Intracellular calcium Flashcards
What is the Sarcoplasmic reticulum and what is its major function
- subcellular structure (like the mitochondria, ER etc.)
- stores large amounts of calcium it receives from L-type calcium channels
Ryanodine Receptors
- embedded in the cell membrane of sarcoplasmic reticulum
- Opening by binding of extracellular calcium from L-type calcium channels allows calcium to flow out of the sarcoplasmic reticulum
- high (pathological) cytosolic calcium inhibits the receptor
What are the two calcium channels on the outer and inner mitochondrial membrane?
- VDAC: voltage-dependent anion channel on outer membrane
- mtCa2+: mitochondrial calcium uniporter on inner membrane
what is the major function of the mitochondria in regards to calcium?
under stressed conditions, calcium can increase ATP production, glucose oxidation and stimulate energetic enzymes to meet the needs of the heart
Na+/Ca2+ exchanger
moves 1 Ca2+ out of myocyte for 3Na+ in to baance ion concentrations/gradients
SERCA
Pumps the majority of the calcium that enters the cytosol during a contraction back into the Sarcoplasmic reticulum (2 Ca2+ for 2H+)
What is the effect of phosphorylation of L-type Calcium channels?
enhancement of calcium entry into the cell from the extracellular space (prolongs the open time)
What happens to RyRs when the cell is treated with a beta adrenergic receptor agonist?
increased rate of opening
PLB
- inhibitor of SERCA
- phosphorylation releases it when there are larger calcium transients to allow faster pumping of calcium back into the SR
SL Ca2+ ATPase
- removes very small amounts of calcium from highly localized areas around caveoli (vaginations of cardiac muscle cell membranes)
- cannot adequately respond to rising Ca2+ tranients
- has a role in signaling to promote appropriate response from heart in response to greater calcium levels (ie: muscle growth)
T tubules
- cell membrane folding to create passages for action potentials to reach deep into the core of the muscle for more even contraction.
- contain large concentrations of L-Ca2+ channels and Na+/Ca2+ exchangers
Caveolin-3
forms invaginations to form T tubules
BIN1
permits lengthening of T tubules
Junctophilin-2
links Sarcoplasmic Reticulum to T tubules at RyRs
What happens when the amount of BIN1 in a cell is decreased?
- Decreased number of T-tubules
- uneven distribution of calcium in the cell
- Less L-type Ca2+ channels (less calcium overall)
Were there improvements in animal or human models with heart failure when they were transfected with BIN1?
- reversal of heart failure in pigs
- more complicated in humans because BIN1 has to be inserted with adenovirus which many humans have antibodies for
Were there improvements in heart failure cases with treatment to induce overexpression of JN2 (junctophilin-2)? Why or why not?
Yes there were improvements. Overexpression of JN2 ensured the proper positioning of RyRs and L-Ca2+ channels and also prolonged the opening of the channels
Calpain
protease that cleaves JN2 under stressed conditions. Cleaved JN2 can travel to the nucleus to decrease the expression of stress-causing genes
CPVT/mechanisms of CPVT
genetic mutations inducing malfunction of RyR receptors causing cardiac dysfunction - arrhythmias
1. increased sensitivity of RyRs to calcium
2. mutation in RyR protein stabilizers
3. mutation RyR itself
What is the impact on SERCA and the NCX exchanger in CPVT?
- SERCA cannot keep up with increased calcium levels
- rely on NCX more
- Na+ ends up entering the cell in higher concentrations as the NCX exchanger tries to remove calcium
- excess sodium induces depolarization and inappropriate contractions (arrhythmias)
Cl- exchanger has the same effect because calcium is removed (Raising the membrane potential
How does caffeine affect the heart?
- unzips RyRs causing them to favour the open conformation
- results in calcium “leakage” which can result in arrhythmias
Dantrolene
treatment for people with caffeine induced heart failure. Re-zips and stabilizes RyR
How does pop affect the heart?
- increases the excretion of potassium
- causes delay in respolarization after action potential, prolonging the action potential and increasing the possibility of overlapping action potentials
- triggers arrhythmias
