EC Coupling/Calcium I & II Flashcards Preview

CVPR: CV Unit I > EC Coupling/Calcium I & II > Flashcards

Flashcards in EC Coupling/Calcium I & II Deck (15):

Sequence of events of cardiac muscle contraction & Ca2+ involvement

  • release of Ca2+ originates at junctions between the terminal cisternae of the sarcoplasmic reticulum (SR) and the plasma membrane, or plasma membrane invaginations termed transverse tubules (t-tubules).
  • Near the plasma membrane side of these junctions, Ca2+ enters the myoplasm via the dihydropyridine receptor (DHPR)—an L-type Ca2+ channel—and activates and opens the ryanodine receptor (RyR2) causing a much larger flux of Ca2+ from the sarcoplasmic reticulum (SR) into the myoplasm.
  • Ca2+ activates contraction by binding to troponin on thin filaments and allowing actin-myosin cross-bridge cycling.


Mechanism of muscle relaxation & Ca2+ involvement

  • Relaxation achieved via removal of Ca2+ from the myoplasm by:

    • SERCA2 pump: located in longitudinal SR (2 Ca2+ per cycle); Ca2+ diffuses within SR to terminal cisternae, where it binds to calsequestrin.

      • SERCA2 dominates since SR surrounds each myofibril; requires less energy since VSR=0.

    • NCX Na+/Ca2+ exchanger: in the junctional domains of plasma membranes and t-tubules. Brings in 3 Na+ for every Ca2+ pumped out.

      • The NCX Na+/Ca2+ exchanged is next in importance and can be arrhythmogenic.

  • ​​In steady-state, Ca2+ released from the SR is recycled back into SR by SERCA2, and surface extrusion balances L-type Ca2+ current.



EC coupling in skeletal muscle

  • ECC does not require entry of external Ca2+
  • Voltage gated channel subunit = CaV1.1(a1s), b1a, a2d1, g1
  • Sarcoplasmic reticulum channel = RyR1


EC Coupling in Cardiac Muscle

  • ECC requires entry of external Ca2+.

  • Voltage-gated channel subunits = CaV1.2(a1C), b2a, a2d1

  • Sarcoplasmic reticulum channel = RyR2


General characteristics of NCX exchanger

  • exchanges 3 Na+ for 1 Ca2+ and can run in either direction
  • The direction of the pump depends on both membrane potential and the gradients for sodium and calcium.


Mechanism of depolarization via NCX exchanger

  • If a cell is at a membrane potential of -74 mV, a sudden increase in [Ca2+]I would result in a net inward current—as a consequence of Ca2+ extrusion.
  • inward current would cause the cell to depolarize.
    • Depolarization triggered by Ca2+ release from the sarcoplasmic reticulum has the capacity to trigger arrhythmias.




Mechanisms of Calcium homeostasis w/in myocardium

  • NCX calcium exchanger.
  • 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)
      • 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.




Consequences of B-adrenergic receptor stimulation & cellular targets (3)

  • results in elevation of cAMP and activation of PKA
  • PKA targets =
    • L-type Ca2+ channels
    • RyR2
    • Phospholamban (PLB)


PKA impact on L-type Ca2+ channels

  •  Phosphorylation of the channel increases the amplitude of the L-type Ca2+ current --> increases the size of the trigger to activation of RyR2.
  • increase dCa2+ entry also helps to increase the quantity of Ca2+ stored in the SR.
  • This contributes to POSTIVE INTROPY.


PKA impact on RyR2 channels

  • phosphorylation of RyR2 causes it to be sensitized to activation by trigger Ca2+.
  • contributes to POSITIVE INTROPY


PKA impact on phospholamban (PLB)

  • association of PLB with SERCA2 inhibits Ca2+ pumping activity (into SR)
  • 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.


Characteristics of Timothy Syndrome

  •  disorder characterized by syncope, cardiac arrhythmias and sudden death, in addition to intermittent hypoglycemia, immune deficiency and cognitive abnormalities including autism.
  • Associated with de novo mutations in CaV1.2 (the principle subunit of the L-type Ca2+ channel).

  • TS2 mutations profoundly suppress voltage-dependent inactivation.

  • Both TS and TS2 patients display AV block, prolonged Q-T intervals and episodes of polymorphic ventricular tachycardia.


Characteristics of 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.
  • 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.
  • 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.
  • 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.
  • These patients have significantly shortened Q-T intervals.


Characteristics of 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.
  • Associated with causative mutations in RyR2—with dominant inheritance—and in the lumenal Ca2+ buffer calsequestrin2 (CasQ2)—with recessive inheritance.
  • RyR2 mutations increase the resting “leak” of Ca2+ out of the SR and/or render RyR2 more sensitive to activation by Ca2+.



Mechanism of ectopic depolarizations relating to CPVT

  • 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.