EC-Coupling - Ca regulation

Question 1

SERCA Subtypes

Answer 1

SERCA2a = slow twitch and heart

SERCA1 = fast twitch skeletal

SERCA2b/3a = non-muscle

Question 2

Function of SERCA

Ca CG

Answer 2

• Returns Ca from cytoplasm to SR in diastole
• Most important ‘extruder’ because most Ca must be returned to the SR
• ATPase that works against the GC of Ca
• [Ca]i = 1 mM
• [Ca]sr = 200 mM

Question 3

Role of SERCA in HF

Answer 3

• Severely reduced SERCA current in HF

* (CUPID 2 2015) gene therapy, terminated early with -ve results

Question 4

SERCA mechanism

Answer 4

• ATP binds to SERCA
• Dissociates to ADP.Pi
• Conformational change in SERCA
• Ca shuttled into SR in the process

Question 5

SERCA regulation

Answer 5

• Phospholamban (PL) binds SERCA to inhibit it
• PL = homopentamer
• PKA phosphorylates PL to relieve this inhibition

Question 6

RyR Structure

Answer 6

• GIANT (1.2 MD)
• Four units form one large large pore region in the centre
• Gathered in ‘clusters’ (2-50) served by (1-2) dedicated L-Types Ca Channels of the t-tubules

Question 7

RyR Function (Cause and effect)

Answer 7

• Extremely high [Ca] in cleft* activates RyR
• RyR initiate high-conductance release of SR Ca
• CICR enables contraction
• Ca is both the trigger, and the result, yet signal is somehow graded, not regenerative
• Cleft = t-tubule-SR interface

Question 8

Modulation of Force in muscle types

Answer 8

Skeletal Muscle

• CNS Recruits/dismisses motor units to modulate force

Cardiac Muscle

• RyR vary force at the level of the sarcomere
• Graded response to amount of Ca trigger

Question 9

RyR CICR

Answer 9

• SR-released Ca triggers contraction (if [Ca]SR is sufficient)

Question 10

SL Ca-ATPase

Answer 10

• Plays little role in beat-to-beat [Ca]

- May be important in long term control of [Ca]

Question 11

Mitochondria and Ca

Answer 11

• Import Ca through uniporter
• Very sensitive to [Ca]
• [Ca] regulates energy production
• Uses NCX to extrude Ca
• NHX to maintain [Na]grad

Question 12

Why Store Ca inside the cell

Answer 12

• To produce contraction/relaxation without an SR would need giant influx/efflux of Ca across the membrane
• This would cause massive Em fluctuation
• Unstable Em can destabilise the CM and the heart

Question 13

Clinical Significance of Unregulated Ca

Answer 13

• Cells with poor Ca control may beat spontaneously
• Can set up foci for arrhythmia
• SERCA in HF, arrhythmias

Question 14

CICR

• Muscle types
• Connections
• Regulation

Answer 14

• Occurs to some extent in all forms of muscle (most exaggerated in cardiac)
• Direct L-Type-RyR communication in skeletal
• Close co-localisation in cardiac
• Influx is voltage-dependent
• RyR-release is influx-dependent