6Muscle Contraction and Relaxation Four actions involved in this processExcitation = nerve action potentials lead to action potentials in muscle fiberExcitation-contraction coupling = action potentials on the sarcolemma activate myofilamentsContraction = shortening of muscle fiberRelaxation = return to resting lengthImages will be used to demonstrate the steps of each of these actions
7Nerve Activation of Individual Muscle Cells (cont.)
8Excitation/contraction coupling Action potential along T-tubule causes release of calcium from cisternae of TRIADCross-bridge cycle
101. Myosin heads form cross bridges Myosin head is tightly bound to actin in rigor stateNothing bound to nucleotide binding site
112. ATP binds to myosinMyosin changes conformation, releases actin
123. ATP hydrolysis ATP is broken down into: ADP + Pi (inorganic phosphate)Both ADP and Pi remain bound to myosin
134. Myosin head changes conformation Myosin head rotates and binds to new actin moleculeMyosin is in high energy configuration
145. Power strokeRelease of Pi from myosin releases head from high energy stateHead pushes on actin filament and causes slidingMyosin head splits ATP and bends toward H zone. This is Power stroke.
156. Release of ADPMyosin head is again tightly bound to actin in rigor stateReady to repeat cycle
16THE CROSS-BRIDGE CYCLE Relaxed state Crossbridge energisedCrossbridge attachmentA + M l ADP l PiCa2+ presentA – M l ATPAlMlADPlPiCrossbridge detachmentTension developsADP + PiATPAlMA, Actin; M, Myosin
18Rigor mortisMyosin cannot release actin until a new ATP molecule bindsRun out of ATP at death, cross-bridges never release
19Need steady supply of ATP! Many contractile cycles occur asynchronously during a single muscle contractionNeed steady supply of ATP!
20Regulation of Contraction Tropomyosin blocks myosin binding in absence of Ca2+Low intracellular Ca2+ when muscle is relaxed
21Ca+2 binds to troponin during contraction Troponin-Ca+2 pulls tropomyosin, unblocking myosin-binding sitesMyosin-actin cross-bridge cycle can now occur
22How does Ca2+ get into cell? Action potential releases intracellular Ca2+ from sarcoplasmic reticulum (SR)SR is modified endoplasmic reticulumMembrane contains Ca2+ pumps to actively transport Ca2+ into SRMaintains high Ca2+ in SR, low Ca2+ in cytoplasm
23The 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?
24Structures involved in EC coupling A band(myosin)I band(actin)Z discContractile proteins in striated muscle are organised into sarcomeresT-tubules and sarcoplasmic reticulum are organised so that Ca release is directed toward the regulatory (Ca binding) proteinsThe association of a t-tubule with SR on either side is often called a ‘triad’ (tri meaning three)Z discM lineZ discsarcoplasmicreticulumt-tubulesTriadjunctional feet
26Ca2+ Controls Contraction Ca2+ Channels and PumpsRelease of Ca2+ from the SR triggers contractionReuptake of Ca2+ into SR relaxes muscleSo how is calcium released in response to nerve impulses?Answer has come from studies of antagonist molecules that block Ca2+ channel activity19
28Dihydropyridine Receptor In t-tubules of heart and skeletal muscleNifedipine and other DHP-like molecules bind to the "DHP receptor" in t-tubulesIn heart, DHP receptor is a voltage-gated Ca2+ channelIn skeletal muscle, DHP receptor is apparently a voltage-sensing protein and probably undergoes voltage-dependent conformational changes20
29The "foot structure" in terminal cisternae of SR Ryanodine ReceptorThe "foot structure" in terminal cisternae of SRFoot structure is a Ca2+ channel of unusual designConformation change or Ca2+ -channel activity of DHP receptor apparently gates the ryanodine receptor, opening and closing Ca2+ channelsMany details are yet to be elucidated!21
30Skeletal muscle The AP: moves down the t-tubule voltage change detected by DHP （双氢吡啶） receptorsDHP receptor is essentially a voltage-gated Ca channelis communicated to the ryanodine receptor which opens to allow Ca out of SRactivates contractionoutinvoltage sensor(DHP receptor)junctional foot(ryanodine receptor)sarcoplasmicreticulumsarcolemmaT-tubule
31Cardiac 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 fibreCa 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!outinvoltage sensor& Ca channel(DHP receptor)junctional foot(ryanodine receptor)sarcoplasmicreticulumsarcolemmaT-tubule
32The Answers! Skeletal Cardiac The trigger for SR release appears to be calcium (Calcium Activated Calcium Release - CACR)The t-tubule membrane has a Ca2+ channel (DHP receptor)The ryanodine receptor is the SR Ca release channelThe ryanodine receptor is Ca- gated & Ca release is proportional to Ca2+ entrySkeletalThe 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 channelCa2+ release is proportional to membrane voltage
33Transverse tubules connect plasma membrane of muscle cell to SR
34Ca2+ release during Excitation-Contraction coupling Action potential on motor endplate travels down T tubulesRyanodyne RCa-release ch.
35Voltage -gated Ca2+ channels open, Ca2+ flows out SR into cytoplasm Ca2+ channels close when action potential ends. Active transport pumps continually return Ca2+ to SRCa ATPase(SERCA)
36Excitation-Contraction Coupling Depolarization of motor end plate (excitation) is coupled to muscular contractionNerve impulse travels along sarcolemma and down T-tubules to cause a release of Ca2+ from SRCa2+ binds to troponin and causes position change in tropomyosin, exposing active sites on actinPermits strong binding state between actin and myosin and contraction occursATP is hydrolyzed and energy goes to myosin head which releases from actin
38Sliding Filament Model I: Actin myofilaments sliding over myosin to shorten sarcomeresActin and myosin do not change lengthShortening sarcomeres responsible for skeletal muscle contractionDuring relaxation, sarcomeres lengthen
41Sliding Filament Theory for Muscle Contraction 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.Huxley AF and Niedergerke R, Nature 173, (1954)Structural changes in muscle during contraction; interferenceMicroscopy 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.
54Sliding Filament Theory for Muscle Contraction Coupling of chemical reactions with vectorial motion.ATP (Crossbridge) ADP + Pi + EnergyCross-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.