Cardiac Electrophysiology I (Weiss) Flashcards
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.
Calsequestrin
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
Digitalis
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)
Phospholamban
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%
