Excitation-Contraction Coupling and Muscle Contraction

Excitation-Contraction Coupling

  • Overview: This section explains how muscle fiber stimulation leads to muscle contraction.
  • Key stages to remember in the process.

Steps in Excitation-Contraction Coupling

  1. Nerve Axon & Acetylcholine Release

    • Nerve axon releases acetylcholine into the synaptic cleft.
    • Acetylcholine binds to receptors on the sarcolemma (muscle fiber membrane).

  2. Action Potential Generation

    • Binding of acetylcholine generates an action potential.
    • Action potential travels along the sarcolemma and down the T tubules.

  3. Calcium Release

    • Action potential in the T tubule triggers calcium release from the terminal cisternae of the sarcoplasmic reticulum.
    • This release is facilitated by specialized channel proteins.

  4. Increase in Calcium Concentration

    • Calcium concentration rises in the sarcoplasm surrounding the muscle filaments.

  5. Calcium Binding to Troponin

    • Calcium ions bind to troponin.
    • Troponin changes shape, removing the blocking action of tropomyosin, which activates the actin binding sites.

  6. Contraction

    • Myosin cross-bridges attach to actin and detach, pulling the actin filaments towards the center of the sarcomere.
    • ATP hydrolysis powers this cyclical process.

  7. Muscle Relaxation - Calcium Removal

    • Calcium is removed from the sarcoplasm by reuptake into the sarcoplasmic reticulum.
    • This occurs via calcium ATPase in the sarcoplasmic reticular membranes.
    • No more excitatory input telling the muscle to contract.

  8. Tropomyosin Blockage Restored

    • Tropomyosin re-blocks the actin binding sites.
    • Contraction ends, and the muscle fiber relaxes.

Additional Points

  • Generation of a peripheral nerve action potential follows a similar concept.

T-Tubule and Sarcoplasmic Reticulum Interaction

  • Crucial for calcium release.
  • Calcium interacts with troponin, causing a conformational shift.
  • Exposes the myosin binding site, allowing myosin heads to attach to actin.

Dihydropyridine Receptors (DHPRs) and Ryanodine Receptors (RYRs)

  • DHPRs (yellow)

    • Voltage sensors located in the T tubules.
    • Detect voltage changes from the action potential.
    • Interact with the sarcoplasmic reticulum.
    • Composed of alpha-1s and Cav1.1 subunits, acting as voltage sensors.
    • Beta-1a subunit interacts with the ryanodine receptor.

  • RYRs (green)

    • Major channel protein in the sarcoplasmic reticulum.
    • Facilitates calcium release.
    • Each RYR is linked to a DHPR tetrad.

  • CASQ

    • Sequester calcium inside the sarcoplasmic reticulum, ready for release.

Ryanodine Receptor Details

  • RYR1 isoform is most common in skeletal muscle.
  • Each ryanodine receptor associated with binding protein known as FK5A6, coordinating opening and closing of RYR monomers.

Intracellular Calcium and Magnesium

  • High intracellular calcium can activate the ryanodine receptor, leading to calcium-induced calcium release.
  • Magnesium acts as a potent inhibitor, competing with calcium at its activation site.
  • Magnesium supplementation is thought to help attenuate uncontrolled calcium release, potentially preventing muscle cramps.

Juxtaphylline Proteins (JPH)

  • Serve as a structural guide or molecular bridge between the terminal cisternae of the sarcoplasmic reticulum and the sarcolemma.
  • Tightly link the ryanodine receptor to the dihydropyridine receptor.
  • Interact with transient receptor potential channel 3 (TRPC3), which is functionally linked to the ryanodine receptor.

Triadin

  • Binds to calsequestrin and ryanodine receptor 1 (RYR1).
  • Essential for electrically induced calcium release.
  • Constructs lacking triadin binding regions lack electrically induced calcium release and demonstrate slow kinetics of ligand induced calcium release.
  • Facilitates calcium release.

Calsequestrin

  • Most abundant calcium-binding protein in the sarcoplasmic reticulum.
  • Binds calcium and brings it towards the ryanodine receptor for release.
  • Two forms:
    • Casc1: Only isoform in type II muscle fibers.
    • Casc1 & Casc2: Both found in type I muscle fibers.
    • Casc2: Only isoform present in heart muscle.

Cross-Bridge Cycle

  • Involves multiple attachment and detachment sites and rotational movement of the cross-bridge head.
Steps
  1. Cross-Bridge Attachment
    • Myosin head in high-energy configuration.
  2. Power Stroke
    • ADP and Pi are released.
    • Myosin head bends, pulling the actin filament.
  3. Cross-Bridge Detachment
    • ATP attaches to the myosin head.
    • Myosin head goes into low-energy configuration.
  4. Cocking of Myosin Head
    • ATP is split into ADP and Pi by myosin ATPase.

Myofibrillar ATPase

  • Splits ATP to yield energy for muscle contractions.
  • Type II fibers have a higher concentration of myofibrillar ATPase.
  • Faster ATP use leads to a faster binding rate, which is a rate-limiting step in muscle contraction.
  • More cross-bridges attached, the greater the force produced.
  • More ATPase activity = greater attachments
  • Less ATPase activity = less attachments

Sarcomere Length

  • Optimal length exists for maximal cross-bridge formation and force production.
  • Too lengthened: Little actin-myosin interaction.
  • Too short: Too much overlap, limiting further contraction.