EC Coupling & Calcium I/II (complete) Flashcards
What is the sequence of major events between the initiation of an AP in a cardiac muscle fiber through contraction?
- AP from another myocyte spread into t-tubules
- Triggers opening of DHPR (L-Type Ca++ channel)
- Ca++ flows from ECM to myoplasm via DHPR
- Triggers opening of RyR2 in sarcoplasmic membrane
- Ca++ from sarcoplasmic reticulum enters myoplasm (much larger amount of Ca++)
- Ca++ binds to troponin on thin filaments => activates contraction => actin-myosin bridge cycling & contraction
Understand the processes that control relaxation of contraction by removing Ca++ from the myophasm
SERCA2 pump is the primary method
- located in SR membrane
- Ca++ diffuses w/in SR => binds to calsequestrin
- dominates Ca++ removal b/c it requires less energy [V(sr) ~= 0]
- Uses 1 ATP
NCX also used
- 3 Na+ in 1 Ca++ out
- Can be arrhythmogenic b/c of next +1 increase
PMCA
- also used but less often b/c Ca++ must go up it’s electrochemical gradient
Describe EC coupling in skeletal muscle
- DOES NOT require entry of external Ca++
- Uses Ca V1.1(a1s), b1a, a2d1, g1
- RyR1
Describe EC coupling in cardiac muscle
- REQUIRES external Ca++ to enter
- CaV1.2(a1C), b2a, a2d1
- RyR2
Describe the NCX sodium/calcium exchanger
- Exchanges 3Na+ for 1Ca++
- Can go in either direction (influx or efflux of either)
- Direction depends on membrane potentials and gradients
Describe the significance of a V(r) of -74mV
- Cell membrane potential is -74mV => Ca++ will be extruded until internal Ca++ falls to 100nm
- Then the NCX net movement will be 0
- at -74mV, a suden increases in internal Ca++ would result in a net inward current => depolarization
- Depolarization triggered by Ca++ release from SR => arrhythmias
What are the basic elements of calcium homeostasis in the myocardium?
- SR calcium content should be roughly constant (except in short term increases/decreases)
Mechanisms:
- NCX exchanger
- L-type Ca++ channel
- Calcium dependent inactivation
Describe the L-type Ca++ channel as it relates to calcium homeostasis
- undergoes inactivation
- depends on concentration of Ca++ near the cytoplasmic side of channel
- think calcium dependent inactivation
Describe calcium dependent inactivation
- if amount of Ca++ in SR increases => greater CDI causes less Ca++ to enter via L-type channel
- If amount decreases => less CDI causes more Ca++ to enter via the L-type channel
How does stimulation of Beta-adrenergic receptors increase contraction strength and rate of relaxation of cardiac muscle?
Stimulating ß-ad receptors => elevation of cAMP and PKA activation
What does PKA target after activation by ß-adrenergic receptor stimulation?
- L-type Ca++ channel => phosphorylates channel => increases amplitude of current => increases size of trigger activation of RyR2 (positive inotropy)
- RyR2 => phosphorylates receptor => sensitive to Ca++ activation (positive inotropy)
- Phospholamban (PLB) => PLB inhibits SERCA2 Ca++ pumping activity => phosphorylation of PLB relieves inhibition => increases Ca++ pumping into SR => speeds relaxation and increases Ca++ quantity in SR (positive inotropy and lusitropy)
What is positive inotropy?
indicates an increase in contractile force
What is positive lusitropy?
indicates an increase in rate of relaxation
What is Timothy syndrome?
- Characterized by syncope, cardiac arrhythmias, sudden death
- Also intermittent hypoglycemia, immune deficiency, cognitive abnormalities (e.g. autism)
Describe mutations associated with Timothy syndrome
- De novo mutations in CaV1.2
- Also mutation in G406R in exon 8a (TS)
- Two mutations of G402S and G406R on exon 8 (TS2)
- TS2 mutations suppress voltage-dependent inactivation
- TS and TS2 pts have AV block, prolonged QT intervals, episodes of polymorphic ventricular trachycardia
OVERALL: associated with lengthened APs
What is Brugada syndrome?
- AKA sudden unexplained death syndrome
- associated with ECG alterations
- These are revealed by admin of class 1C anti-arrhythmics (Na+ blockers)
Describe the mutations associated with Brugada syndrome
- mutations in cardiac Na channel (KChip2 subunit)
- A subset of pts have mutations in principle subunit or in main accessory subunit
- These mutations causes large reduction in magnitude of L-type Ca++ current
- Have shortened QT intervals
OVERALL: shortened APs
What is Catecholaminergic Polymorphic Ventricular Tachycardia?
- Do not display ECG abnormalities at rest
- They do during exercise or infusion of catecholamines
- Associated with mutations in RyR2 and CasQ2
- Mutations + increase SR Ca++ => release of Ca++ not directly triggered by L-type Ca++ current during plateau of AP — actually occur either shortly or long after repolarization
- Extrusion of Ca++ via NCX => depolarizations that trigger ectopic APs and arrhythmias
Describe the RyR2 mutations associated with CPVT
- Dominant inheritance
- Increase resting leak of Ca++ out of SR
- Can also be more sensitive to activation by Ca++
Describe the CasQ2 mutations associated with CPVT
- Mutations in lumenal Ca++ buffer calsequestrin2
- Recessive inheritance
- Some mutations esult in dramatic loss of luminal Ca++ buffering
- Thought to have a role in regulation of RyR2 function => if altered causes leaky RyR2
