EC Coupling II

Question 1

What are the effects of norepinephrine released by sympathetic nerve terminals and circulating on cardiac muscle?

Answer 1

1) incr HR (positive chonotropy) by increasing the firing rate of SA nodal pacemaker cells
2) alter propagation thru conduction pathways
3) incr contractile force (positive inotropy)
4) incr rate of relaxation (positive lusitropy)

Question 2

___ and ____ involve activation of beta adrenergic receptors, elev of cyto cAMP and activation of PKA

Answer 2

incr contractile force and incr rate of relaxation

Question 3

What are the 3 targets for PKA in myocardium?

Answer 3

1) L-type Ca2+ channel
2) RyR2
3) phospholamban (PLB)

Question 4

What is the effect of phosphorylation of L-type Ca2+ channel?

Answer 4

Increases amplitude of L-type Ca2+ current

• -> trigger for activation of RyR2 over time
• -> increases amount of Ca2+ stored in SR

Question 5

What is the effect of phosphorylation of RyR2?

Answer 5

Causes RyR2 to be sensitized to activation by trigger Ca2+

Question 6

What is the effect of phosphorylation of PLB?

Answer 6

PLB dissoc with SERCA2 (normally assoc and inhib Ca2+ pump)

• -> incr Ca2+ pumping into SR
• -> incr relaxation and incr amount of Ca2+ in SR

Question 7

Which effects of phosphorylation contribute to positive inotropy and which contributes to both positive inotropy and lusitropy?

Answer 7

Phosphorylation of L-type Ca2+ and RyR2 = positive inotropy

Phosphorylation of PLB = positive inotropy + positive lusitropy

Question 8

What are symptoms of Timothy Syndrome?

Answer 8

cardiac arrhythmia
sudden death

immune deficiency
autism

Question 9

What is the mutation underlying Timothy Syndrome?

Answer 9

de novo mutations in CaV1.2 (in L-type Calcium channel)

Question 10

why are there multiple variants of Timothy syndrome?

Answer 10

different mutations

Question 11

What are the cardiac effects of TS and TS2?

Answer 11

Decr voltage-dependent inactivation of Ca2+ current

• -> prolong phase 2
• -> Long QT syndrome

–> AV block and episodes of polymorphic ventricular tachycardia

Question 12

What mutations are assoc with Brugada syndrome

Answer 12

mutations of
NaV1.5 (phase 0)
Kchip2 (subunit of IKto) = phase 1
Ankyrin (links NaV1.5 to cytoskeleton)

also
CaV1.2 mutations

Question 13

What are cardiac effects of Brugada syndrome?

Answer 13

1) Impaired membrane trafficking –>
2) Large reduction in magnitude of L-type Ca2+ current
3) Shortened QT interval = shorten ventricular AP

Question 14

What is unique about CPVT?

Answer 14

No EKG abnormalities at rest

But yes EKG abnoralities on exercise/infusion of catecholamines

Question 15

What mutations associated with CPVT?

Answer 15

dominant mutations in RyR2

recessive mutations of calsequestrin 2

Question 16

Effect of mutations in RyR2

Answer 16

incr resting “leak” out of calcium from SR (make RyR2 more sensitive to activation by Ca2+)

(similar RyR1 mutation = malignant hyperthermia/central core disease in skeletal muscle)

Question 17

Effect of mutations in calsequestrin 2 in cardiac muscle

Answer 17

loss of luminal calcium buffer

also loss of regulation of RyR2

Question 18

Problems with RyR2 and Calsequestrin 2 with activation of beta adrenergic receptors?

Answer 18

release of Ca2+ not triggered by L-type Ca2+ current during phase 2 but instead before/after repol

–> trigger ectopic APs and arrhythmias