Part 4 · Chapter 4.4

Excitation-Contraction Coupling

Excitation-contraction coupling (EC coupling) is the mechanism by which membrane depolarisation is transduced into mechanical contraction. Skeletal, cardiac, and smooth muscle each use a different mechanism. Skeletal is mechanical coupling; cardiac is Ca-induced Ca release (CICR, Fabiato 1985); smooth is pharmacomechanical and Ca-sensitising.

1. Skeletal EC Coupling

Action potentials propagate down the t-tubule membrane. Voltage sensor DHPR (L-type Ca_v1.1) in the t-tubule is mechanically linked to RyR1 in the apposed SR membrane. DHPR voltage-induced conformational change directly opens RyR1 — no Ca²⁺ trigger needed. SR Ca²⁺ pours into cytosol, rising from ~100 nM to ~10 µM in <10 ms. Ca²⁺ binds troponin C, displaces tropomyosin, exposes actin-binding sites on myosin heads, cross-bridges cycle.

2. Cardiac EC Coupling — CICR

In cardiomyocytes, L-type Ca²⁺ (Ca_v1.2) in the t-tubule admits a small Ca²⁺ flux. This trigger Ca²⁺ encounters RyR2 in the junctional SR across a ~12 nm dyadic cleft. Each RyR2 is highly Ca²⁺-sensitive (open probability rises sharply above ~1 µM). A single Ca²⁺ spark opens ~10 RyR2s; summation of sparks across thousands of dyads gives the whole-cell Ca²⁺ transient. The process is graded — stronger Ca_v1.2 influx recruits more RyR2 clusters (Bers 2002).

\[ \text{I}_{Ca} \to \text{Ca}^{2+}_{\text{dyad}} \to \text{RyR2 open} \to \text{Ca}^{2+}\text{ spark} \to \Sigma\text{ sparks} = \text{transient} \]

Simulation: Skeletal vs Cardiac EC Coupling

Python

script.py53 lines

import numpy as np, matplotlib
matplotlib.use('Agg')
import matplotlib.pyplot as plt

# Skeletal EC coupling: AP -> DHPR conformational -> RyR1 open -> Ca release
t = np.linspace(0, 100, 1000)
# AP
V = np.where((t > 5) & (t < 7), 30, -85)
# DHPR activation tracks V
DHPR = np.where(V > -30, 1, 0)
# RyR1 activation follows DHPR (skeletal: mechanical coupling, no Ca trigger needed)
RyR_skel = np.zeros_like(t)
for i in range(1, len(t)):
    RyR_skel[i] = RyR_skel[i-1] + (t[i]-t[i-1])*(5*DHPR[i] - 0.1*RyR_skel[i-1])

# Cytosolic Ca (skeletal)
Ca_skel = np.zeros_like(t)
for i in range(1, len(t)):
    Ca_skel[i] = Ca_skel[i-1] + (t[i]-t[i-1])*(10*RyR_skel[i-1] - 0.15*Ca_skel[i-1])

# Cardiac EC: CICR - L-type Ca triggers RyR2
ICa = np.where((t > 5) & (t < 250), 0.5, 0)
RyR_card = np.zeros_like(t)
for i in range(1, len(t)):
    # RyR2 opens on Ca in dyadic cleft
    Ca_dyad = ICa[i] + 0.1*RyR_card[i-1]  # self-reinforcing
    RyR_card[i] = RyR_card[i-1] + (t[i]-t[i-1])*(4*Ca_dyad - 0.05*RyR_card[i-1])
Ca_card = np.zeros_like(t)
for i in range(1, len(t)):
    Ca_card[i] = Ca_card[i-1] + (t[i]-t[i-1])*(8*RyR_card[i-1] - 0.05*Ca_card[i-1])

fig, (ax1, ax2) = plt.subplots(1, 2, figsize=(14, 5), facecolor='#0a0f1e')
for ax in (ax1, ax2):
    ax.set_facecolor('#111e2f'); ax.tick_params(colors='#bae6fd')
    for s in ax.spines.values(): s.set_color('#334155')
    ax.grid(True, color='#334155', alpha=0.3)

ax1.plot(t, Ca_skel, color='#60a5fa', lw=2.5)
ax1.set_xlabel('Time (ms)', color='#bae6fd')
ax1.set_ylabel('Cytosolic Ca (rel)', color='#bae6fd')
ax1.set_title('Skeletal: AP -> DHPR-RyR1 direct coupling',
              color='#67e8f9', fontweight='bold')

ax2.plot(t, Ca_card, color='#f87171', lw=2.5)
ax2.set_xlabel('Time (ms)', color='#bae6fd')
ax2.set_ylabel('Cytosolic Ca (rel)', color='#bae6fd')
ax2.set_title('Cardiac: Ca-induced Ca release (CICR)',
              color='#67e8f9', fontweight='bold')

plt.tight_layout()
plt.savefig('output.png', dpi=120, bbox_inches='tight', facecolor='#0a0f1e')
print('Skeletal EC: mechanical coupling DHPR->RyR1; no external Ca needed')
print('Cardiac EC: CICR via dyadic L-type Ca -> RyR2 Ca spark -> whole-cell transient')

Click Run to execute the Python code

Code will be executed with Python 3 on the server

3. Smooth-Muscle EC Coupling

Smooth muscle uses multiple Ca²⁺ sources: L-type Ca_v1.2 on plasma membrane (voltage-dependent), IP₃R on SR (receptor-operated from G_q), and store-operated Ca²⁺ entry (SOCE) via STIM-Orai. No troponin; regulation is via MLCK phosphorylation of myosin (M4.3). Pharmacomechanical coupling — force changes without membrane voltage change — is routine and characteristic.

4. Pathologies of EC Coupling

Malignant hyperthermia: gain-of-function RYR1 mutation, anaesthetic halothane triggers massive Ca²⁺ release, fatal hyperthermia + rhabdomyolysis. Catecholaminergic polymorphic ventricular tachycardia (CPVT): RYR2 gain-of-function causes Ca²⁺ leak in diastole, afterdepolarisations, arrhythmias. Heart failure: downregulation of SERCA2a prolongs Ca²⁺ transient decay, impairs contraction–relaxation coupling.

Key References

• Fabiato, A. (1985). “Time and calcium dependence of activation and inactivation of calcium-induced release of calcium from the sarcoplasmic reticulum.” J. Gen. Physiol., 85, 247–289.

• Bers, D. M. (2002). “Cardiac excitation-contraction coupling.” Nature, 415, 198–205.

• Cheng, H. & Lederer, W. J. (2008). “Calcium sparks.” Physiol. Rev., 88, 1491–1545.

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