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Excitation Contraction Coupling Dr. Atif Mahmood May 14, 2010.

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Presentation on theme: "Excitation Contraction Coupling Dr. Atif Mahmood May 14, 2010."— Presentation transcript:

1 Excitation Contraction Coupling Dr. Atif Mahmood May 14, 2010





6 Muscle Contraction and Relaxation Four actions involved in this process – Excitation = nerve action potentials lead to action potentials in muscle fiber – Excitation-contraction coupling = action potentials on the sarcolemma activate myofilaments – Contraction = shortening of muscle fiber – Relaxation = return to resting length Images will be used to demonstrate the steps of each of these actions

7 7 Nerve Activation of Individual Muscle Cells (cont.)

8 8 Action potential along T-tubule causes release of calcium from cisternae of TRIAD Cross-bridge cycle Excitation/contraction coupling

9 Begin cycle with myosin already bound to actin

10 10 1. Myosin heads form cross bridges Myosin head is tightly bound to actin in rigor state Nothing bound to nucleotide binding site

11 11 2. ATP binds to myosin Myosin changes conformation, releases actin

12 12 3. ATP hydrolysis ATP is broken down into: ADP + P i (inorganic phosphate) Both ADP and P i remain bound to myosin

13 13 4. Myosin head changes conformation Myosin head rotates and binds to new actin molecule Myosin is in high energy configuration

14 14 5. Power stroke Release of P i from myosin releases head from high energy state Head pushes on actin filament and causes sliding Myosin head splits ATP and bends toward H zone. This is Power stroke.

15 15 6. Release of ADP Myosin head is again tightly bound to actin in rigor state Ready to repeat cycle

16 16 THE CROSS-BRIDGE CYCLE ATP ADP + P i A M A – M ATP A M ADP P i A + M ADP P i Relaxed state Crossbridge energised Crossbridge attachment Tension develops Crossbridge detachment Ca 2+ present A, Actin; M, Myosin

17 17 Cross Bridge Cycle

18 18 Rigor mortis Myosin cannot release actin until a new ATP molecule binds Run out of ATP at death, cross-bridges never release

19 19 Many contractile cycles occur asynchronously during a single muscle contraction Need steady supply of ATP!

20 20 Regulation of Contraction Tropomyosin blocks myosin binding in absence of Ca 2+ Low intracellular Ca 2+ when muscle is relaxed

21 21 Ca +2 binds to troponin during contraction Troponin-Ca +2 pulls tropomyosin, unblocking myosin-binding sites Myosin-actin cross-bridge cycle can now occur

22 22 How does Ca 2+ get into cell? Action potential releases intracellular Ca 2+ from sarcoplasmic reticulum (SR) SR is modified endoplasmic reticulum Membrane contains Ca 2+ pumps to actively transport Ca 2+ into SR Maintains high Ca 2+ in SR, low Ca 2+ in cytoplasm

23 The action potential triggers contraction How does the AP trigger contraction? This question has the beginning (AP) and the end (contraction) but it misses lots of things in the middle! We should ask: how does the AP cause release of Ca from the SR, so leading to an increase in [Ca] i ? how does an increase in [Ca] i cause contraction?

24 Z disc A band (myosin) I band (actin) Z disc M line Z disc sarcoplasmic reticulum t-tubules junctional feet Triad Contractile proteins in striated muscle are organised into sarcomeres T-tubules and sarcoplasmic reticulum are organised so that Ca release is directed toward the regulatory (Ca binding) proteins The association of a t-tubule with SR on either side is often called a triad (tri meaning three) Structures involved in EC coupling

25 Structures involved in EC coupling - Skeletal Muscle - out in voltage sensor? junction foot sarcoplasmic reticulum sarcolemma T-tubule

26 26 Ca 2+ Controls Contraction Ca 2+ Channels and Pumps Release of Ca 2+ from the SR triggers contraction Reuptake of Ca 2+ into SR relaxes muscle So how is calcium released in response to nerve impulses? Answer has come from studies of antagonist molecules that block Ca 2+ channel activity

27 27

28 28 Dihydropyridine Receptor In t-tubules of heart and skeletal muscle Nifedipine and other DHP-like molecules bind to the "DHP receptor" in t-tubules In heart, DHP receptor is a voltage-gated Ca 2+ channel In skeletal muscle, DHP receptor is apparently a voltage-sensing protein and probably undergoes voltage-dependent conformational changes

29 29 Ryanodine Receptor The "foot structure" in terminal cisternae of SR Foot structure is a Ca 2+ channel of unusual design Conformation change or Ca 2+ -channel activity of DHP receptor apparently gates the ryanodine receptor, opening and closing Ca 2+ channels Many details are yet to be elucidated!

30 out in voltage sensor (DHP receptor) junctional foot (ryanodine receptor) sarcoplasmic reticulum sarcolemma T-tubule Skeletal muscle The AP: moves down the t-tubule voltage change detected by DHP receptors DHP receptor is essentially a voltage-gated Ca channel is communicated to the ryanodine receptor which opens to allow Ca out of SR activates contraction

31 Cardiac muscle The AP: moves down the t-tubule voltage change detected by DHP receptors (Ca channels) which opens to allow small amount of (trigger) Ca into the fibre Ca binds to ryanodine receptors which open to release a large amount of (activator) Ca (CACR) Thus, calcium, not voltage, appears to trigger Ca release in Cardiac muscle! out in voltage sensor & Ca channel (DHP receptor) junctional foot (ryanodine receptor) sarcoplasmic reticulum sarcolemma T-tubule

32 The Answers! Skeletal The trigger for SR release appears to be voltage (Voltage Activated Calcium Release- VACR) The t-tubule membrane has a voltage sensor (DHP receptor) The ryanodine receptor is the SR Ca release channel Ca 2+ release is proportional to membrane voltage Cardiac The trigger for SR release appears to be calcium (Calcium Activated Calcium Release - CACR) The t-tubule membrane has a Ca 2+ channel (DHP receptor) The ryanodine receptor is the SR Ca release channel The ryanodine receptor is Ca- gated & Ca release is proportional to Ca 2+ entry

33 33 Transverse tubules connect plasma membrane of muscle cell to SR

34 34 Ca 2+ release during Excitation-Contraction coupling Ryanodyne R Ca-release ch. Action potential on motor endplate travels down T tubules

35 35 Voltage -gated Ca 2+ channels open, Ca 2+ flows out SR into cytoplasm Ca 2+ channels close when action potential ends. Active transport pumps continually return Ca 2+ to SR Ca ATPase (SERCA)

36 36 Excitation-Contraction Coupling Depolarization of motor end plate (excitation) is coupled to muscular contraction Nerve impulse travels along sarcolemma and down T-tubules to cause a release of Ca 2+ from SR Ca 2+ binds to troponin and causes position change in tropomyosin, exposing active sites on actin Permits strong binding state between actin and myosin and contraction occurs ATP is hydrolyzed and energy goes to myosin head which releases from actin

37 37 Summary: Excitation-Contraction Coupling

38 Sliding Filament Model I: Actin myofilaments sliding over myosin to shorten sarcomeres – Actin and myosin do not change length – Shortening sarcomeres responsible for skeletal muscle contraction During relaxation, sarcomeres lengthen

39 Sliding filament model II:

40 Sarcomere Shortening

41 Muscle contraction occurs when actin and myosin, the major proteins of the thin and thick filaments, respectively, slide past each other in an ATP-driven enzymatic reaction. Sliding Filament Theory for Muscle Contraction Huxley AF and Niedergerke R, Nature 173, (1954) Structural changes in muscle during contraction; interference Microscopy of living muscle fibers. Huxley HE and Hanson J, Nature 173, (1954) Changes in cross-strations of muscle during contraction and stretch and their structural interpretation.


43 Structure of Actin and Myosin


45 Myosin structure:

46 Thick filament structure:

47 Structure of the M-line:


49 Structure of thin filament:

50 Cross-bridge formation:




54 Cross-bridge hypothesis of muscle contraction : Sliding of thin and thick filaments is caused by the cross-bridges that extend from the myosin filament, attach to actin, pull the thin filaments toward the center of the sarcomere and detach. This cyclic interaction is coupled with the hydrolysis of ATP. Sliding Filament Theory for Muscle Contraction ATP (Crossbridge) ADP + P i + Energy Coupling of chemical reactions with vectorial motion.

55 Initiation of Contraction, Ca 2+ release:



58 The micrograph shows myosin bound to actin EM evidence for sliding filament theory Contraction of one sarcomere

59 Mechanism of muscle contraction

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