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![Cross Bridge Cycle
Cycle repeats as long as Ca2+ is elevated
and sufficient ATP is there
Muscle cells do not regulate cross-bridge
cycling by modifying [ATP]i
Instead, skeletal muscle and cardiac
muscle control this cycle by preventing
cross-bridge formation until the
tropomyosin moves out of the way in
response to an increase in [Ca2+]i](https://image.slidesharecdn.com/muscle3-excitationcontractioncoupling-180414105857/75/Excitation-Contraction-coupling-34-2048.jpg)
![Steps in Relaxation
Cell may extrude Ca2+ using either an Na-
Ca exchanger (NCX) or a Ca2+ pump(PMCA)
However, would eventually deplete the cell of
Ca2+ and is thus a minor mechanism for Ca2+
removal from the cytoplasm
Instead, Ca2+ re-uptake into the SR is the
most important mechanism by which the
cell returns [Ca2+]i to resting levels
Ca2+ re-uptake by the SR is mediated by a
SERCA(s arcoplasmic or e ndoplasmic
r eticulum C a2+A TPase )-type Ca2+ pump](https://image.slidesharecdn.com/muscle3-excitationcontractioncoupling-180414105857/75/Excitation-Contraction-coupling-45-2048.jpg)
![Steps in Relaxation
SR Ca2+-pump activity is inhibited by high [Ca2+]
within the SR lumen
Inhibition of SR Ca2+-pump activity is delayed by
Ca2+-binding proteins within the SR lumen
Buffer the Ca2+ increase in the SR during Ca2+ re-uptake
and thus markedly increase the Ca2+ capacity of SR
Proteins have a tremendous capacity to bind Ca2+ with
up to 50 binding sites per protein molecule
Principal Ca2+ binding protein in skeletal muscle,
calsequestrin
also present in cardiac and some smooth muscle
Calreticulin - Ca2+-binding protein found in particularly
high concentrations within the SR of smooth muscle](https://image.slidesharecdn.com/muscle3-excitationcontractioncoupling-180414105857/75/Excitation-Contraction-coupling-46-2048.jpg)
Uploaded byPradeep Singh Narwat
Excitation - Contraction coupling
The document summarizes the mechanism of skeletal muscle contraction. It describes how an action potential leads to a rise in intracellular calcium levels through excitation-contraction coupling. This triggers the sliding filament theory where actin and myosin filaments slide past each other through cross-bridge cycling powered by ATP hydrolysis. Calcium binds to troponin C, allowing the power stroke to occur as myosin heads pull the actin filaments towards the center of the sarcomere. Relaxation occurs as calcium is re-sequestered in the sarcoplasmic reticulum, breaking the cross-bridges.
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Excitation - Contraction coupling
- 1. Mechanism of Skeletal MuscleContraction (Excitation Contraction Coupling)
- 2. Contraction For contraction,skeletal muscle must: be stimulated by a nerve ending propagate an action potential, along its sarcolemma have a rise in intracellular Ca2+ levels, the final stimulus for contraction Ca2+ levels may rise from its resting level of less than 10-7 M to greater than 10-5 M
- 3. Theories of MuscleContraction New elastic body theory (1840 – 1920 ) Fenn observed that total energy released by muscle (work +heat) increases as muscle work increases this is known as “FENN EFFECT” Continuous filament theory – According to this theory, during contraction actin & myosin combine to form 1 continuous filament which undergoes folding & shortening Electron microscope observations do not support this theory as after contraction length of thick & thin filament is not altered only their relative position changes
- 4. Theories of MuscleContraction Sliding Filament Theory (1954): Huxley and Niedergerke Sliding filament theory was transformed into Cross Bridge cycle (1957): Huxley Thin filament slides past thick filament Molecular basis of sliding motion is by globular head of myosin forming cross bridges with actin monomers (Huxley’s Cross Bridge theory) or Ratchet theory of muscle contraction / Walk along Theory
- 5. Sliding Filament Theory Thin filament slides over the thick Width of A band constant Z-lines move closer – contraction move apart – relaxation A. Relaxed I band A band sarcomere M lineZ disk B. Contracted
- 6.
- 8. Excitation –Contraction Coupling Sequence of events linking the transmission of an action potential along the sarcolemma to muscle contraction (the sliding of myofilaments)
- 9. Excitation Contraction(EC) coupling The entire process, extending from depolarization of the T-tubule membrane to the initiation of cross-bridge cycling, is termed Excitation Contraction coupling or EC coupling Action potential travels along T-Tubules leading to Ca++ release from sarcoplasmic reticulum leading to contraction
- 10. Excitation Contraction(EC) coupling Electrical Event Action potential generated in muscle fiber memb. due to depolarization of motor end plate AP transmitted along muscle fiber – initiates contractile response Mechanical Event Contraction via contractile protein myosin and cytoskeletal protein actin ` Single AP causes a brief contraction followed by relaxation – Simple Muscle Twitch
- 11. Electrical and MechanicalResponse Plotted on the same time scale Twitch starts about 2 ms after start of depolarization of membrane & before repolarization is complete Duration of twitch varies with type of muscle "Fast" muscle fibers- fine, rapid, precise movement - twitch durations as short as 7.5 ms "Slow" muscle fibers - strong, gross, sustained movements - twitch durations up to 100 ms
- 12. Action Potential RMP= -90mv AP lasts for 2-4 milliseconds (ms), conducted along muscle fiber at 5 m/sec with ARP = 1-3 msec Ends before contraction occurs Period between action potential initiation and the beginning of contraction is called the latent period Excitation-contraction coupling occurs within the latent period
- 15.
- 16. STEPS IN CONTRACTION Neurotransmitter acetylcholine (ACh) binds to its receptors on the motor end plate Ligand gated ion channels in the receptors open and allow Na+ and K+ to move across the membrane depolarization
- 17. Action Potential Propagated alongSarcolemma Reaches the T Tubules Triads
- 18. T – systemor Transverse Tubular System Contains L-type Ca2+ channels clustered in groups of four called "tetrads“ Each is in fact a heteropentameric protein Each of the four Ca2+ channels is also called a DHP receptor because inhibited by class of antihypertensive drugs known as dihydropyridines Function as voltage sensor in EC coupling Depolarization of T-tubule activates longitudinal sarcoplasmic reticulum via DHP receptors
- 19. Ca2+ channel inSarcoplasmic Reticulum a.k.a ryanodine receptor Because inhibited by class of drugs that include the plant alkaloids ryanodine and caffeine Homotetrameric structure Each of the four subunits of these channels has a large extension-also known as a "foot.“ Ligand gated Ca2+ channel with calcium as its natural ligand Ca2+ -induced Ca2+ release (CICR)
- 20. Depolarization of T-tubule Each L-type Ca2+ channel interacts with foot of one of the 4 subunits of the Ca2+-release channel Depolarization of T-tubule evokes conformational changes in each of the four L-type Ca2+ channels and has two effects Conformational changes allow Ca2+ to enter through the four channel pores Second, and much more important, the conformational changes in the four L-type Ca2+ channels induce a conformational change in each of the four subunits of another channel-the Ca2+-release channel-that is located in the SR membrane
- 25. Ca++ bindswith Troponin C Troponin – Tropomyosin complex inhibits the interaction between actin and myosin When Ca++ binds to Trop C, active sites of actin are uncovered & ATP is split to ADP releasing P- energy & contraction occurs Excitation Contraction(EC) coupling
- 26. Troponin Each troponinC molecule in skeletal muscle has 2 high-affinity Ca2+ -binding sites 2 low-affinity Ca2+-binding sites Binding of Ca2+ to low-affinity sites induces a conformational change in the troponin complex that has two effects troponin I moves away from the actin/tropomyosin filament, thereby permitting the tropomyosin molecule to move troponin T pushes tropomyosin away from the myosin- binding site on the actin and into the actin groove With the steric hindrance removed, the myosin head is able to interact with actin and engage in cross-bridge cycling
- 28. Cross Bridge Cycle In presence of calcium, myosin head binds to an actin filament Changes its orientation relative to myosin filament which causes filaments to slide relative to each other - Power Stroke During the Cross-Bridge Cycle, Contractile Proteins Convert the Energy of ATP Hydrolysis Into Mechanical Energy Each power stroke shortens sarcomere by 10nm Cross bridge cycling is asynchronous 500 myosin in one thick filament, each head cycling 5 times per second
- 30. Cross Bridge Cycle Occurs in 5 steps :- 1. Cross – Bridge formation – cocked myosin head (perpendicular or at a 90-degree angle to the thick and thin filaments) binds to actin filament Cocked head has the stored energy derived from the cleaved ATP
- 31. Cross Bridge Cycle 2.Release of Pi from the myosin Dissociation of Pi from the myosin head triggers power stroke Conformational change - myosin head bends approximately 45º about the hinge Pulls the actin filament about 11 nm toward the tail of the myosin molecule Generating force and motion
- 32. Cross Bridge Cycle 3.ADP release – Dissociation of ADP from myosin Myosin head remains in the same position (45º angle with respect to the thick and thin filaments) 4. ATP binding – ATP binding to the head of the myosin heavy chain (MHC) reduces the affinity of myosin for actin Myosin head releases actin filament
- 33. Cross Bridge Cycle 5.ATP hydrolysis – Breakdown of ATP to ADP and inorganic phosphate (Pi) occurs on myosin head Products of hydrolysis are retained on the myosin As a result of hydrolysis, the myosin head pivots around the hinge into a "cocked" position (perpendicular or at a 90º angle to the thick and thin filaments) Rotation causes the tip of the myosin to move about 11 nm along the actin filament so that it now lines up with a new actin monomer two monomers further along the actin filament
- 34. Cross Bridge Cycle Cycle repeats as long as Ca2+ is elevated and sufficient ATP is there Muscle cells do not regulate cross-bridge cycling by modifying [ATP]i Instead, skeletal muscle and cardiac muscle control this cycle by preventing cross-bridge formation until the tropomyosin moves out of the way in response to an increase in [Ca2+]i
- 36.
- 37.
- 38. Movement of 10nm Force in pico N Cross Bridge cycle
- 39.
- 40.
- 41.
- 42.
- 43.
- 44.
- 45. Steps in Relaxation Cell may extrude Ca2+ using either an Na- Ca exchanger (NCX) or a Ca2+ pump(PMCA) However, would eventually deplete the cell of Ca2+ and is thus a minor mechanism for Ca2+ removal from the cytoplasm Instead, Ca2+ re-uptake into the SR is the most important mechanism by which the cell returns [Ca2+]i to resting levels Ca2+ re-uptake by the SR is mediated by a SERCA(s arcoplasmic or e ndoplasmic r eticulum C a2+A TPase )-type Ca2+ pump
- 46. Steps in Relaxation SR Ca2+-pump activity is inhibited by high [Ca2+] within the SR lumen Inhibition of SR Ca2+-pump activity is delayed by Ca2+-binding proteins within the SR lumen Buffer the Ca2+ increase in the SR during Ca2+ re-uptake and thus markedly increase the Ca2+ capacity of SR Proteins have a tremendous capacity to bind Ca2+ with up to 50 binding sites per protein molecule Principal Ca2+ binding protein in skeletal muscle, calsequestrin also present in cardiac and some smooth muscle Calreticulin - Ca2+-binding protein found in particularly high concentrations within the SR of smooth muscle
- 48. Steps in Relaxation When Ca++ conc. outside has lowered, interaction of actin & myosin ceases & muscle relaxes ATP required for both contraction &relaxation Pump concentrates Ca++ about 10,000fold Normal/Resting Ca++ conc. (less than 10-7 moles of Ca++ ) rises to 10-5 M Total duration of Ca++ ions stay in fluid is 1/30th of sec
- 49. Contracture Ca2+ movementinhibited Relaxation fails to occur Cross bridges don’t break Sustained contraction despite no action potential
- 50. Role of ATP Provides energy for power stroke of myosin head Brings about a dissociation of myosin head from actin filament Brings about muscle relaxation by pumping Ca2+ back into sarcoplasmic reticulum
- 51. Rigor Mortis Musclesof body become very stiff and rigid shortly after death Due to loss of ATP in the muscle cell In absence of ATP, the myosin cross bridges with actin is not broken, so, no relaxation occurs 15-25 hrs later, muscle proteins deteriorate and rigor disappears
- 57. EC Coupling: Drugs Blocking release of Ca++ from SR keeps muscle relaxed, even in the presence of action potential eg Ryanodine receptor blocker like Protamine sulphate Caffeine cause release of Ca++ produces contraction without action potential Drugs which increase the release of Ca++ from sarcoplasmic reticulum. eg. Digitalis increase the force of cardiac muscle contraction
- 58. Malignant Hyperthermia Channelopathyof calcium release channel in muscle (Ryanodine receptors) constant leak of SR Ca2+ through ryanodine receptor triggered by halogenated anesthetics (isoflurane, halothane) or severe exercise familial tendency - can be tested for by muscle biopsy Symptoms Normal muscle function under normal conditions increased body temperature -more heat produced skeletal muscle rigidity lactic acidosis (hypermetabolism)
- 59. Thank you References: Guyton- Textbookof Medical Physiology Ganong’s- Review of Medical Physiology Boron-Medical Physiology Kandel-Principles of Neural Science Silbernagl-Color atlas of Physiology Ira Fox- Medical Physiology
Editor's Notes
- #4 When muscle contracts, work is performed and energy required. Greater the amount of work performed by muscle, greater is the amount of ATP cleaved – phenomenon is called FENN Effect
- #23 A tetrad of four L-type Ca2+ channels on the T tubules faces a single Ca2+-release channel of the SR, so that each L-type Ca2+ channel interacts with the foot of one of the four subunits of the Ca2+-release channel.
- #56 Contraction remainder after fatigued muscle due to ATP depletion also. Heat Rigor – temp above 50°C cause coagulation of muscle protein – can be demonstrated in isolated muscle preparations