Part 6 · Chapter 6.1

Tight Junctions

Tight junctions (TJs) seal adjacent epithelial cells at the apical margin, creating a paracellular barrier whose permeability varies 1000-fold between “leaky” (intestinal) and “tight” (blood-brain barrier) epithelia. TJs are built from claudin and occludin tetraspan membrane proteins anchored to the cytoskeleton via ZO scaffolds. Claudin composition determines both permeability magnitude and ion selectivity.

1. Molecular Architecture

TJs appear in freeze-fracture EM as strands of intramembranous particles (Farquhar & Palade 1963). Claudins (27 family members) form paired strands; extracellular loops of opposing cells interdigitate. Some claudins form selective paracellular ion channels (claudin-2 for Na⁺, claudin-16 for Mg²⁺); others are sealing (claudin-1, -3, -5). Occludin and tricellulin contribute to bicellular and tricellular sealing respectively. Inside the cell, ZO-1/2/3 adaptors link claudins to actin.

2. TER & Epithelial Leakiness

Transepithelial resistance (TER) is measured in Ohm · cm² across an epithelial monolayer. Values range over three orders of magnitude:

\[ \text{Leaky} \ (\sim 50\ \Omega\,\text{cm}^2) \ \to \ \text{Tight} \ (\gtrsim 5000\ \Omega\,\text{cm}^2) \]

Jejunum (~50 Ohm·cm²) allows massive paracellular flow of Na⁺ and water. Distal nephron, colon, and urinary bladder are tight. Blood-brain barrier (>5 000 Ohm·cm²) is the tightest barrier, excluding essentially all hydrophilic solutes.

Simulation: TER Across Epithelia

Python

script.py32 lines

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

# TER (transepithelial resistance) across different tissues
tissues = ['Jejunum','Ileum','Proximal tubule','Distal tubule','Colon',
           'Urinary bladder','Blood-brain barrier']
TER = [50, 100, 5, 500, 300, 5000, 8000]
claudin_profile = {
    'Jejunum':'CLDN2,15 (cation pore)',
    'Ileum':'CLDN2,15',
    'Proximal tubule':'CLDN2,10',
    'Distal tubule':'CLDN8,14,16',
    'Colon':'CLDN4,7,8',
    'Urinary bladder':'CLDN4,8',
    'Blood-brain barrier':'CLDN3,5 (sealing)'
}

fig, ax = plt.subplots(figsize=(11, 6), facecolor='#0a0f1e')
ax.set_facecolor('#111e2f'); ax.tick_params(colors='#bae6fd')
for s in ax.spines.values(): s.set_color('#334155')
idx = np.argsort(TER)
ax.barh([tissues[i] for i in idx], [TER[i] for i in idx], color='#60a5fa', edgecolor='#bae6fd')
ax.set_xscale('log')
ax.set_xlabel('Transepithelial resistance TER (ohm cm^2)', color='#bae6fd')
ax.set_title('Leaky -> tight epithelia span 3 orders of magnitude',
             color='#67e8f9', fontweight='bold')
ax.grid(True, color='#334155', alpha=0.3, axis='x', which='both')
plt.tight_layout()
plt.savefig('output.png', dpi=120, bbox_inches='tight', facecolor='#0a0f1e')
print('Leaky epithelia (jejunum, proximal tubule): paracellular flow dominant')
print('Tight epithelia (BBB, urothelium): near-zero paracellular; transcellular only')

Click Run to execute the Python code

Code will be executed with Python 3 on the server

3. Regulation & Pathology

TJ permeability is dynamically regulated by MLCK (pMLC tension opens paracellular pathway), Rho-kinase, cytokines (TNF-α, IFN-γ open junctions in inflammation), and intracellular Ca²⁺. TJ disruption is central to inflammatory bowel disease, coeliac disease (zonulin-mediated opening by gluten peptides), and leaky-gut-linked metabolic disease. Tumour metastasis often involves claudin expression changes.

Key References

• Anderson, J. M. & Van Itallie, C. M. (2009). “Physiology and function of the tight junction.” Cold Spring Harb. Perspect. Biol., 1, a002584.

• Tsukita, S., Furuse, M. & Itoh, M. (2001). “Multifunctional strands in tight junctions.” Nat. Rev. Mol. Cell Biol., 2, 285–293.

• Gunzel, D. & Yu, A. S. L. (2013). “Claudins and the modulation of tight junction permeability.” Physiol. Rev., 93, 525–569.

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