Excitation Contraction Coupling in Cardiac Muscle

Introduction

The heart’s ability to pump blood efficiently depends on the precise conversion of electrical signals into mechanical contraction, a process known as excitation–contraction (E–C) coupling. In cardiac muscle, this process integrates:

Ventricular and atrial action potentials
Calcium handling by the sarcoplasmic reticulum and T-tubules
Myofilament activation and cross-bridge cycling

This post provides a detailed overview of cardiac E–C coupling, explores the Frank–Starling mechanism at the cellular level, and discusses lusitropy—the control of cardiac relaxation.

1. Overview of Excitation–Contraction Coupling

Cardiac E–C coupling links electrical depolarization (action potential) to mechanical contraction (systole). The sequence involves:

Depolarization of the sarcolemma via sodium and calcium currents
Calcium influx through L-type channels in T-tubules
Calcium-induced calcium release (CICR) from the sarcoplasmic reticulum (SR) via ryanodine receptors
Activation of myofilaments (troponin, tropomyosin, actin, myosin)
Cross-bridge cycling and sarcomere shortening
Relaxation via calcium reuptake and extrusion

Cardiac E–C coupling differs from skeletal muscle in reliance on extracellular calcium, slower kinetics, and graded contraction strength.

2. Stepwise Sequence of E–C Coupling

2.1 Action Potential Initiation

The process begins with an action potential (AP) in ventricular myocytes.
Phase 0 depolarization opens fast Na⁺ channels, producing the steep upstroke.
Phase 2 plateau opens L-type calcium channels (Cav1.2) in T-tubules.
This calcium entry is small but crucial—it triggers SR calcium release.

2.2 Calcium Influx via L-Type Channels

L-type channels are located at junctional regions of T-tubules and SR.
Depolarization opens these channels, allowing 0.1–0.2 μM of Ca²⁺ to enter the cytoplasm.
This “trigger calcium” initiates the next step: calcium-induced calcium release.

2.3 Calcium-Induced Calcium Release (CICR)

The SR is the main calcium store in cardiac muscle (~1 mM).
L-type Ca²⁺ influx binds ryanodine receptors (RyR2) on the SR membrane.
RyR2 channels open, releasing 10–20 times more Ca²⁺ into the cytoplasm.
Result: cytosolic [Ca²⁺] rises from ~100 nM to ~1 μM.

Spatial organization:

Dyads: Close apposition of T-tubule L-type channels and junctional SR RyR2
Ensures rapid, uniform calcium release across the sarcomere

2.4 Calcium Binding to Troponin C

Troponin C (TnC) is the calcium sensor on thin filaments.
Ca²⁺ binding induces conformational changes in troponin–tropomyosin complex, exposing myosin-binding sites on actin.
This allows cross-bridge cycling to occur.

2.5 Cross-Bridge Cycling and Sarcomere Shortening

ATP binds myosin head → myosin detaches from actin
ATP hydrolysis → myosin head “cocks” into high-energy state
Cross-bridge formation → myosin binds actin
Power stroke → myosin pivots, sliding actin toward M-line
ADP and Pi release → force generation

Result: sarcomere shortening and ventricular contraction.

2.6 Relaxation (Diastole) – Lusitropy

Relaxation requires removal of cytosolic calcium:
1. SERCA pump: reuptake of Ca²⁺ into SR (regulated by phospholamban)
2. Na⁺/Ca²⁺ exchanger (NCX): extrudes Ca²⁺ across sarcolemma
3. Minor contributions from plasma membrane Ca²⁺ ATPase
Lusitropy: Rate of relaxation
- Enhanced by β-adrenergic stimulation → phospholamban phosphorylation → faster SERCA activity
- Impaired lusitropy → diastolic dysfunction

3. Role of T-Tubules

T-tubules are invaginations of the sarcolemma penetrating deep into the myocyte.
Function: Ensure simultaneous depolarization across the cell
Position L-type channels adjacent to RyR2 → rapid, uniform CICR
T-tubule disruption (heart failure) → dyssynchronous Ca²⁺ release → weak contraction

4. Calcium Dynamics in E–C Coupling

4.1 Calcium Transient

Rapid rise (systole) → plateau (~100–200 ms)
Rapid decline (diastole) → relaxation
Measured via Fluo-4 or Indo-1 dyes in research

4.2 SR Calcium Load

Determines strength of contraction
High SR Ca²⁺ → strong contraction
Low SR Ca²⁺ → weak contraction (e.g., heart failure)

5. Frank–Starling Mechanism at Cellular Level

The Frank–Starling law states: stroke volume increases with ventricular filling.

Mechanistic Basis at Sarcomere Level

Sarcomere length dependence:
- Optimal actin–myosin overlap at ~2.2 μm sarcomere length
- Longer sarcomere → more force generated (within physiological range)
Sensitivity to Ca²⁺:
- Stretch increases myofilament Ca²⁺ sensitivity, enhancing contraction
- May involve titin-based mechanosensing and troponin C regulation
Functional significance:
- Ensures output matches venous return
- Adjusts contraction strength beat-to-beat without neural input

6. Modulation by Autonomic Nervous System

6.1 β-Adrenergic Stimulation

Activates PKA, phosphorylating:
- L-type Ca²⁺ channels → ↑Ca²⁺ influx
- Phospholamban → ↑SERCA activity → faster relaxation
- Troponin I → ↑cross-bridge cycling rate

Result: Increased inotropy (force), lusitropy (relaxation), and chronotropy (rate)

6.2 Parasympathetic Stimulation

Vagus nerve releases acetylcholine → decreases L-type Ca²⁺ current
Reduces contractile strength → slows heart rate

7. Clinical Correlations

7.1 Heart Failure

Reduced SERCA activity → impaired calcium reuptake → diastolic dysfunction
Leaky RyR2 → calcium leak → arrhythmias, contractile inefficiency

7.2 Ischemia

ATP depletion → impaired SERCA and NCX function → cytosolic Ca²⁺ overload
Leads to contracture, impaired relaxation, arrhythmogenic substrate

7.3 Pharmacological Modulation

Drug/Class	Target	Effect
Digitalis	Na⁺/K⁺ ATPase	↑SR Ca²⁺ load → ↑contractility
β-agonists	β1-receptor	↑Ca²⁺ influx and SR uptake → ↑inotropy and lusitropy
Calcium channel blockers	L-type Ca²⁺ channels	↓contractility, slow AV conduction

8. Sarcomere Proteins and Contraction Regulation

8.1 Troponin Complex

TnC: Calcium binding → cross-bridge activation
TnI: Inhibits actin–myosin interaction at low Ca²⁺
TnT: Anchors troponin to tropomyosin

8.2 Tropomyosin

Blocks actin binding sites in diastole
Shifted by TnC–Ca²⁺ complex during systole

8.3 Titin

Passive tension → contributes to Frank–Starling mechanism
Connects Z-line to M-line, acts as mechanosensor

9. Excitation–Contraction Coupling Efficiency

Efficiency = ratio of force generated to ATP consumed
Optimized by:
- Proper sarcomere length
- Synchronous calcium release via T-tubules
- Adequate SR calcium load
Dysfunction → reduced ejection fraction (systolic heart failure) or impaired filling (diastolic heart failure)

10. Summary Table: Steps in Excitation–Contraction Coupling

Step	Key Players	Outcome
1. AP depolarization	Na⁺ channels (Phase 0), L-type Ca²⁺ channels (Phase 2)	Membrane depolarization
2. Trigger Ca²⁺ influx	L-type Ca²⁺ channels	Initiates CICR
3. SR Ca²⁺ release	Ryanodine receptors	Cytosolic Ca²⁺ rise
4. Troponin binding	TnC	Exposes actin binding sites
5. Cross-bridge cycling	Actin, myosin, ATP	Sarcomere shortening, contraction
6. Relaxation	SERCA, NCX, phospholamban	Cytosolic Ca²⁺ removal, diastolic relaxation

11. Integrative View with Frank–Starling and Lusitropy

Frank–Starling: Increased preload → longer sarcomere → stronger contraction
Lusitropy: β-adrenergic phosphorylation enhances SERCA → faster relaxation → accommodates higher heart rates
Together, they fine-tune cardiac output beat-to-beat in health and disease.