5. Physiology of muscle contraction Flashcards
How does troponin unmask the myosin binding site on actin?
4 Ca2+ bind to troponin C (C = calcium binding),
In heart TnC only binds to 3 Ca2+ ions
TnC changes conformation
conformational change in TnC “shuts off” TnI
tropomyosin-troponin leaves F-actin groove
unmasks the myosin binding site on actin
What happens after actin’s myosin binding site is exposed?
next myosin heads make cross bridges (cycling) to actin
Myosin breaks down ATP
Myosin pulls thin filaments
What is TnI a marker for?
Total TnI = marker for total muscle breakdown
Cardiac TnI = marker for myocardial infarct
What is cross bridge cycling?
Molecular cycle of actin-myosin interaction
Mechanism of Contraction at Molecular level
What does contraction depend on?
contraction depends on binding of myosin heads to thin filaments (actin) at specific binding sites
What stops contraction when the sarcomere is at rest?
in resting state of sarcomere, myosin heads are blocked from binding to actin by tropomyosin, which occupies the specific binding sites (in F-actin double helical groove)
Force generation vs sarcomere length
Increasing overlap thin and thick filaments -> increased force UP TO the optimal length
Greatest force generation occurs when sarcomere is at optimal length
When sarcomere is really small, everything overlaps so get no force at all
BUT if stretch sarcomere really far, then myosin heads don’t overlap with any actin so can’t generate any force
Cross bridge cycle reactions
- Myosin releases actin
- Myosin head cleaves ATP
- Myosin binds actin
- Power stroke
Creatine
creatine found in muscle fibres
phosphorylated to creatine phosphate
Stored in muscle as creatine phosphate
What role does creatine have in cross bridge cycling?
keeps ATP levels stable (buffering and regenerating it)
when ATP is hydrolysed to ADP and Pi, creatine phosphate donates a high energy phosphate to ADP, restoring it to ATP
What enzymes catalyse ATP to ADP + Pi with creatine phosphate?
the reaction is catalysed in both directions by the enzyme creatine phosphokinase (a/k/a CK, CPK)
Is creatinine and creatine the same?
No!
Creatine is a small molecule that can accept high energy phosphate bonds from ATP
Creatine-phosphate is the above molecule after phosphate has been added to it
Creatine-phosphokinase (CPK) is the enzyme the adds phosphate to creatine
This is a plasma marker of muscle destruction
It is a large molecule detected by antibodies
Creatine-kinase (CK) is just another name for creatine phosphokinase (above). They are the same thing.
Creatinine is a diagnostic marker of kidney function. It is a breakdown product of creatine.
What triggers contraction?
Calcium triggers contraction
Calcium gradients in contraction
There are two Ca2+ gradients
Extracellular vs. cytosolic free Ca2+
SR vs. cytosolic free Ca2+
efflux of Ca2+ from sarcoplasmic reticulum to cytoplasm provides most of calcium
Calcium entering cell from outside provides only small fraction of calcium needed for contraction
What does depolarisation lead to?
Increase in Ca2+
Depolarisation
ACh -> Depolarisation
Active Nicotinic AChR -> net inward current
depolarisation spreads via T-Tubules
Local action potentials trigger Ca2+ efflux from terminal cisternae
->
Across membrane of sarcoplasmic reticulum
->
into the fibre cytoplasm
Excitation contraction (EC) coupling
the molecular mechanism for how the depolarisation of the plasma membrane leads to the release of Ca2+ into the cytoplasm followed by contraction.
Ryanodine receptor (RyR) aka Ca2+ release channel
In SR membrane
Releases Ca2+
From SR
Triggered by voltage sensor on Ca2+ channel