L12 - Ion Channels and Muslce Contraction Flashcards
What is the structure of muscles?
Sarcomeres –> myofibril –> fibre –> fascicle
What is cross bridge theory?
Tension generated in muscle is dependent on the area of overlap between actin and myosin
The greater the area of overlap, the more cross bridges can form
- Brings the Z lines closer together
What is the sliding myofilament hypothesis?
Neuronal action potential in motor neuron
Leads to muscle action potential
Activation of voltage gated Ca channels - increased intracellular Ca2+
Myofilments slide leading to muscle contraction
What is a motor unit of the neuromuscular junction?
The motor neurone and all the muscle fibres it innervates
- Muscles have multiple motor units
- Defines fine muscle control
A motor unit with more muscle fibres allows?
A more finely graded contraction – spatial summation
What are the 4 key channels of the neuromuscular junction?
Voltage gated Na channel - pre and post synaptically
- Depolarisation
- Depolarisation caused by Ach triggers opening and closing of these Na channels
Voltage gated K channel – pre and post synaptically
- Repolarisation
Voltage gated Ca channels - pre and post synaptically
- Triggers release of Ach containing vesicles
Ach receptor – post synaptically
Skeletal muscle action potential characteristics?
Same as neuronal action potentials
- Some differences in voltage-gated ion channel family members
Takes 1-2 ms
What is the nicotinic AchR selective for?
A non-selective ligand-gated cation channel – Na, Ca and K
Nicotinic AchR Nernst potential?
0 mV
Half way between Na and K Nernst potentials
What is the role of the nicotinic AchR?
Causes depolarisation
This depolarisation causes opening of voltage gated Na channels
It alone is not enough to trigger an action potential
What is the structure of the nicotinic AchR?
4 types subunits
5 subunits needed to make receptor – pentameric (2 alpha subunits)
- Can have different receptors with a different mix of subunits
2 binding sites for Ach
4 transmembrane spanning domains
What is the gating process of the nicotinic AchR?
Closed
Closed – 1 agonist bound
Closed – 2 agonists bound
Open – both binding sites have to have Ach bound to open the channel
What are the genes coding for the alpha subunit of the nicotinic AchR?
CHRNA1
9 different genes coding for alpha subunits
- CHRNA1 – found in skeletal muscle
- CHRN2-8 - found in neuronal tissue
What are the genes coding for the beta subunit of the nicotinic AchR?
CHRNB1
4 different genes coding for beta subunits
- CHRNB1 – found in skeletal muscle
- CHRNB2-4 – found in neuronal tissue
What is Myasthenia gravis?
Autoimmune disease - NMJ disorder
2-7 in 10,000 UK
What causes Myasthenia gravis?
Antibodies made against AchR on postsynaptic membrane of NMJ
Lead to a block and degradation of AchR
What are the symptoms of Myasthenia gravis?
Weakness and tiredness in skeletal muscles
Can be fatal – respiratory failure
Females peak incidence – 30s
Males peak incidence – 60-70s
What is the antibody evidence for myasthenia gravis?
87% of patients positive for antibodies
Injection of mice with antibodies to AchR – experimental MG
- Loss of ability to contract muscle
What are the 6 different treatments for myasthenia gravis?
Acetycholinesterase inhibitors Immunosuppressants - corticosteroids Immunosuppressants – other IV immunoglobulins Plasmapheresis Thymectomy
Acetylcholinesterase inhibitors overview
E.g. Pyridostigmine
Use - mild
Block breakdown of Ach - enhances Ach levels
Immunosuppressants - corticosteroids overview
E.g. Prednisolone
Use - moderate to severe
Immunosuppressant that reduces antibody levels
Side effects – downregulates the whole immune system, weight gain
Immunosuppressants - other overview
E.g. cyclosporin
Reduces antibody levels
IV immunoglobulins overview
Use - severe
400mg/kg for 5 days
Mops up antibodies reducing levels
Plasmapheresis overview
E.g. filtration, immunoadsorption
Use - when acute intervention needed
Removal of antibodies from the plasma – reduces antibody levels
Thymectomy overview
Use - tumour removal or severe
Removal of AchR antibody secreting B cells
What are transverse tubules?
Specialist skeletal/cardiac muscle structures
Membrane invaginations important for action potential propagation into myofibrils
Stimulates the release of Ca from sarcoplasmic reticulum – Ca store
What are the two types of Ca channel found in the neuromuscular junction?
Transverse tubule membrane – L-type Ca channel
Ryanodine receptors
L-type Ca channel overview
Clusters of 4 Voltage gated Activation - Allows Ca to move from extracellular fluid into the cell - Opens ryanodine receptor
Ryanodine receptor overview
A type of Ca channel
Stimulate Ca release from sarcoplasmic reticulum
- Moves into cytoplasm leading to contraction
Ca channels in skeletal muscle
Mechanical coupling is the main driver of opening ryanodine receptors
A few Ca channels will open because of the influx of Ca through L-type receptors
Ca channels in cardiac muscle
Ca induced Ca release is the main driver of opening ryanodine receptors
What are the 2 ways Ca is reup taken by the cell membrane?
Ca ATPase
- Pump Ca out in exchange for halogen ions
Na/Ca exchanger
- Pump Ca out in exchange for Na
What are the 2 ways Ca is reup taken by the sarcoplasmic reticulum membrane?
Ca ATPase
- Pump Ca in in exchange for halogen ions
Calreticulin and calsequestrin
- Ca binding
- Acts as a calcium buffer within the sarcoplasmic reticulum
