This document provides an overview of excitation-contraction coupling in the heart. It discusses how an action potential leads to a rise in intracellular calcium concentration, triggering calcium-induced calcium release from the sarcoplasmic reticulum and muscle contraction. It describes the roles of the sarcoplasmic reticulum calcium ATPase, phospholamban, and calsequestrin in calcium reuptake and storage. Sympathetic stimulation and changes in sarcomere length can further modulate contraction force. Species differences in calcium handling between humans and rabbits are also noted.

1. G1BH 2012-2013 - HC-15
Excitation-contraction coupling
Paul Steendijk, PhD
Associate Professor Cardiovascular Physiology
Department of Cardiology, LUMC
p.steendijk@lumc.nl
2013.02.13

2. G1BH 2012-2013 HC-15
Excitation-contraction coupling
Contraction mechanisms
Excitation-contraction
coupling
Pump function

3. Cross-bridge cycling & calcium

4. Calcium & cross-bridge cycling

5. Calcium concentrations
Extracellular Ca concentration: [Ca]o ~ 1.2 mM (1200 μM)
Intracellular Ca concentration: [Ca]i ~ 100 nM (0.1 μM)
- 104-fold concentration gradient
During action potential:
- Ca enters via L-type Ca channels
- Free [Ca]i increases ~10-fold

6. [Ca]o , [Ca]i and Force
- [Ca]i depends on [Ca]o
- Developed force is dependent on free [Ca]i

7. Calcium-induced calcium release from SR
- Ca influx is not sufficient to raise [Ca]i and initiate contraction
- Sarcoplasmic reticulum stores large amounts of Ca
- Ca entry (L-type Ca channels) triggers Ca release from SR via
Ryanodine receptors

8. Calcium re-uptake into the SR
- Ca is sequestered into SR by SERCA pump (SR Ca-ATPase)
- Phospholamban regulates SERCA; phosphorylation removes
its inhibitory effect
- Calsequestrin is a SR Ca-binding protein

9. Calcium removal initiates relaxation
- Ca must be removed from the cytosol to lower [Ca]i and allow relaxation
- Routes: SERCA (SR-ATPase), Na/Ca exchange (NCX), SL-ATPase
Species differences: Humans ≈ Rabbit

10. Calcium handling

11. Beta-receptor stimulation & ECC
- Sympathetic activation >> release norepinephrine >> stimulate betareceptors on SL >> stimulates cAMP production >> protein kinase A
- Phosphorylation of L-type Ca-channels: positive inotropic effect
(improves contraction)
- Phosphorylation of phospholamban (PLB) and troponin-I (TnI): positive
lusitropic effect (improves relaxation)

12. Anatomy & E-C coupling
- Myofilaments (Actine-Myosine)
- Myofibrils
- Mitochondria (ATP)
-Sarcolemma, T-tubule
- Sarcoplasmic reticulum
- Cisterna

13. Sarcomere length and intracellular calcium control force
Isometric force is increased by:
Increased intracellular calcium
- binding to Tn-C >>
actine-myosin interaction
Increased sarcomere length
(“Starling’s Law of the Heart”)
- Optimal actine-myosine overlap
- Reduced lattice spacing
- Altered myosin head orientation
Interaction of two mechanisms
- increased calcium sensitivity