What is happening (high level) APs are turned into contraction?
electrochemical signals are transduced into mechanical force
This receptor is activated from transient Ca++ entering the cell from L-Type channels, and promotes release of Ca++ from the SR that leads to contraction:
After contraction, this receptor takes up free Ca++, what is it and where?
SERCA (on SR) ... note ATP dependent process
Describe the structure of the L-Type Calcium channel:
comprised of a pore-forming subunit plus
three accessory subunits that are required for proper function
What are the monomers in the Ryanodine receptor? how many are there and what is their function?
RyR2 (four of them)
form Ca++ releasing channel in SR --> release during systole
What is a major regulator of SERCA? what is it's active state?
Phospholamban (PL): allows Ca++ in/active when phosphorylated (inhibitory when dephosphorylated)
*What is the effect of increased PL phosphorylation on contraction?
beta-adrenergic stimulation increases the force and shortening velocity of contraction (i.e., positive inotropy), and increases the rate of relaxation (i.e., positive lusitropy).
What is meant by "E-C Coupling Gain"?
describes the efficiency of I-Ca at triggering Ca2+ release from the SR (I-Ca is the current of Ca++ entering cell via L-Type from the AP)
*What are potential causes for a decrease in E-C coupling gain as seen in heart
functional defects in the L type calcium channel.
low extracellular calcium
increased space between the L type channel and ryanodine receptor
abnormalities in the ryanodine receptor
there are three mechanisms to lead to a decrease in SR calcium content:
1. One was reduced uptake in the calcium and to the SR
2. if we have more extrusion from the cell, and leaving less calcium that can be taken up into the SR
3. ryanodine receptors that are not fully closed in diastole so they actually are leaking calcium in diastole and therefore, there's less calcium in the SR that can be released when it's really needed.
What is a mutation in the RyR2 associated with?
general: human muscle diseases
Arrhythmias and sudden death
What are the roles of actin and myosin in myofilaments?
Actin (thin filaments) provide a scaffolding for myosin binding
Myosin (thick filaments) head and neck important for contraction
recall: myosin is "cocked" in the relaxed and energized (ADP) state
What is the troponin complex? and what is the role of each component?
Troponin Complex: Regulates actin-myosin binding
• Troponin T (Tn-T) Holds troponin complex to tropomyosin
• Troponin I (Tn-I) Inhibits actin-myosin binding at rest
• Troponin C (Tn-C) Binds Ca2+, displaces Tn-I from actin-myosin binding site
Notes: T=tropomyosin holding
What are the three general groupings of cardiomyopathies? (note: limited to myocardium, LV)
hypertrophic, dilated and restrictive.
*Describe the difference between isometric and isotonic contraction:
Isometric (constant length): Both ends of the muscle are fixed, so that it cannot shorten
Isotonic (constant force/resistance): One end of muscle is free, and the muscle is compelled to lift a weight
What is the preload in the intact heart?
The volume of blood in the chamber, *muscle length
(Stretches a muscle before it contracts)
What is the afterload? (in the intact heart)?
Afterload can also be described as the pressure that the chambers of the heart must generate in order to eject blood out of the heart and thus is a consequence of the aortic pressure (for the left ventricle).
Afterload is the tension or stress developed in the wall of the left ventricle during ejection.
What does increased preload do to afterload contraction? increased afterload to afterload contraction?
more preload = more change in length (more SV)
more afterload = less change in length, but with more total load (less SV)
What is is the inherent capacity of myocardial cells to develop force independent of the initial muscle length (preload) or afterload?
*What role to protein kinases play in myocyte contractility? how does the autonomic nervous system influence this?
L-Type Ca++ Channels allow more in
RyR allow more Ca++ release
PL promotes more Ca++ uptake by SR
TnI promotes more actin/myosin binding
--> enhance rate of both contraction and relaxation
Sympathetic: NE --> B1 receptor --> increases cAMP conversion (increases kinase activity)
Parasympathetic: ACh --> muscarinic --> decreases cAMP conversion
what role does Phosphodiesterase (PDE) play in myocyte contraction?
decreases: PDE reduces cAMP, thus decreases kinase activity and decreases contractility
--> PDE inhibitors, thus increase contractility
what happens to contractility control in heart failure?
b1 adrenergics decrease effect
muscarinic increase effect
cAMP levels and overall contractility falls
current heart failure therapies involve b1 agonists and PDE inhibitors...
experimental therapies target the RyR, PL and SERCA function of the SR