The Sarcoplasmic Reticulum

Question 1

Effects of [Ca]SR

Answer 1

• Controls rate of release of Ca

- RyR sensitivity is modulated by SR-Ca binding within the SR

Question 2

Digoxin and SR-Ca

Answer 2

• Inhibits Na/K-ATPase
• ^[Na] reverses NCX mode
• Ca influx taken in SR by SERCA
• Ca may build up and increase probability of spontaneous beats

Question 3

Factors of increasing contraction

Answer 3

• Increase [Ca]SR
• Gain
  (How effectively L-TCC triggers RyR)
• Lower Ca efflux (cardiac glycosides)
• Adrenergic Stimulation

Question 4

Timing of Ca release

Answer 4

• At the point of I(Ca) influx

- Not at the start of upstroke

Question 5

Regenerative Release

Answer 5

• At the level of the RyR cluster, yes

- Doesn’t occur beyond this

Question 6

What comprises the Ca transient?

Answer 6

• Not one global Ca release
• Summation of of many Ca ‘packets’ released at once
• Synchronised, but independent

Question 7

Local Control Model of CICR

Stern 1999

Answer 7

1. L-Type and RyR are co-localised in micro-domains
2. RyR are in clusters, that do not communicate
3. RyR has low sensitivity to Ca (High [Ca] needed in cleft)
4. SR-released Ca diffuses away very quickly

Question 8

The AP and Contraction

- Cellular Level

Answer 8

• AP depolarises membrane
• Many L-TCCs open simultaneously
• Many Ca packets released simultaneously
• Synchronised contraction

Question 9

The AP and Contraction

- Level of the heart

Answer 9

• Atria contract in syncytium to help fill the ventricles
• Ventricles then contract in syncytium
• Efficient filling and ejection depend on synchrony CICR in millions of micro-domains

Question 10

The Ca spark

Answer 10

• The release unit of the SR
• Localised Ca transient due to random action in a micro-domain
• More than one RyR, but only one cluster
• May also be occurring randomly anywhere else

Question 11

Sparks and contractions

Answer 11

• No spark/number of sparks can directly trigger a contraction in a CM
• Enough sparks will raise [Ca]
• NCX will extrude Ca, raising membrane potential
• If threshold potential reached, AP and contraction will follow

Question 12

Ca release termination within the unit

Answer 12

1. RyR inactivation (time/Ca)
   - Far too slow to be whole answer
2. Depletion of local SR-Ca
   - RyR Po lower
3. Stochastic attrition
   - Mechanism to terminate release

Question 13

Stochastic Attrition

Answer 13

• RyR flicker open and shut when activated
• Probability that [Ca]cleft drops while the RyR is flickered shut
• Will not reopen as L-TCC not providing Ca influx anymore

Question 14

SR membrane potential compensation

Answer 14

• Ca release is electrogenic
• K channel influx
• Cl channel efflux
• Reversed to compensate for SERCA uptake