Part 7 · Chapter 7.1

Calcium Channels

Ca²⁺ is a universal second messenger: resting cytosolic [Ca²⁺] is ~100 nM while extracellular is ~1 mM and ER lumen is ~500 µM, so even modest channel opening produces large concentration jumps. This chapter covers voltage-operated channels (VOCCs: Ca_v1-3), receptor-operated channels, and store-operated Ca²⁺ entry (SOCE) via STIM-Orai.

1. Voltage-Operated Ca²⁺ Channels

VOCCs are classified by activation voltage and pharmacology:

Cav1 (L-type): high-voltage activated, slow inactivating. Cav1.2 (cardiac, smooth, neurons), Cav1.1 (skeletal), Cav1.3, Cav1.4. Dihydropyridine target (amlodipine, nifedipine).
Cav2 (P/Q, N, R): HVA, presynaptic. Cav2.1 = P/Q-type neurotransmitter release. Omega-conotoxin (N-type), omega-agatoxin (P/Q).
Cav3 (T-type): low-voltage activated, fast inactivating. SA pacemaker, thalamic burst firing, smooth muscle. Ethosuximide target for absence seizures.

2. Store-Operated Ca²⁺ Entry (SOCE)

When ER Ca²⁺ is depleted (by IP₃R activation, M7.2), STIM1 in the ER membrane clusters and physically interacts with Orai1 in the plasma membrane, opening the Ca²⁺-release-activated channel (CRAC). CRAC/Orai mediates sustained Ca²⁺ entry during prolonged stimulation, refilling stores and triggering transcription via NFAT. Loss-of-function STIM1/ Orai1 mutations cause severe combined immunodeficiency.

Simulation: I-V & Channel Family

Python

script.py43 lines

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

# Ca_v1.2 L-type current-voltage (I-V) relationship
V = np.linspace(-80, 60, 200)
# Activation m_inf: V50=-10, k=6
m_inf = 1 / (1 + np.exp(-(V + 10)/6))
# Driving force: V - E_Ca (E_Ca ~+60 mV for Ca gradient 10000:1)
E_Ca = 60
I = m_inf**2 * (V - E_Ca) * 2.5
I = np.where(V < E_Ca, I, 0)

# SOCE vs VOCC vs ROC activation
conditions = ['Depolarisation\n(L-type)', 'Depletion of ER\n(SOCE/Orai)',
              'IP3R Ca release\n(RyR/IP3R)', 'Receptor-operated\n(ligand-gated)']
activation = [-20, 0, 0, 0]   # mV threshold (depol vs store)

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(V, I, color='#fbbf24', lw=2.6)
ax1.axhline(0, color='#94a3b8', lw=0.7)
ax1.set_xlabel('Voltage (mV)', color='#bae6fd')
ax1.set_ylabel('Ca current (rel)', color='#bae6fd')
ax1.set_title('L-type Cav1.2 I-V curve: U-shape',
              color='#67e8f9', fontweight='bold')

families = ['Cav1 (L)','Cav2 (P/Q/N)','Cav3 (T)','Orai (SOCE)','TRP (multiple)','IP3R/RyR']
counts =   [4, 3, 3, 3, 28, 6]
ax2.bar(families, counts, color='#60a5fa', edgecolor='#bae6fd')
ax2.set_ylabel('# Members in family', color='#bae6fd')
ax2.set_title('Ca channel family sizes', color='#67e8f9', fontweight='bold')
plt.setp(ax2.get_xticklabels(), rotation=15)

plt.tight_layout()
plt.savefig('output.png', dpi=120, bbox_inches='tight', facecolor='#0a0f1e')
print('Cav1 (L-type): HVA, slow-inactivating, smooth/cardiac EC coupling')
print('Cav2.1 (P/Q): presynaptic, neurotransmitter release')
print('Cav3 (T): LVA, pacemaker in SA node + thalamic burst firing')

Click Run to execute the Python code

Code will be executed with Python 3 on the server

3. TRP Channels

Transient receptor potential (TRP) channels are a diverse family of cation- permeable channels (28 human members, 7 subfamilies). Many conduct Ca²⁺. TRPV1 (capsaicin, heat), TRPM8 (menthol, cold), TRPA1 (mustard oil, pain), TRPC1-7 (Ca²⁺ store refill), TRPV5/6 (epithelial Ca²⁺uptake). Sensory TRPs are major pain-therapy targets.

Key References

• Catterall, W. A. (2011). “Voltage-gated calcium channels.” Cold Spring Harb. Perspect. Biol., 3, a003947.

• Prakriya, M. & Lewis, R. S. (2015). “Store-operated calcium channels.” Physiol. Rev., 95, 1383–1436.

• Clapham, D. E. (2003). “TRP channels as cellular sensors.” Nature, 426, 517–524.

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