Calcium Induced Calcium Release

1. Introduction

The heart’s ability to contract rhythmically and forcefully relies on precise regulation of intracellular calcium (Ca²⁺). Calcium is the key signaling molecule that links electrical excitation of the cardiac membrane to mechanical contraction of the myocardium—a process known as excitation–contraction coupling (ECC).

In cardiac muscle, the primary mechanism driving cytosolic calcium increase is calcium-induced calcium release (CICR). This highly orchestrated process ensures that a small calcium influx through the plasma membrane triggers a much larger release of calcium from the sarcoplasmic reticulum (SR), amplifying the signal to initiate robust contraction.

This post explores the molecular basis of CICR, the role of L-type Ca²⁺ channels and ryanodine receptors, the impact on contraction strength, and mechanisms of calcium reuptake including the SERCA pump.

2. Overview of Excitation–Contraction Coupling

ECC in cardiac muscle converts the action potential into a forceful contraction via a sequence of events:

Depolarization of the sarcolemma and T-tubules.
Opening of L-type Ca²⁺ channels in T-tubules.
Influx of extracellular Ca²⁺, triggering SR calcium release.
Calcium binds to troponin C, initiating actin–myosin cross-bridge cycling.
Relaxation occurs as calcium is re-sequestered into the SR and extruded from the cell.

CICR serves as the amplification step, converting a small trigger signal into a substantial cytosolic calcium transient.

3. L-Type Calcium Channels

3.1 Definition and Location

Voltage-gated L-type calcium channels (Cav1.2) are located in the T-tubule membrane at the junction with the SR.
Also called dihydropyridine receptors (DHPRs) because they are sensitive to this class of calcium channel blockers.

3.2 Activation Mechanism

Depolarization during Phase 0 of ventricular myocytes opens L-type channels.
Calcium enters the cytosol from the extracellular space.
In cardiac muscle, this influx is relatively modest but sufficient to trigger SR release via ryanodine receptors.

3.3 Functional Significance

Provides the trigger calcium for CICR.
Determines action potential duration, as L-type current contributes to the plateau phase.
Modulated by autonomic input: β-adrenergic stimulation enhances channel opening → stronger contractions.

4. Ryanodine Receptors (RyR2)

4.1 Definition

RyR2 is the predominant ryanodine receptor isoform in cardiac muscle, located on the junctional SR membrane.
Functions as a calcium release channel, responding to calcium entering through L-type channels.

4.2 Mechanism of CICR

L-type calcium channels open in response to depolarization.
Local calcium influx increases calcium concentration near RyR2 (forming a calcium nanodomain).
RyR2 channels detect this rise and open, releasing large quantities of calcium from the SR.
The resulting calcium transient diffuses throughout the cytosol, activating contraction.

4.3 Regulation

Luminal SR calcium: RyR2 sensitivity is influenced by SR calcium content; low SR calcium reduces release probability.
Phosphorylation: PKA and CaMKII phosphorylation enhance channel opening during sympathetic stimulation.
Accessory proteins: FKBP12.6 stabilizes RyR2, preventing excessive diastolic calcium leak.

4.4 Clinical Relevance

RyR2 dysfunction leads to diastolic calcium leak, contributing to heart failure and arrhythmias.
Mutations in RyR2 cause catecholaminergic polymorphic ventricular tachycardia (CPVT).

5. Calcium-Induced Calcium Release: Stepwise Process

5.1 Trigger Calcium Entry

Small calcium influx through L-type channels initiates RyR2 opening.

5.2 Amplification by RyR2

Each RyR2 opening releases ~10–20 times more calcium than the trigger influx.
Calcium release occurs in localized units called calcium sparks; summation produces the global calcium transient.

5.3 Spread to Sarcomeres

Released calcium binds troponin C on thin filaments.
Tropomyosin shifts, allowing myosin heads to bind actin, initiating contraction.

5.4 Termination

Calcium release is self-limiting:
- RyR2 channels close as cytosolic calcium rises (calcium-dependent inactivation).
- Calcium reuptake into SR and extrusion reduce cytosolic calcium.

6. Importance of CICR in Contraction Strength

6.1 Frank-Starling Mechanism

CICR links SR calcium content to contraction force.
Higher preload stretches myocytes → more calcium released → stronger contraction.

6.2 Frequency-Dependent Regulation

Bowditch effect (“staircase phenomenon”): increased heart rate → enhanced CICR → stronger contractions.
Mechanisms: increased intracellular Ca²⁺, faster SR refilling, augmented L-type channel activity.

6.3 Sympathetic Modulation

β-adrenergic stimulation enhances L-type channel opening and RyR2 sensitivity.
Result: positive inotropy (increased contraction strength).

7. Calcium Reuptake Mechanisms

After contraction, cytosolic calcium must be cleared for relaxation (lusitropy).

7.1 SERCA Pump (SR Ca²⁺-ATPase)

Located on the SR membrane; actively pumps calcium from cytosol back into the SR.
Regulated by phospholamban (PLB):
- Unphosphorylated PLB inhibits SERCA.
- β-adrenergic stimulation → PKA phosphorylates PLB → disinhibits SERCA → faster relaxation.

7.2 Sodium-Calcium Exchanger (NCX)

Exchanges 1 Ca²⁺ out of the cell for 3 Na⁺ into the cell.
Plays a secondary role (~28%) in calcium removal.

7.3 Plasma Membrane Ca²⁺-ATPase (PMCA)

Minor contribution; maintains low basal cytosolic calcium.

7.4 Mitochondrial Uptake

Mitochondria sequester small amounts of calcium; contributes to energy coupling but not primary contraction regulation.

8. Coordination Between T-Tubules and SR

Dyads: T-tubules and junctional SR are closely apposed (~12–15 nm).
Ensures that trigger calcium reaches RyR2 rapidly, leading to uniform sarcomere activation.
Disruption of T-tubule organization (e.g., in heart failure) → dyssynchronous calcium release → reduced contraction efficiency.

9. Differences Between Ventricular and Atrial Myocytes

Feature	Ventricular Myocytes	Atrial Myocytes
T-tubules	Well-developed, facilitate uniform CICR	Sparse or absent; relies on peripheral release
RyR2 distribution	Junctional SR near Z-lines	Central corbular SR compensates for lack of T-tubules
Calcium transient amplitude	Large, uniform	Smaller, slower; may be heterogeneous
Contraction strength	Strong, high-pressure output	Lower, contributes mainly to ventricular filling

These differences explain why ventricular myocytes generate powerful contractions, whereas atrial contractions are weaker and mainly function to “top off” the ventricles.

10. Pathophysiological Implications

10.1 Heart Failure

Reduced SERCA expression → slower calcium reuptake → diastolic dysfunction
RyR2 hyperphosphorylation → calcium leak → arrhythmogenesis

10.2 Arrhythmias

Excessive or asynchronous CICR can trigger delayed afterdepolarizations (DADs).
Drugs targeting RyR2 or SERCA are being investigated to reduce arrhythmic risk.

10.3 Pharmacological Modulation

Digitalis: Inhibits Na⁺/K⁺ ATPase → increased intracellular Na⁺ → reduced NCX activity → higher SR calcium load → stronger contraction.
Calcium channel blockers: Reduce trigger calcium → decrease CICR → negative inotropy.
β-adrenergic agonists: Increase L-type channel opening and RyR2 activity → positive inotropy.

11. Experimental Approaches

Confocal microscopy: Visualizes calcium sparks and waves.
Patch-clamp electrophysiology: Measures L-type Ca²⁺ currents.
Genetic models: Knockout/knock-in of RyR2, SERCA, or PLB to study CICR regulation.
Calcium-sensitive fluorescent dyes (e.g., Fura-2): Quantify cytosolic calcium transients.

12. Clinical Relevance

Understanding CICR is critical for:

Diagnosing heart failure: Impaired calcium handling is a hallmark.
Developing targeted therapies: SERCA activators, RyR2 stabilizers, and calcium channel modulators.
Managing arrhythmias: Drugs or interventions that reduce spontaneous calcium release prevent DAD-induced tachyarrhythmias.