EC Coupling & Calcium I-II

Question 1

Contraction of cardiac and skeletal muscle is elicited by what?

Answer 1

increase in the myoplasmic [Ca2+]

Question 2

what is the chief source of the calcium that causes contraction in cardiac and skeletal muscle?

Answer 2

sarcoplasmic reticulum (SR)

Question 3

Where does the release of Ca2+ originate in both cardiac and skeletal muscle?

Answer 3

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)

Question 4

what is dihydropyridine receptor or DHPR ?

Answer 4

voltage-gated Ca2+ channel

Located on the plasma membrane side of EC junctions

Question 5

What is the ryanodine receptor (RyR)?

Answer 5

Ca2+ channel

located on the junctional SR side

Question 6

What is Excitation-Contraction Coupling (ECC)?

Answer 6

a way to link muscle excitation (the depolarization of the action potential) to Ca++ release from the sarcoplasmic reticulum

Question 7

Which type of muscle fibers require entry of external Ca2+ for ECC?

Answer 7

Cardiac requires external Ca2+ entry, but skeletal muscle doesn’t

Question 8

What receptors are involved in cardiac ECC?

Answer 8

-CaV1.2 (α1C), β2a or β2b, α2δ1 RyR2

Question 9

What receptors are involved in skeletal ECC?

Answer 9

-CaV1.1 (α1S), β1a, α2δ1, γ1 RyR1

Question 10

Briefly list the sequence of events taking place during excitation, contraction and relaxation of cardiac muscle cells.

Answer 10

• 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.

Question 11

What is SERCA2?

Answer 11

pump located in longitudinal SR (2 Ca2+ per cycle), dominates Ca2+ removal since SR surrounds each myofibril; requires less energy since VSR≈0.

Question 12

T or F: NCX can be arrhythmogenic

Answer 12

True

Question 13

How is calcium balance maintained during steady state?

Answer 13

Ca2+ released from SR is recycled back into SR by SERCA2, and surface extrusion (by NCX & Ca pump) balances L-type Ca2+ current (inward).

Question 14

What does the The NCX sodium/calcium exchanger do?

Answer 14

exchanges 3 Na for 1 Ca and can run either direction, depending on Vm and Ca & Na gradients

Question 15

What is the membrane potential (Vr) at which the NCX transport reverses direction?

Answer 15

Vr= 3ENa-2ECa (Not sure if we need to know)

Question 16

What is the role of NCX during depolarization?

Answer 16

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).

Question 17

What happens to the NCX towards end of AP?

Answer 17

• 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).

Question 18

A sudden increase in [Ca]i would result in net _______current

Answer 18

Inward, as a consequence of 1Ca2+ extrusion (and 3Na+ in) via NCX

Question 19

What roles does the NCX play in SA node?

Answer 19

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.

Question 20

What are the mechanisms of Ca2+ homeostasis?

Answer 20

• The NCX calcium exchanger

- Calcium-dependent inactivation (CDI) of LTCCs

Question 21

What is calcium-dependent inactivation (CDI)?

Answer 21

Channel inactivation depends on the concentration of Ca2+ near the cytoplasmic side (e.g. L-type Ca2+ channel ).

Question 22

What effect does Norepinephrine released by sympathetic nerve terminals and circulating epinephrine have?

Answer 22

1. positive chronotropy: raising firing rate in the SA node.
2. Alter propagation through the conduction pathways
3. positive inotropy
4. positive lusitropy

Question 23

How is PKA activated?

Answer 23

activation of β-adrenergic receptors, elevation of cytoplasmic cAMP, which activates PKA

Question 24

What are the 4 targets of PKA?

Answer 24

• The L-type Ca2+ channel
• RyR2
• Phospholamban (PLB)
• Troponin

Question 25

Phosphorylation of the DHPR results in what?

Answer 25

increases the amplitude of the L-type Ca2+ current, thus increases the size of the trigger to activation of RyR2. Also increased Ca2+ load

Question 26

Phosphorylation of RyR2 results in what?

Answer 26

Increased Ca2+ sensitivity

Question 27

Phosphorylation causes PLB to do what?

Answer 27

to dissociate from SERCA2, which relieves the inhibition and thus increases Ca2+ pumping into the SR: speeds relaxation and increases Ca2+ load

Question 28

Phosphorylation of what targets results in positive inotropy?

Answer 28

LTCCs, RyRs, PLB

Question 29

Phosphorylation of what targets results in positive lusitropy?

Answer 29

PLB and troponin

Question 30

Phosphorylation of troponin results in what?

Answer 30

speeds the rate of Ca2+ dissociation from thin filaments

Question 31

What is Timothy Syndrome?

Answer 31

debilitating disorder resulting in syncope, cardiac arrhythmias and sudden death. Also, intermittent hypoglycemia, immune deficiency and cognitive abnormalities including autism.

Question 32

What is the molecular abnormality associated w/ Timothy Syndrome?

Answer 32

recurrent, de novo mutations in CaV1.2, profoundly suppress voltage-dependent inactivation.

Question 33

What is the result of mutations in Timothy Syndrome?

Answer 33

TS and TS2 patients display AV block = prolonged Q-T intervals (prolonged ventricular action potential) and episodes of polymorphic ventricular tachycardia.

Question 34

What is Burgada Syndrome?

Answer 34

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)

Question 35

What mutations are associated w/ Burgada Syndrome?

Answer 35

• 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)

Question 36

What are the consequences of mutations in Burgada Syndrome?

Answer 36

large reduction in the magnitude of L-type Ca2+ current. Significantly shortened Q-T interval.

Question 37

What is Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)?

Answer 37

ECG abnormalities displayed upon exercise or infusion of catecholamines, but not at rest.

Question 38

What mutations are found in CPVT?

Answer 38

• RyRs mutation, dominant

- lumenal SR Ca2+ buffer calsequestrin2 (CasQ2), recessive

Question 39

What is the function of calsequestrin?

Answer 39

• buffering lumenal Ca2+,

- regulate the function of RyR2 (Regulation may be altered by the CPVT causing mutations)

Question 40

Describe the effect of RyR mutation in CPVT

Answer 40

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

Question 41

Describe the effect β-adrenergic receptors have on CPVT patients

Answer 41

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