Question 8

College Answer

This question required a description of excitation- contraction coupling. Marks were gained for a brief outline of the structure of a sarcomere and how it facilitates shortening. An explanation of membrane processes, receptor interactions and the contraction processes was required. Mention of the role of ATP was also required and marks were gained for commenting on the mechanism of return to the relaxed state.
Most candidates wrote extensively on the nerve action potential and neuromuscular junction transmission, with minimal reference to events occurring within the skeletal muscle cell membrane. They could not gain marks for this. Few candidates  demonstrated knowledge of the ATP dependent walk along processes of myosin heads during contraction.

Discussion

• Excitation-contraction coupling is the series of events that link the sarcolemma action potential to muscle contraction and relaxation
• Action potentials propagate from the motor endplate along skeletal myocytes at 3-5m/s
  • Each cell is electrically isolated from others, and is activated independently by its own motor endplate
  • Skeletal muscle action potentials are short (4ms)
  • They access the centre of the myocyte (depth of up to 50 μm) by propagating along T tubules
• Voltage-gated L-type calcium channels (dihydropyridine receptors) are activated by the action potential
  • These are connected directly to the ryanodine receptor
  • The ryanodine receptor then acts as a calcium channel, releasing stored calcium from the sarcoplasmic reticulum.
• Calcium release from the sarcoplasmic reticulum occurs
  • Cytoplasmic free calcium concentration increases to 20 μmol/L
  • This occurs in the "triad" area immediately adjacent to the T tubule, bordered by sarcoplasmic reticulum and the Z lines of sarcomeres
• Intracellular calcium acts on regulatory proteins
  • Troponin C binds calcium and dissociates from the actin/tropomyosin complex, exposing active sites and allowing cross-bridge cycling
• Crossbridge cycling occurs
  • Myosin binds ATP, dissociates from actin, and "cocks" its head to a 90º angle.
  • Then its head binds actin again, which forms the cross-bridge
  • It then releases the inorganic phosphate and returns its head to its original position, which results in the movement of the myosin molecule about 11 nm along the actin filament.
  • When the myosin head binds ATP again, the cycle repeats.
• Sarcometre shortening occurs (by about 11 nm each cycle)
  • Contractile proteins are arranged into sarcomere units, composed of overlapping regular bands of thin (actin) and thick (myosin) filaments
  • Cross-bridge cycling increases the overlap between these proteins
  • Because the thin filaments are tethered to the myocyte cytoskeleton at the Z band, the mechanical force generated by actin and myosin sliding along each other is transmitted to the surrounding myocyte structures.
• Calcium buffering by proteins removes some calcium from the cytosol
  • Free calcium concentration decreases when it binds to troponin, ATP and parvalbumin
• Calcium removal from the cytosol is required for striated muscle relaxation
  • Calcium is removed mainly by the SERCA ATPase pump which removes it from the cytosol and returns it to the sarcoplasmic reticulum.
  • In the absence of calcium, troponin and tropomyosin block the myosin binding sites on the actin filament, preventing cross-bridge formation

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Craig, R., and Raúl Padrón. "Molecular structure of the sarcomere." Myology 3 (2004): 129-144.

Sweeney, H. Lee, and David W. Hammers. "Muscle contraction." Cold Spring Harbor Perspectives in Biology 10.2 (2018): a023200.

Calderón, Juan C., Pura Bolaños, and Carlo Caputo. "The excitation–contraction coupling mechanism in skeletal muscle." Biophysical reviews 6.1 (2014): 133-160.