal cisterna (special parts of the SR) interact with T-tubules to form a triad microfibrils are long strings of repeating structures and the repeated unit is a ______ sarcomere 1 / 14 - M-line is the central line (orange) - H-zone surrounds the M-line (white) - A-band (blue) name the bands and lines in sarcomeres - I-band straddles across two sarcomthat give skeletal muscles their striated eres (yellow) - Z-line indicates the boundary between appearance two sarcomeres - thick filaments (red) composed of myosin and titin - thin filaments (blue) composed of actin and nebulin - both type of filament are connected to the Z-lines - thick filaments also connected to the M-line role of titin spring-like function enables muscle to return to its resting state after being stretched largest known mammalian protein the abundance of proteins in muscle 1. myosin 2. actin 3. titin 4. nebulin the mechanism of contraction involves the filaments sliding over each other actin of the thin filaments interacts with why does the banding pattern depend on the heads of myosin molecules from the how much the muscle is contracted? thick filaments - thin filaments move closer together (H-zone shortens) 2 / 14 - titin compresses at ends of the thick filaments (I-bands shortens) which muscle filaments would be present in a cross-section of the A-band? both thick (myosin) and thin (actin) which muscle filaments would be present in a cross-section of the H-zone? only thick filaments (myosin) which muscle filaments would be present in a cross-section of the I-band? only thin filaments (actin) where there is optimum overlap between the myosin heads and the actin strectching the muscle means they cant interact anymore and the force of conwhy does muscle have an optimum opertraction decreases ating range? over compressing the muscle will also decrease the force of contraction relationshiop between the sarcomere length and the force of contraction the frank-starling law of the heart relates... the degree of stretch of cardiac muscle to the force of contraction hexamer formed of 2 heavy chains with large head groups that interact with actin from thin filaments and tails which coil together to form an alpha helix 4 light chains (2 regulatory, 2 essential) associated with the necks of the heavy chains structure of myosin conformation changed by the binding and hydrolysis of ATP, head groups have built-in ATPase activity, myosin motor is powered by the hydrolysis of ATP what is the function of the essential light chains? 3 / 14 structural myosin is a member of a highly diverse family of motor proteins which class of myosins is muscle myosin apart of? myosin class II in humans how many kinds of myosin II are there? 9 (8 skeletal/cardiac and 1 smooth) which of fibre proteins found in muscle is also a major component of eukaryotic cytoskeletons? actin what are the two forms of actin? globulus form (G actin) filamentous form (F actin) - the one found in muscle there is one tropomyosin molecule for every ______ actin monomers 7 1. tropomyosin runs along the actin chain - consists of two alpha-helical proteins name some of the other proteins associ- coiled ated with actin in skeletal muscle 2. troponin - a complex of 3 separate proteins, allows regulation of muscle contraction by calcium name the three troponin proteins and what they associate with 1. troponin T - associates with tropomyosin 2. troponin I - inhibits the formation of cross-bridges between myosin and actin by binding with actin and holding the complex in a position that covers the myosin binding sites 3. troponin C - binds calcium 4 / 14 1. myosin heads bound to actin chain 2. myosin head binds ATP which causes it to dissociate from the actin chain 3. myosin's built-in ATPase hydrolyses the ATP into ADP and P which remain bound to the myosin head, conformational change of myosin tilts the head into it's 'cocked' state 4. formation of a new weak cross-bridge describe the stages in muscle contrac- between the myosin and actin 2 tion monomers down the chain 6. P dissociates and the myosin head returns to its non-cocked state, moving the filaments relative to each other, the bonds between the myosin and the actin strengthen 7. ADP dissociates and we return to the starting state but myosin and actin have moved relative to each other so the muscle is contracted for each tropomyosin there is ______ trimeric troponin complex 1 what happens when troponin C binds calcium? conformational change of the troponin complex causes its position on the actin to change, complex pulls the tropomyosin further into the actin groove uncovering the myosin binding sites on the actin cross bridges can now form and the muscle can contract what neurotransmitter is released by moacetylcholine (binds to nicotinic acetyltor neurons in skeletal muscle neurocholine receptors) muscular junctions? an influx of what ion across the post-synaptic muscle membrane causes an action potential to occur? 5 / 14 sodium (later converted into the calcium-based signal that triggers actin-myosin cross bridges to form) what are T-tubules? transverse tubules continuations of the sarcolemma (muscle fibre cell membrane) that tunnel into the muscle fibre when inside the muscle fibre it associates with the sarcoplasmic reticulum to form terminal cisternae, two terminal cisternae are associated with each T-tubule to form a triad continuous with the outer surface of the muscle fibre so facilitates the spread of action potentials into the interior of the muscle give the approximate concentrations of calcium within these compartments outside muscle cell in cytoplasm of muscle cell in sarcoplasmic reticulum outside muscle cell - 2mM cytoplasm - 100nM SR - 2mM what does SERCA stand for? sarcoplasmic endoplasmic reticulum calcium ATPase what are SERCA pumps doing? pumping calcium out of the cytoplasm into the SR powered by ATP hydrolysis 1. action potential activates the l-type voltage-gated calcium channels (VGCCs) present in the muscle membrane so calcium moves into the cytoplasm from the extracellular fluid (not how is the cytoplasmic calcium concennecessary or sufficient to trigger muscle tration raised to levels that activate trocontraction) ponin C? 2. calcium channels called ryanodine receptors in the sarcoplasmic reticulum membrane open, when an action potential activates the DHPs in the T-tubule membrane this is transmitted via a phys6 / 14 ical linkage to the ryanodine receptors to open what channels are receptors of dihydropyridine (DHP)? l-type calcium channels which membrane are dihydropyridine receptors found in? the T-tubule membrane describe the interaction between the 4 DHPs (called a tetrad) from the T-tubule DHP receptors and the ryanodine recep- membrane associate with 1 ryanodine tors receptor in the sarcoplasmic membrane what pump is responsible for restoring calcium concentrations to normal and terminating muscle contraction? SERCA - acetylcholine released by motor neuron - activates NACh receptors - depolarises the sarcolemma and triggers an AP that is spread into the T-tubules - voltage change activates DHP receptors in the muscle membrane - conformational change of DHP translist the events leading from nerve activamits activation via physical linkage to tion to muscle contraction ryanodine receptors - ryanodine receptors open so calcium ions move out of SR - troponin C is activated by binding calcium - muscle contraction is initiates - SERCA pumps take calcium back into the SR using energy from ATP hydrolysis what is a motor unit? a motor neuron and all the muscle fibres it synapses with define arborization the splitting of a motor neuron axon into a series of finely branched presynaptic nerve terminals/boutons what is an end plate? the portion of the muscle membrane under the motor nerve terminals 7 / 14 what is the name of the folds in the muscle fibre membrane under each presynaptic nerve terminal where the nAChRs are located? junctional folds what is myasthenia gravis (MG) and what are the symptoms? - an autoimmune disease that attacks skeletal muscle - muscle weakness, fatigue, droopy eyelids, double vision, difficulty smiling, change to a more nasal voice, slurred speech, trouble breathing or swallowing (can cause pneumonia) - nicknamed the 'rag doll' disease - can be fatal due to the respiratory muscles being skeletal muscles true or false - MG is more common in males false - like all autoimmune diseases MG is more common in females (about 2x) thymus gland removal of the thymus gland has proved the definite causes of MG are currently beneficial for many patients and lots of unknown however what gland is thought sufferers turned out to have issues with to play a key role in the disorder? their thymus gland such as tumours (thymomas) nicotinic receptors on the muscle memwhat receptors are targeted by the au- brane (these ligand-gated ion channels toimmune attack in MG? trigger muscle contraction, without them no contraction will be triggered) prevalence rates of MG 2/10000 true or false - MG occurs mostly in childhood false - occurs mostly between ages 20-40 (but can occur at any age) 8 / 14 how can MG be diagnosed? - assessment of symptoms (painless weakness and fatigue) - tests to see how long patients can hold up their arm/leg or stare in one direction - testing serum for immune antibodies targeting the nAChRs (not all patients will have an increase level, especially ones with symptoms limited to their eyes) - EMG results will show a progressive decline in the size of the AP with repeated stimulation - biopsy of muscle cells (widening of the neuromuscular synapse is characteristic of MG) - endrophonium (tensilon) test, it is a short-acting acetylcholinesterase inhibitor so will produce an improvement in symptoms if patient has MG nAChRs are pentameric proteins - what is different about the types of subunits in an adult nAChR and a foetal nAChR? adult - 2±, 1², 1´, 1µ foetal - ³instead of µ what is similar about the subunits in the all have 4 TMDs and a large extracellular nAChRs? N-terminus amino acids from which nAChR subunits come together to form two acetylcholine binding sites on the extracellular part of the receptor? primarily in the ±subunits, also the ´and µ the ______ TMDs of each nAChR subunit come together to form the lining of the channel second which part of the nAChR is targeted by the antibodies produced in MG? the main immunogenic region (MIR) in the extracellular part of the ±subunits, specifically amino acids 67-76 9 / 14 mechanisms of MG pathology 1. when antibodies bind to the MIR the cell to which the receptor belongs recognises that the receptor must be faulty and internalises it via endocytosis, once inside the cell as a vesicle it will be broken down into amino acids - depletion of nAChRs from the membrane means the muscle will not depolarise when it should 2. destruction and simplification of the end plate, the folding pattern is lost and most of the nAChRs are gone, leads to widening of the synapse 3. some antibodies will not bind to the MIR and instead act as competitive antagonists to block the acetylcholine binding sites (least important mechanism) what is the purpose of the folding in the end plate of the muscle membrane? maximise surface area true or false - the nAChRs are not found in all parts of the muscle membrane, they are localised to the tops of the folds in the end plate true treatments for myasthenia gravis - removal of thymus gland - acetylcholinesterase inhibitors (for mild MG) - immunosuppressants (can increase the risk of infections and cancer) - plasmapheresis or plasma exchange to remove the autoantibodies from the patients circulation (used in myasthenic crisis) give examples of acetylcholinesterase inhibitors used in the treatment of MG pyridostigmine and neostigmine - terminate the signal at neuromuscular junctions by breaking down acetylcholine what is the role of acetylcholinesterase? in the synapse - cleaves the ester bond between acetate 10 / 14 and choline (choline taken back into neuron to be recycled) true or false - pyridostigmine is a reversible acetylcholinesterase inhibitor true in myasthenic synapses the number of nAChRs is greatly reduced, administration of a reversible AChE inwhy are acetylcholinesterase inhibitors hibitor will stop AChE from breaking an effective treatment for MG? down ACh and increase the concentration of ACh in the synapse so action potentials can still be generated what was the sarin initially developed as? an insecticide nerve gases/agents are irreversible AChE inhibitors typified by what compound? sarin what is more deadly - sarin of cyanide? sarin is 500x more deadly how can sarin by taken into the body? easily absorbed through the skin or inhalation describe the pathophysiology of sarin AChE inhibitor for nicotinic and muscarinic ACh receptors in both the neuromuscular junction and the cholinergic synapses in the autonomic nervous system in the brain symptoms of sarin poisoning - first victims will have difficulty breathing and they will drool uncontrollably - they will then experience convulsions and paralysis, enter and coma and eventually die from respiratory failure 1. nAChRs enter their desensitised state irreversible inhibitors of AChE will not where the receptor still has acetylcholine cause continuous contraction of skeletal tightly bound but the channel closes muscle as after a few contractions the 2. if nAChRs are left open the muscle will remain continuously depolarised so muscle will become limp - why? will not be able to fire new APs as the 11 / 14 voltage-gated sodium channels will be largely inactivated the enzymatic mechanism of AChE centres around a group of three amino acids - name them serine, glutamate and histidine which of the amino acids in AChE accepts the acetate group from acetylcholine to release free choline? serine (forms an acetyl-serine residue) sarin attaches to the ______-______ residue and forms an irreversible bond that means the enzyme can not be recycled and is essentially dead acetyl-serine 1. the muscarinic antagonist atropine, administered as an intramuscular injecwhat two drugs can save the life of some- tion one exposed to sarin? 2. pralidoxime, recycles AChE back into an active form, must be administered immediately suggest why the electric organs of fish are controlled by nAChRs they are embryologically derived from muscle torpedo electric rays can produce a discharge of ______V at up to ______A 200V at up to 30A what is a cholinergic neuron? neuron that uses primarily acetylcholine as its neurotransmitter the electroplaques of the torpedo electric ray are kidney-shaped organs located either side of the body, they consist of a series of flat, disc-like cells called ______ electrocytes electroplaques are innervated by cholinergic neurones and their firing is triggered by the action of acetylcholine electroplaque tissue from torpedo can be on nicotinic acetylcholine receptors, this used to study nAChRs, it is possible to means that the electroplaque is the rich- obtain mg quantities of the receptor est-known naturally occurring source of nicotinic receptors - why is this useful? 12 / 14 provoke an immune response that culminates in autoimmunity against the animals own receptors (induced experimental myasthenia gravis) what will happen to a mouse injected with purified nAChRs from torpedo? d. thin filaments (actin) the I band in skeletal muscle is formed by: a. the attachment site for thin filaments b. the overlap of thin and thick filaments c. thick filaments d. thin filaments there are however other proteins contained within the Z line and proteins such as nebulin (associated with actin) and titin (which stretches from the Z line to the M line) the I band is the portion of the thin filament that does not overlap with the thick filaments (myosin) the terminal cisternae (aka lateral sacs) they are the portion of the sarcoplasmic reticulum adjacent to the t-tubules and they contain ryanodine receptors (calcium channels whose opening is triggered calcium required for muscle contraction via a physical linkage to voltage gated enters the cytoplasm via where? l-type calcium channels/DHP receptors in the T tubules) opening of the ryanodine receptors releases the Ca2+ that is accumulated in the SR by the Ca2+ ATPase. the MIR is located in which nicotinic acetylcholine receptor subunit? alpha the functional unit of myosin in mammalian skeletal muscle is a: a. dimer b. trimer c. tetramer d. hexamer d. hexamer myosin is a heterohexamer, it has six subunits: two heavy chains, two regulatory light chains and two essential light chains what triggers the formation of strong cross bridges between actin and myosin? a. binding of ATP d. release of phosphate 13 / 14 b. hydrolysis of ATP c. release of ADP d. release of phosphate 14 / 14