Molecular Basis of Cardiac Muscle Contraction (Homsher) Flashcards
Cardiac myocytes
Muscle cells of the heart
Cylindrical, mono-nucleate, striated
Adhere end to end via intercalated disks (allow electrical activity to pass from one cell to next)
Thick filaments of myosin and thin filaments of actin
Long, coiled flexible cytoskeletal protein titin which holds thick filaments to the Z-disk
Sarcoplasmic reticulum that holds Ca2+ for release
T-tubules are invaginations of surface membrane (ventricles only!?)
What happens on the thin (actin) filament in the presence and absence of Ca2+?
No Ca2+: tropomyosin lies on top of actin, troponin (C) binds to tropomyosin and actin to BLOCK myosin’s binding site
Yes Ca2+: Ca2+ binds to troponin (C), so troponin no longer brings tropomyosin over binding sites, and myosin can bind actin
Troponin C binds calcium when Ca2+ around, but when it’s not around, TnC is what brings tropomyosin and actin together to block myosin’s binding site. Troponin I binds actin. Troponin T tropomyosin? All form a globule to act together?
TItin
Long elastic protein that connects thick filaments to Z-disk and to thin filaments
During diastole, is responsible for diastolic pressure and promotes sarcomere uniformity along length of the muscle
About how long is unstrained cardiac myocyte? How much does it stretch (diastole) and contract (systole)?
Unstrained: 1.7 um
Systole: 1.4 um
Diastole: 2.4 um
What allows for the gradation of force (or pressure) exerted during systole?
The gradation of the number of cross bridges attached!
More cross bridges attaching to thin filament mean more force generated
Ultimately, amount of Ca2+ released into the sarcoplasm determines how many myosin binding sites are exposed on actin and thus how many cross bridges can form
Steps in which cross bridges power the sliding of thick and thin filaments past one another to produce force and shortening of muscle
0) Myosin is bound tightly to actin (rigor)
1) ATP binds actin monomer and causes myosin jaws to open
2) Cross bridge detaches from actin
3) Myosin hydrolyzes ATP –> ADP, which causes myosin to change conformation so lever arm is cocked
4) Ca2+ bound to troponin so myosin binds actin again and closes jaws to hold onto actin
5) Myosin changes conformation again to straighten lever arm, which allows Pi to be released, which stretches the S2 coil (Power stroke that actually displaces thin filament)
6) ADP dissociates from actin monomer, and you get back to rigor
What happens on a molecular level during MI or hypoxia that affects the force the heart can exert?
During MI or hypoxia, Pi concentrations increase and it binds to the actin monomer-ADP stage and reverses the power stroke, which reduces the force the heart can exert
Increased H+ concentration during hypoxia can also inhibit power stroke and decrease Ca2+ activation of thin filaments
During isovolumic contraction (large force exerted), what limits the rate of cross-bridge cycling?
ADP dissociation/release from actin monomer during step 6
Note: when force is not large, steps 4 and 5 are rate-limiting
Three states of actin-tropomyosin and cooperative activation
1) Blocked when no Ca2+ (diastole) and troponin blocks all strong (S) myosin binding sites
2) Closed when some Ca2+ able to bind and move troponin so weak (W) and part of S sites exposed; once myosin is bound, it doesn’t let troponin back over, so you get cooperative activation of thin filament
3) Open when Ca2+ around (systole) to bind and move troponin away so W and S sites all exposed and myosin can bind
Under normal resting conditions, what percent of maximal force is produced?
Only 30% of maximal force of the heart is produced at rest!
Things that can promote more and less Ca2+ release
More Ca2+ release: NE, EPI, angiotensin II, caffeine, elevated serum Ca2+
Less Ca2+: beta blockers, hypoxia, barbituates
