EC Coupling & Calcium I-II Flashcards
Contraction of cardiac and skeletal muscle is elicited by what?
increase in the myoplasmic [Ca2+]
what is the chief source of the calcium that causes contraction in cardiac and skeletal muscle?
sarcoplasmic reticulum (SR)
Where does the release of Ca2+ originate in both cardiac and skeletal muscle?
at junctions between the terminal cisternae of the SR (junctional SR, jSR) and the plasma membrane, or plasma membrane invaginations termed transverse tubules (t-tubules)
what is dihydropyridine receptor or DHPR ?
voltage-gated Ca2+ channel
Located on the plasma membrane side of EC junctions
What is the ryanodine receptor (RyR)?
Ca2+ channel
located on the junctional SR side
What is Excitation-Contraction Coupling (ECC)?
a way to link muscle excitation (the depolarization of the action potential) to Ca++ release from the sarcoplasmic reticulum
Which type of muscle fibers require entry of external Ca2+ for ECC?
Cardiac requires external Ca2+ entry, but skeletal muscle doesn’t
What receptors are involved in cardiac ECC?
-CaV1.2 (α1C), β2a or β2b, α2δ1 RyR2
What receptors are involved in skeletal ECC?
-CaV1.1 (α1S), β1a, α2δ1, γ1 RyR1
Briefly list the sequence of events taking place during excitation, contraction and relaxation of cardiac muscle cells.
• Ca2+ enters via DHPR (“L-type Ca2+ channel”) and activates RyR2 to cause a much larger flux of Ca2+ from SR into myoplasm.
• Ca2+ activates contraction by binding to troponin on thin filaments.
• Ca2+ is removed from the myoplasm by:
(i) SERCA2
(ii) NCX Na+/Ca2+ exchanger in junctional domains of plasma membrane and t-tubules.
What is SERCA2?
pump located in longitudinal SR (2 Ca2+ per cycle), dominates Ca2+ removal since SR surrounds each myofibril; requires less energy since VSR≈0.
T or F: NCX can be arrhythmogenic
True
How is calcium balance maintained during steady state?
Ca2+ released from SR is recycled back into SR by SERCA2, and surface extrusion (by NCX & Ca pump) balances L-type Ca2+ current (inward).
What does the The NCX sodium/calcium exchanger do?
exchanges 3 Na for 1 Ca and can run either direction, depending on Vm and Ca & Na gradients
What is the membrane potential (Vr) at which the NCX transport reverses direction?
Vr= 3ENa-2ECa (Not sure if we need to know)
What is the role of NCX during depolarization?
NCX exchange becomes a significant source of Ca2+ entry, reflected as an outward current since every Ca2+ ion that enters is accompanied by the extrusion of 3 Na+ ions (Phase 1 of AP).
What happens to the NCX towards end of AP?
- extrusion of Ca2+ via NCX.
- In the steady-state Ca2+ extrusion via NCX precisely balances the entry of external Ca2+ (via the L-type current and the NCX exchanger itself).
A sudden increase in [Ca]i would result in net _______current
Inward, as a consequence of 1Ca2+ extrusion (and 3Na+ in) via NCX
What roles does the NCX play in SA node?
oscillatory Ca2+ release from the SR of SA nodal cells during diastole resulting in the activation of Na+ entry via NCX, which causes (or at least contributes to) the pacemaker depolarization.
What are the mechanisms of Ca2+ homeostasis?
- The NCX calcium exchanger
- Calcium-dependent inactivation (CDI) of LTCCs
What is calcium-dependent inactivation (CDI)?
Channel inactivation depends on the concentration of Ca2+ near the cytoplasmic side (e.g. L-type Ca2+ channel ).
What effect does Norepinephrine released by sympathetic nerve terminals and circulating epinephrine have?
- positive chronotropy: raising firing rate in the SA node.
- Alter propagation through the conduction pathways
- positive inotropy
- positive lusitropy
How is PKA activated?
activation of β-adrenergic receptors, elevation of cytoplasmic cAMP, which activates PKA
What are the 4 targets of PKA?
- The L-type Ca2+ channel
- RyR2
- Phospholamban (PLB)
- Troponin
Phosphorylation of the DHPR results in what?
increases the amplitude of the L-type Ca2+ current, thus increases the size of the trigger to activation of RyR2. Also increased Ca2+ load
Phosphorylation of RyR2 results in what?
Increased Ca2+ sensitivity
Phosphorylation causes PLB to do what?
to dissociate from SERCA2, which relieves the inhibition and thus increases Ca2+ pumping into the SR: speeds relaxation and increases Ca2+ load
Phosphorylation of what targets results in positive inotropy?
LTCCs, RyRs, PLB
Phosphorylation of what targets results in positive lusitropy?
PLB and troponin
Phosphorylation of troponin results in what?
speeds the rate of Ca2+ dissociation from thin filaments
What is Timothy Syndrome?
debilitating disorder resulting in syncope, cardiac arrhythmias and sudden death. Also, intermittent hypoglycemia, immune deficiency and cognitive abnormalities including autism.
What is the molecular abnormality associated w/ Timothy Syndrome?
recurrent, de novo mutations in CaV1.2, profoundly suppress voltage-dependent inactivation.
What is the result of mutations in Timothy Syndrome?
TS and TS2 patients display AV block = prolonged Q-T intervals (prolonged ventricular action potential) and episodes of polymorphic ventricular tachycardia.
What is Burgada Syndrome?
is associated with a number of ECG alterations, which in some instances are revealed by administration of class IC anti-arrhythmics (sodium channel blockers)` (aka Sudden Unexplained Death Syndrome)
What mutations are associated w/ Burgada Syndrome?
- cardiac sodium channel (NaV1.5),
- KChip2 a modulatory subunit association with Kv4.3 to produce IKto, and
- several other proteins including ankyrin (a protein that links NaV1.5 to the cytoskeleton)
What are the consequences of mutations in Burgada Syndrome?
large reduction in the magnitude of L-type Ca2+ current. Significantly shortened Q-T interval.
What is Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)?
ECG abnormalities displayed upon exercise or infusion of catecholamines, but not at rest.
What mutations are found in CPVT?
- RyRs mutation, dominant
- lumenal SR Ca2+ buffer calsequestrin2 (CasQ2), recessive
What is the function of calsequestrin?
- buffering lumenal Ca2+,
- regulate the function of RyR2 (Regulation may be altered by the CPVT causing mutations)
Describe the effect of RyR mutation in CPVT
The RyR2 mutations are thought to increase the resting “leak” of Ca2+ out of the SR and/or render RyR2 more sensitive to activation by Ca2
Describe the effect β-adrenergic receptors have on CPVT patients
β-adrenergic receptors increase intracellular Ca2+ results in releases of Ca2+ not directly triggered by phase 2 L-type Ca2+ current. Extrusion of this Ca2+ via NCX results in depolarizations that can trigger ectopic action potentials and thus initiate arrhythmias
