Part 7 · Chapter 7.3

Calcium Pumps

After a Ca²⁺ transient, cytosolic Ca²⁺ must be cleared back to resting 100 nM. Three systems act in parallel: SERCA (SR/ER reuptake), PMCA (plasma-membrane extrusion), and NCX (Na/Ca exchange). MCU (mitochondrial Ca uniporter) buffers on a slower timescale. The mix differs across cell types.

1. SERCA

Sarco/Endoplasmic Reticulum Ca²⁺-ATPase: P-type ATPase pumping 2 Ca²⁺/ATP into the ER/SR against a ~1000× gradient. Isoforms SERCA1 (skeletal), SERCA2a (cardiac/slow-skel), SERCA2b (ubiquitous), SERCA3. Inhibited by thapsigargin (research) and SERCA2a downregulation is central to heart failure. Phospholamban (PLN) inhibits SERCA2a; PKA phosphorylation of PLN relieves the inhibition, accelerating Ca²⁺ uptake during β-adrenergic stimulation.

2. PMCA

Plasma-Membrane Ca²⁺-ATPase: P-type ATPase pumping 1 Ca²⁺/ ATP out to extracellular space. Four isoforms (PMCA1-4), most ubiquitously expressed. Low capacity, high affinity — responsible for fine tuning resting [Ca²⁺]. Ca²⁺/CaM activates PMCA auto-regulatorily. Contributes modestly to clearance after large transients but critical for steady-state balance.

3. NCX

Na/Ca exchanger: 3 Na⁺ in / 1 Ca²⁺ out, driven by Na⁺gradient. Electrogenic (net +1 inward current). Reversal potential:

\[ V_{rev} \;=\; 3 E_{Na} - 2 E_{Ca} \]

At rest NCX extrudes Ca²⁺; during depolarisation or elevated [Na⁺] (e.g., digoxin-induced Na/K ATPase block), NCX runs reverse and brings Ca²⁺in. High capacity, low affinity; dominant Ca²⁺ extruder in cardiomyocytes (25% of cardiac clearance).

Simulation: Pump Kinetics & Tissue Contributions

Python

script.py50 lines

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

# SERCA vs PMCA vs NCX Ca clearance kinetics
t = np.linspace(0, 2, 1000)
Ca0 = 1.0  # uM initial transient
# SERCA: high capacity, low affinity (K ~0.3 uM)
Ca_SERCA = Ca0 * np.exp(-t/0.3)
# PMCA: low capacity, high affinity
Ca_PMCA = Ca0 * np.exp(-t/1.0)
# NCX: very high capacity during cardiac recovery, electrogenic 3Na/1Ca
Ca_NCX = Ca0 * np.exp(-t/0.15)

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_SERCA, color='#34d399', lw=2.5, label='SERCA (ER uptake)')
ax1.plot(t, Ca_PMCA, color='#60a5fa', lw=2.5, label='PMCA (fine-tune)')
ax1.plot(t, Ca_NCX, color='#fbbf24', lw=2.5, label='NCX (fast, cardiac)')
ax1.set_xlabel('Time after transient (s)', color='#bae6fd')
ax1.set_ylabel('[Ca]_cytosol (uM)', color='#bae6fd')
ax1.set_title('Ca clearance kinetics', color='#67e8f9', fontweight='bold')
ax1.legend(facecolor='#1e293b', edgecolor='#334155', labelcolor='#cbd5e1')

# Contribution by tissue
tissues = ['Cardiomyocyte','Skeletal','Smooth','Neuron']
SERCA = [70, 92, 60, 55]
NCX   = [25, 3, 15, 25]
PMCA  = [3, 2, 20, 15]
MCU   = [2, 3, 5, 5]

x = np.arange(len(tissues))
w = 0.2
ax2.bar(x - 1.5*w, SERCA, w, color='#34d399', label='SERCA')
ax2.bar(x - 0.5*w, NCX, w, color='#fbbf24', label='NCX')
ax2.bar(x + 0.5*w, PMCA, w, color='#60a5fa', label='PMCA')
ax2.bar(x + 1.5*w, MCU, w, color='#a78bfa', label='MCU')
ax2.set_xticks(x); ax2.set_xticklabels(tissues)
ax2.set_ylabel('% Ca clearance', color='#bae6fd')
ax2.set_title('Tissue-specific balance', 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('SERCA2a: major cardiac Ca pump; downregulation drives heart failure')
print('NCX 3Na:1Ca electrogenic; reverses during AP depolarisation')

Click Run to execute the Python code

Code will be executed with Python 3 on the server

4. Mitochondrial Uniporter (MCU)

Inner-mitochondrial-membrane Ca²⁺ channel (MCU complex, De Stefani 2011). Driven by mitochondrial membrane potential (~180 mV). Activated only above ~1 µM cytosolic Ca²⁺, so buffers large transients. Matrix Ca²⁺ activates TCA dehydrogenases, matching ATP supply to metabolic demand. MCU overload contributes to ischaemia-reperfusion cell death through the mitochondrial permeability transition pore (mPTP).

Key References

• MacLennan, D. H. & Kranias, E. G. (2003). “Phospholamban: a crucial regulator of cardiac contractility.” Nat. Rev. Mol. Cell Biol., 4, 566–577.

• Blaustein, M. P. & Lederer, W. J. (1999). “Sodium/calcium exchange: its physiological implications.” Physiol. Rev., 79, 763–854.

• De Stefani, D. et al. (2011). “A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter.” Nature, 476, 336–340.

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