EC Coupling and Calcium I

Question 1

Map the sequence of major events between the initiation of an action potential in a cardiac muscle fiber, through contraction (action potential spreads into t system, Ca2+ channel in t-membrane opens and allows entry of extracellular Ca2+, which triggers the opening of RyR2 in the SR membrane, Ca2+ ions leave SR lumen and enter myoplasm, bind troponin, allowing actin-myosin cross-bridge cycling and contraction.

Answer 1

• The 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.

Question 2

Describe the processes that control relaxation of contraction by removing f Ca2+ from the myoplasm

Answer 2

• Relaxation is achieved via:
o Removal of Ca2+ from the myoplasm by SERCA2 pump and NCX Na+/Ca2+ exchanger.
o In steady-state, Ca2+ released from the SR is recycled back into SR by SERCA2, and surface extrusion balances L-type Ca2+ current.

Question 3

ERCA2 pump:

Answer 3

• –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.

Question 4

NCX Na+/Ca2+ exchanger:

Answer 4

• -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.

Question 5

Skeletal muscle

Answer 5

o ECC does not require entry of external Ca2+
o CaV1.1(a1s), b1a, a2d1, g1
o RyR1

Question 6

Cardiac muscle:

Answer 6

o ECC requires entry of external Ca2+.
o CaV1.2(a1C), b2a, a2d1
o RyR2

Question 7

NCX sodium/calcium exchanger:

Answer 7

exchanges 3 Na+ for 1 Ca2+ and can run in either direction—calcium efflux in exchange for sodium influx or calcium influx in exchange for sodium efflux. The direction in which is turn depends on both membrane potential and the gradients for sodium and calcium

Question 8

Describe how the exchange of 1 Ca2+ ion for 3 Na+ ions, together with membrane potential and the sodium and calcium gradients, governs the direction of Ca2+ and Na+ movements via NCX

Answer 8

• Vr=-74 mV
• What does this mean?
o If the cell membrane potential is -74 mV, Ca2+ will be extruded until the [Ca2+]i falls to 100 nm at which point net movement via NCX will be zero.
—If the [Na+]i were to increase (causing a ↓ in ENa and a negative shift in Vr), then the steady state level of [Ca2+]I would increase.

Question 9

Explain why the extrusion of Ca2+ from the cytoplasm via NCX can cause membrane depolarization

Answer 9

• 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.
o This inward current would cause the cell to depolarize.
— Depolarization triggered by Ca2+ release from the sarcoplasmic reticulum has the capacity to trigger arrhythmias