Cardiac Electrophysiology I (Weiss) Flashcards Preview

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Flashcards in Cardiac Electrophysiology I (Weiss) Deck (21)
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Components of cardiac muscle cell

Sarcomeres from Z line to Z line

Thick filaments: myosin whose heads have actin-binding sites and ATPase activity

Thin filaments: actin with myosin-binding site; tropomyosin blocks myosin-binding site; troponin binds Ca2+ and then removes tropomyosin so actin and myosin can interact

T tubules invaginate cells at Z line

Sarcoplasmic reticulum is site of storage and release of Ca2+


General cardiac cell contraction

1) Action potential causes depolarization outside the cell and into T tubules

2) Depolarization causes voltage-gated L-type Ca2+ channels (dihydropyridine receptors) to open and let some Ca2+ into cell

3) Ca2+ that comes into cell activates Ryanodine receptors (SR Ca2+ release channels) and triggers release of more Ca2+ from inside sarcoplasmic reticulum

4) Ca2+ binds troponin, and actin and myosin form cross bridges and contract

5) SR Ca2+ ATPase (SERCA pump) brings Ca2+ from intracellular space back into sarcoplasmic reticulum

6) Calsequestrin binds 47 molecules of Ca2+ each so you can store lots of Ca2+ inside SR


What does contractility correlate with?

Contractility correlates directly with:

1) Size of initial inward Ca2+ from outside cell

2) Amount of Ca2+ previously stored in SR

Note: need L-type Ca2+ channel NEAR ryanodine receptor to open that ryanodine receptor. Also, L-type Ca2+ channels open randomly (stochastically).

Ca2+ Microdomains/Release Units/Couplons operate independently to create graded response.



1) Polymerizes to bind 47 Ca2+ ions per molecule in the SR

2) Inhibits Ca2+ release from the SR via RyR by binding triadin and junctin in RyR complex


Calsequestrin (CSQN) changes activity with different [Ca]

Low SR lumenal [Ca]: Without Ca2+ bound, CSQN binds accessory proteins triadin, junctin, FKBP in RyR complex and this inhibits RyR from releasing Ca2+

High SR lumenal [Ca]: With Ca2+ bound, CSQN dissociates from triadin and junctin and allows RyR to open and release Ca2+

This way, when Ca2+ has built up in the SR, calsequestrin lets Ca2+ out to cause Ca2+ spark. But when lots of Ca2+ has been let out of the SR, calsequestrin binds triadin, junctin, FKBP to inhibit RyR from releasing any more Ca2+.


Ca2+ Signaling Microdomain (Ca Release Unit, or Couplon)

Contains voltage-gated L-type Ca channel, RyR and accessory proteins

Operate independently, so if one microdomain activated (creating "Ca2+ spark" it won't make other nearby units create spark)

Each Microdomain separated by cleft or dyadic space


How do we create graded contractility?

More open L-type Ca2+ channels = more Ca2+ sparks = stronger contraction

Note: Ca2+ Microdomains/Release Units/Couplons operate independently to create graded response of independent Ca2+ sparks

Note: Ca2+ channels open randomly so total amt of Ca2+ released is proportional to number of Ca2+ channels in cell open during AP


Mechanisms to remove Ca2+ from intracellular space

1) Na-Ca exchanger: pumps 3 Na+ into cell and 1 Ca2+ out of cell (secondary active transport using Na+ gradient; generates 1 positive charge inside cell; is MAJOR mechanism of Ca2+ removal)

2) SL Ca2+ ATPase: on surface membrane (sarcolemma) and just removes Ca2+ (MINOR mechanism of Ca2+ removal)

3) SR Ca2+ ATPase (SERCA): takes released Ca2+ back into SR, is regulated by phospholamban



1) Inhibits membrane Na/K pump (2 K+ in for 3 Na+ out)

2) Na+ builds up inside cell

3) Ca/Na exchanger doesn't want to put more Na+ in, so Ca2+ cannot get out

4) More that usual Ca2+ goes into SR

5) Contractility increases


Positive inotropic effect (increased contractility)

1) Inhibit Na-Ca exhange via Na-K pump inhibition (digitalis)

2) Enhance Ca2+ current and SERCA via cAMP (beta agonists or phosphodiesterase inhibitors)

3) Increase myofilament Ca2+ sensitivity (experimental drugs)



Binds and inhibits SERCA

When phosphorylated by PKA, phospholamban can no longer bind SERCA, so SERCA brings lots of Ca2+ back into SR


ANS regulation of contraction

1) Sympathetic stimulation releases beta-agonists

2) Beta-agonist Receptor is G-coupled protein --> adenylate cyclase --> cAMP --> PKA

3) PKA phosphorylates:

L-type Ca2+ channels to increase open probability and let more Ca2+ in (inotropic)

RyR which sensitizes them and makes them more ready to release Ca2+ (inotropic)

Phospholamban which now can't inhibit SERCA so there's more Ca2+ reuptake into SR and enhanced relaxation in addition to stronger contractile force on next beat (relaxant)

Troponin I which reduces Ca2+ sensitivity of myofilaments so enhanced relaxation (relaxant)

Note: PARASYMPATHETIC Ach inhibits adenylate cyclase, stopping cAMP production



Why is cardiac relaxation important?

1) Ventricular filling depends on suction created by relaxation of ventricles

2) Diasotle (relaxation) is when you have coronary artery flow (blood flow to supply heart wall tissue)


Heart failure

Overall problem: too much Ca2+ in cell outside of SR, and not enough Ca2+ in SR

Chronic beta-stimulation causes hyperphosphorylation of RyR complexes (causing dissociation of FKBP) which makes them more sensitive to Ca2+ --> RyR channels leaky --> Ca2+ leaves SR during diastole, creating arrhythmias AND depleting Ca2+ in SR available during systole (less contractility)

Also, downregulation of SERCA pump and upregulation of Na-Ca exchanger, which also decreases SR Ca2+ content

Increase RyR leakiness

Decrease SERCA pump

Increase Na-Ca exchange


Percent of Ca2+ from outside and from SR

From outside via L-type Ca2+ channels: 10-30%

From inside SR via RyR: 70-90%



Increasing strength of contraction

Increased inotropy when SR fills with Ca2+ more because then when contraction does occur, it's really strong because there's SO much Ca2+ released from the SR



Increasing rate of depolarization (increasing heart rate)



Increasing velocity of conduction (in AV node?)



Increasing relaxability (complex term, might be increase in elasticity...)


When does the 3Na/1Ca exchanger work best?

1) When the cell is more negative (because the exchanger brings in a positive charge)

2) When there is less Na+ in the cell (because the exchanger brings in 3 Na+)


Why are beta blockers good to give after heart failure?

1) Decrease O2 demand because decreased HR and decreased contractility

2) Prevent "maladaptive genetic remodeling" that happens in heart failure (reverses the downregulation of SERCA, reverses the upregulation of Na/Ca)