Part 7 · Chapter 7.2

Intracellular Ca²⁺ Release

Two families of ER/SR Ca²⁺-release channels shape intracellular Ca²⁺ signals: inositol 1,4,5-trisphosphate receptor (IP₃R) and ryanodine receptor (RyR). Both show bell-shaped Ca²⁺ dependence that supports Ca²⁺-induced Ca²⁺-release (CICR), the mechanism behind Ca²⁺ sparks, puffs, waves, and oscillations.

1. IP₃R

Tetrameric 1,2,3 kDa channels on ER membrane. Activation requires binding of both IP₃ (from PLC, M3.4) and cytosolic Ca²⁺. The response to Ca²⁺ is bell-shaped: low Ca²⁺ activates, high Ca²⁺inactivates — a feature that enables self-terminating release and oscillatory behaviour. Three isoforms (IP3R1, 2, 3) with different tissue expression and pharmacology (2-APB, heparin block).

2. Ryanodine Receptor

Largest known ion channel (~2.2 MDa tetramer). Three isoforms: RyR1 (skeletal muscle), RyR2 (cardiac, neurons), RyR3 (brain, smooth muscle). Cardiac RyR2 is Ca²⁺-gated (CICR); skeletal RyR1 is mechanically gated by DHPR (M4.4). Malignant hyperthermia = RYR1 gain-of-function + halothane; catecholaminergic polymorphic VT = RYR2 gain-of-function.

Simulation: IP₃R Bell Curve & Oscillations

Python

script.py51 lines

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

# IP3R bell-shaped Ca dependence: activated by low Ca, inhibited by high
Ca = np.logspace(-8, -4, 400)
# Bell curve: two Ca sites
P_open = (Ca/3e-7)**2 / (1 + (Ca/3e-7)**2) * (1 / (1 + (Ca/3e-6)**4))
# IP3 modulates
P_open_low_IP3 = P_open * 0.1
P_open_high_IP3 = P_open

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.semilogx(Ca*1e6, P_open_high_IP3, color='#f87171', lw=2.5, label='High IP3')
ax1.semilogx(Ca*1e6, P_open_low_IP3, color='#60a5fa', lw=2.5, label='Low IP3')
ax1.set_xlabel('[Ca]_cytoplasm (uM)', color='#bae6fd')
ax1.set_ylabel('IP3R open probability', color='#bae6fd')
ax1.set_title('Bell-shaped Ca dependence of IP3R',
              color='#67e8f9', fontweight='bold')
ax1.legend(facecolor='#1e293b', edgecolor='#334155', labelcolor='#cbd5e1')

# Ca oscillations from CICR + IP3R feedback
t = np.linspace(0, 100, 2000)
Ca_cyto = np.zeros_like(t); Ca_ER = np.zeros_like(t)
Ca_cyto[0] = 0.1; Ca_ER[0] = 500
for i in range(1, len(t)):
    dt = t[i]-t[i-1]
    IP3 = 1.0   # saturating
    Pipr = (Ca_cyto[i-1]/0.3)**2/(1+(Ca_cyto[i-1]/0.3)**2)/(1+(Ca_cyto[i-1]/3)**4)
    J_release = Pipr * Ca_ER[i-1] * IP3 * 0.02
    J_SERCA = 0.1 * Ca_cyto[i-1]
    J_leak = 0.003 * Ca_ER[i-1]
    Ca_cyto[i] = max(0, Ca_cyto[i-1] + dt*(J_release + J_leak - J_SERCA))
    Ca_ER[i] = Ca_ER[i-1] + dt*(J_SERCA - J_release - J_leak)*10

ax2.plot(t, Ca_cyto, color='#fbbf24', lw=2, label='Cytosolic Ca')
ax2.plot(t, Ca_ER/50, color='#34d399', lw=2, label='ER Ca / 50')
ax2.set_xlabel('Time (s)', color='#bae6fd')
ax2.set_ylabel('[Ca] (uM)', color='#bae6fd')
ax2.set_title('CICR oscillations', color='#67e8f9', fontweight='bold')
ax2.legend(facecolor='#1e293b', edgecolor='#334155', labelcolor='#cbd5e1')

plt.tight_layout()
plt.savefig('output.png', dpi=120, bbox_inches='tight', facecolor='#0a0f1e')
print('Bell-shaped Ca sensitivity generates CICR oscillations')
print('Low Ca activates IP3R; high Ca inactivates -> self-terminating release')

Click Run to execute the Python code

Code will be executed with Python 3 on the server

3. Ca²⁺ Sparks, Puffs, Waves

Elementary events. Ca²⁺ spark(Cheng 1993): ~10 RyR2 opening simultaneously in a dyad, lasting ~30 ms. Ca²⁺ puff: analogous IP₃R cluster event. When neighbouring release sites are sufficiently close and Ca²⁺ is high, CICR propagates as a wave across the cell (velocity ~10–100 µm/s). Fertilisation Ca²⁺ wave, cortical glial waves, and hepatocyte spiral waves are examples.

Key References

• Berridge, M. J. (2016). “The inositol trisphosphate/calcium signaling pathway in health and disease.” Physiol. Rev., 96, 1261–1296.

• Cheng, H. et al. (1993). “Calcium sparks: elementary events underlying excitation-contraction coupling in heart muscle.” Science, 262, 740–744.

• Zalk, R. et al. (2015). “Structure of a mammalian ryanodine receptor.” Nature, 517, 44–49.

← 7.1 Channels 7.3 Pumps →

Intracellular Ca2+ Release

1. IP3R