Excitation-Contraction Coupling Flashcards
How is contraction strength regulated in myocytes
Individual myocytes change contraction strength
What factors can regulate cardiac contraction
- Length dependent
- frank starling relationship (F/SV vs EDV)
- length tension relationship - Length independent
- changes in contractility that are not related to sarcomere length
How does the frank-starling graph change when increased contractility? what possible inotropes can cause this?
SV vs EDV: Shift left and up (causes smaller EDV)
Positive inotropes: noradrenaline, adrenaline, cocaine, amphetamines, digitalis (digoxin)
How does the frank-starling graph change when decreased contractility? what possible inotropes can cause this?
SV vs EDV: shift right and down (less blood pushed out, larger EDV)
Negative inotropes: propranolol, nifedipine, ACh
What are inotropes?
Inotropes are drugs that tell your heart muscles to beat or contract with more power or less power
How does sympathetic and parasympathetic stimulation effect contractility? State shifts of Frank-starling curve.
Sympathetic- increases contractility. Shift up and left.
Parasympathetic- decreases contractility. Shift down and right.
Define inotropy
Force of contraction
Define chronotropy
Rate of heart beating
Dromotropy
Rhythmicity ofcontraction
Where does excitation-contraction coupling begin
T tubules
What ways can myocytes use to vary contraction
- Change length of AP
- Amount of Ca2+ let into the cell from Cav1.2 channel OR sarcoplasmic reticulum (SR)
What is the name of the calcium channel in sarcolemma
Cav1.2
What releases Ca from the SR
Ryanodine receptor RyR2
How is calcium released from SR
Calcium enters cell through Cav1.2 channels in sarcolemma. This calcium binds to ryanodine receptors of SR and allows RyR2 to open releasing calcium. Mechanism- Ca induced, Ca release (CICR)
Name the L-type Ca channel, when does it open
Cav1.2
Opens at -35mV
Alpha1c subunit
Name the two calcium sources used in excitation-contraction coupling and state their contribution percents
Cav1.2- 10-40%
RyR2- 60-90%
Is Ca moving up or down its concentration gradient when going through: Cav1.2 or NCX channels
Cav1.2- down gradient (into cell)
NCX- up gradient (out of cell)
What does NCX channel exchange? How can it function like this?
3 Na into cell, 1 Ca out of cell (net +1 in)
Energy generated by Na in, is used to get Ca out
How does SERCA-2A work? What does it pump?
2 Ca enter SR with the help of ATP (active transport)
What is the role of PLB?
PLB- phospholamban inhibits ATP activity
For excitation- contraction coupling- it inhibits ATP used in SERCA-2A therefore no Ca re-absorbed into SR
Name all the channels in the sarcolemma
Cav1.2
NCX
Sodium-potassium pump (3 Na out, 2 K in)
How is cAMP used in myocytes vs sinoatrial node?
Myocytes: cAMP binds to protein kinase A (PKA) which phosphorylates phospholamban (PLB), Cav1.2, TnI
SAN: cAMP activates HCN channels
What phosphorylates PLB and how does this effect PLB
PLB- phospholamban
PKA phosphorylates PLB
Causes PLB to detach from SERCA-2A- allowing more Ca reuptake
What happens to force of contraction if SERCA activity is increased? How?
PKA increases SERCA activity
Force of contraction is increased
- faster relaxation
- more SR Ca release (b/c more uptake with PLB removed- so more load in SR)
- larger depolarization phase
What three components of excitation-contraction coupling are increased by PKA activity? How do these components affect the force of contraction?
SERCA-2A activity
CA2+ entry via Cav1.2 channels
Relaxation rate
all increase force of contraction
How does PKA affect Cav1.2 channels? What does this mean for the cell in general?
Phosphorylates channel, increases open probability.
This increases Ca current into cell and calcium-induced calcium release (CICR)
In general- increases force of contraction
What is the outcome of PKA phosphorylating TnI
TnI directly bound to actin and TnC.
Phosphorylation causes a decreased affinity of TnC site II for Ca2+ (site II-initiate contraction). This promotes faster relaxation rate.
Overall force of contraction increases- Ca stripped faster therefore can be reused faster
What is the sympathetic regulation pathway related to excitation-contraction coupling in myocytes
Noradrenaline binds to beta1 adrenergic receptor- Gs subunit leaves to activate adenylyl cyclase- creates cAMP- activates PKA- which then phosphorylates many things (PLB, Cav1.2, TnI, RyR)
RyR- increase fractional Ca release from SR
Parasympathetic stimulation effect on excitation-contraction coupling
Decrease contractility, inhibit cAMP production therefore PKA can not be activated
Pharmacological regulation of excitation-contraction coupling in full
Sympathomimetics - stimulate sympathetic NS
• cocaine - blocks NA re-uptake by neurons
• amphetamines - release NA from storage vesicles
• positive inotrope
Sympatholytics - inhibit the sympathetic NS
• β blockers (e.g. propranolol)
• negative inotrope
Digitalis (Digoxin)
• a positive inotrope
• inhibits Na/K-ATPase
Pharmacological regulation of E-C coupling: what things stimulate sympathetic nervous system, provide examples
Sympathomimetics
Ex. Cocaine, amphetamines, positive inotropes
Pharmacological regulation of E-C coupling: what things inhibit sympathetic nervous system, provide examples
Sympatholytics
Ex. Beta blockers (propranolol), negative inotropes
What does cocaine do
Blocks noradrenaline re-uptake by neurons
What do amphetamines do
Release noradrenaline from storage vesicles
What does digitalis (digoxin) do and what problems does this cause E-C coupling
Inhibits Na/K ATPase (3Na out, 2K in). When no pump, the NCX channel works in the opposite direction Na out of cell and down gradient (b/c now high concentration inside). Ca into cell and down gradient.
normal NCX- 3Na into cell and down gradient, 2Ca out of cell and up gradient
Overall this will increase the resting membrane potential!
Which pharmacological regulation increase the resting membrane potential? how?
Digitalis (digoxin)
Inhibit Na/K ATPase.
High Na concentration inside cell and reduction in K in cell increases resting membrane potential
