Neuromuscular junction (HY)

https://youtu.be/_k6QINRcdV4?si=cmfHOuV6JpyxQCm4

Definition

• Is the synapse between axons of motorneurons and skeletal muscles

Presynaptic neuron

• Action potential → depolarization of the presynaptic membrane → opening of voltage-gated Ca2+ channels → influx of Ca2+ into the presynaptic terminal→ release of acetylcholine (ACh) from vesicles into the synaptic cleft.

Post synaptic neuron

• Binding of Ach with postsynaptic nicotinic receptors (ligand gated channels)→ Na influx and K outflux→ forming **miniature end plate potential (MEPPs)**→ MEPPs summate to produce full **end plate potential (EPP)**→ once end plate region is depolarized→ local currents spread causing depolarization and action potential of the adjacent muscle tissue.

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  Miniature end plate potential (MEPPs) vs end plate potential (EPP)

  • MEPPs→ Contents of one synaptic vesicle (one quantum) produces a miniature end plate potential.
  • EPP→ Refers to the depolarization of the specialized muscle end plate. </aside>

Synaptic cleft

• Acetylcholinesterase (AChE) breaks down ACh → acetate and choline → reuptake of choline into the presynaptic membrane → resynthesis of ACh

Muscles

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Sarcomere

• Composed of overlapping filaments of actin and myosin as well as structural and binding proteins (eg, titin, a-actinin).
• A single sarcomere is defined as the distance between two Z lines.
• Thin (actin) filaments are bound to structural proteins at the Z line </aside>

Skeletal muscle

Skeletal muscle contraction and relaxation (HY to understand the sequence)

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T-tubules (Transverse tubules)

• Extensions of the plasma membrane that transmit depolarization signals to the sarcoplasmic reticulum to trigger the release of calcium and induce muscle contraction allowing for the coordinated contraction of striated muscles
• ↓ numbers of functional T-tubules in affected muscle fibers lead to uncoordinated contraction of myofibrils, which manifests as muscle weakness.
  • Explanatory picture </aside>

1. Postsynaptic ACh binding leads to muscle cell depolarization at the motor end plate.

2. Depolarization travels over the entire muscle cell and deep into the muscle via the T-tubules.

3. Membrane depolarization induces conformational changes in the voltage sensitive dihydropyridine receptor (DHPR) and **its mechanically coupled ryanodine receptor (RR)**→ Ca2+ release from the sarcoplasmic reticulum into the cytoplasm.

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   Normally Ca release from sarcoplasmic reticulum is prevented by calsequestrin in the resting state.

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4. Tropomyosin is blocking myosin-binding sites on the actin filament. Released Ca2+ binds to troponin C (TnC), shifting tropomyosin to expose the myosin binding sites.

5. Myosin head binds strongly to actin (cross-bridge). P$_i$ released, initiating power stroke.

6. During the power stroke, force is produced as myosin pulls on the thin filament. Muscle shortening occurs

   • H and I bands between Z lines → shortened (HI, I’m wearing shortZ)
   • A bands → remains the same length (A band is Always the same length)
   • ADP is released at the end of the power stroke.

7. Binding of new ATP molecule causes detachment of myosin head from actin filament and Ca2+ is re-sequestered.

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   Clinical relevance

   • After death, loss of ATP prevents both myosin head detachment and clearance of cytoplasmic calcium, leading to diffuse and persistent skeletal muscle stiffening (rigor mortis). </aside>

8. ATP hydrolysis into ADP and P$_i$ results in myosin head returning to high-energy position (cocked). The myosin head can bind to a new site on actin to form a cross-bridge if Ca2+ remains available.

9. Reuptake of calcium by sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA)→ muscle relaxation

<aside> ♻️ Summary of Muscle Contraction

Action Potential → ACh Release → Muscle Depolarization → Calcium Release → Crossbridge Formation → Power Stroke → Relaxation.

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Types of Skeletal Muscle Fibers

• Overview
  • Two types, normally distributed randomly within muscle.
  • Muscle fiber type grouping commonly occurs due to reinnervation of denervated muscle fibers in peripheral nerve damage.
    • More explanation

checkerboard pattern of type I and type II fibers