The endoplasmic reticulum, specifically the sarcoplasmic reticulum in muscle cells, stores and releases calcium which acts as a second messenger. In cardiac muscle, relatively small amounts of calcium move in and out of the cell during each cycle, while much larger amounts are released from and taken back up by the sarcoplasmic reticulum. Ryanodine receptors and inositol trisphosphate receptors on the sarcoplasmic reticulum release calcium, causing contraction through interaction of actin and myosin. Calcium is then actively transported back into the sarcoplasmic reticulum by SERCA pumps to promote relaxation. Phospholamban regulates the activity of SERCA pumps and thus contraction and relaxation in the heart.

4. Endoplasmic reticulum
• The primary intracellular Ca2+ storage
and release organelle in most cells is the
endoplasmic reticulum
• In muscles, it is sarcoplasmic reticulum

9. Calcium
• A common second messenger
• Regulate many processes in cells (e.g., contraction,
secretion, synaptic transmission, fertilization, nuclear pore
regulation, transcription)
• Cells are bathed a relatively high Ca2+ conc and the
cytoplasm of cells have much lower resting Ca2+ conc
• Ca2+ entry across the surface membrane can substantially
elevate cytosolic Ca2+ levels

11. Relatively small amounts of calcium
ions enter and leave the cell during
each cardiac cycle
But much larger amounts move in
and out of the SR

12. Ca2+ release channels
Two families
The ryanodine receptors (RyR) and
Inositol trisphosphate receptors (IP3R)

18. • Calcium released by the SR increases the
intracellular calcium conc from 10-7 to 10-5 M
• Results in ratcheting movement between the
myosin heads and the actin
• Actin and myosin filaments slide past each other
shortening sarcomere length
• Ratcheting cycles occur as long as the cytosolic
calcium remains elevated

20. Ryanodine receptor
• Binds with ryanodine a potential insecticide
• A calcium release channel
• A macromolecular signaling complex
• Rigid paralysis in skeletal muscle and
flaccid paralysis in cardiac muscle.

22. Calcium fluxes in the myocardium

24. How contraction ends
• Release of Ca is linked tightly to the L type-Ca channel
• Rising Ca inhibit calcium induced calcium release- perhaps
acting through calmodulin
• Rising cytosolic Ca ion concentration activates SERCA
• Ca release continues only for the duration of AP
Cytosolic calcium falls - binding with troponin
C lessens - tropomyosin again starts to
inhibit actin - myosin interaction - relaxation

25. Transport of Ca2+ out cytosol
By 4 pathways
SR Ca2+-ATPase (SERCA) pump
A sarcolemmal Na/Ca exchanger
A sarcolemmal Ca2+-ATPase
A mitochondrial uniporter

26. Calcium uptake into the sarcoplasmic reticulum

27. SERCA pump
• Most important cellular mechanism for Ca2+ removal
• Account for 70% of Ca2+ removal,
• Na/Ca exchanger - 28% of Ca2+ removal
• Most important cellular mediator of relaxation,

28. Phospholamban
• Means "phosphate receiver"
• The major regulator of calcium uptake pump
• Crucial role in beta-adrenergic response of the myocardium
• Activity governed by its state of phosphorylation
• Has two major protein kinases, the one activated by
calcium ions and the other by c-AMP

29. Phospholamban
• Responds to beta-adrenergic stimulation by enhancing (de-
inhibiting) the uptake of calcium by SERCA
• Thyroxine mediates the action via phospholamban -
SERCA system
• Transgenic mouse model deficient in phospholamban –
– rates of contraction and relaxation are maximal and
– do not vary with added beta-adrenergic stimulation

33. CALCIUM SPARKS
• Very small quantities of calcium released spontaneously and
locally from SR with out L-channel opening
• Fails to activate the neighbouring calcium release channels -
contraction not initiated
• Summation of sparks could produce a normally propagating
calcium wave that triggers excitation-contraction coupling
• Catecholamine toxicity or during early reperfusion - SR
overloaded with Ca - sparks can lead to propagated calcium
waves - risk of serious arrhythmias or impaired contractility

34. In Heart Failure
• Cardiac contraction and relaxation is impaired
• Rate of Ca uptake by SERCA 2a is depressed
• Impaired expression of certain genes encoding specific
SR proteins
• mRNA for RYR2, SERCA and phospholamban are deficient
• Regulation of SERCA 2a is upset, perhaps the
phosphorylation

35. Excitation-Contraction Coupling
Action potential at surface membrane
Transmission into interior along t-tubules
Release of calcium from lateral sacs of SR
Calcium diffuses to filaments
Initiates contraction
Calcium taken up by SR causes relaxation