EC Coupling and Calcium II Flashcards
Identify basic elements of calcium homeostasis in the myocardium
o NCX calcium exchanger.
o L-type Ca2+ channel: undergoes a form of inactivation that depends on the concentration of Ca2+ near the cytoplasmic side of the channel.
— Calcium dependent inactivation (CDI)
Explain how stimulation of β-adrenergic receptors increases both contraction strength, and rate of relaxation, of cardiac muscle
Stimulation of β-adrenergic receptors leads to elevation of cAMP and activation of PKA
targets of PKA
L-type Ca2+ channel
RyR2
PLB
PKA target: L-type Ca2+ channel
Phosphorylation of the channel increases the amplitude of the L-type Ca2+ current and thus increases the size of the trigger to activation of RyR2. The increase Ca2+ entry also helps to increase the quantity of Ca2+ stored in the SR. This contributes to positive inotropy
PKA target: RyR2
phosphorylation of RyR2 causes it to be sensitized to activation by trigger Ca2+. This contributes to positive inotropy.
PKA target: Phospholamban (PLB)
The association of PLB with SERCA2 inhibits Ca2+ pumping activity. Phosphorylation causes PLB to dissociate from SERCA2, which relieves the inhibition and thus increases Ca2+ pumping into the SR. This speeds relaxation and increases the quantity of Ca2+ stored in the SR. This contributes to both positive inotropy and positive lusitropy
What is Timothy syndrome?
disorder characterized by syncope, cardiac arrhythmias and sudden death, in addition to intermittent hypoglycemia, immune deficiency and cognitive abnormalities including autism.
o Associated with de novo mutations in CaV1.2 (the principle subunit of the L-type Ca2+ channel).
Describe why Timothy syndrome mutations of the L-type Ca2+ channel could result in a lengthened cardiac action potential
o One variant (TS) arises from the mutation G406R in exon 8a and another variant TS2 arises from two mutations (G402S and G406R) of exon 8 (which encodes the same region as exon 8a.
o TS2 mutations profoundly suppress voltage-dependent inactivation.
o Both TS and TS2 patients display AV block, prolonged Q-T intervals and episodes of polymorphic ventricular tachycardia.
What is Brugada syndrome?
associated with a number of ECG alterations, which in some instances are revealed by administration of class IC anti-arrhythmics (sodium channel blockers) including ajmaline. o Associated with mutations of the cardiac sodium channel, KChip2 a modulatory subunit associated with Kv4.3 to produce IKto and several other proteins including ankyrin.
Describe why Brugada syndrome mutations of the L-type Ca2+ channel could result in shortened action potentials
o A subset of Brugada syndrome patients either have mutations in the principle subunit or a mutation in the main accessory subunit of the L-type Ca2+ channel.
o These mutations appear to cause a large reduction in the magnitude of L-type Ca2+ current which may be a consequence of impaired membrane trafficking.
o These patients have significantly shortened Q-T intervals.
Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT):
patients with CPVT do not display ECG abnormalities at rest, but do display abnormalities upon exercise or infusion of catecholamines.
o Associated with causative mutations in RyR2—with dominant inheritance—and in the lumenal Ca2+ buffer calsequestrin2 (CasQ2)—with recessive inheritance
Identify the mechanism whereby CPVT mutations, in combination with activation of β-adrenergic receptors, causes ectopic depolarizations
- CPVT mutations + increased SR Ca2+ (increased as a consequence of activation of β-adrenergic receptors) is presumed to result in releases of Ca2+ that are not directly triggered by the L-type Ca2+ current during the plateau of the action potential but instead occur either shortly or long after repolarization.
- Extrusion of the Ca2+ via NCX results in depolarizations that can trigger ectopic action potentials and thus initiate arrhythmias.
If the amount of Ca2+ in the SR increases,
greater CDI causes less Ca2+ to enter via the L-type channel.
If the amount of Ca2+ in the SR decreases,
less CDI causes more Ca2+ to enter via the L-type channel
