Intercellular Connections (Cell Junctions)

1. Fastening/structural junctions - hold cells together and anchor them to their basal laminas
2. Communicating junctions - permit transfer of ions and molecules between cells

1. Tight Junction (Zonula Occludens)

• Location: Surrounds the apical margin of epithelial cells (intestinal mucosa, renal tubules, choroid plexus, blood-brain barrier endothelium)
• Structure: Ridges formed half from each cell; adjacent membranes appear fused in TEM. The seal results from interactions among three main transmembrane protein families: occludin, claudins, and junctional adhesion molecules (JAMs). Cytosolic scaffold proteins (e.g., ZO-1) anchor these to the actin cytoskeleton.
• Functions:
  • Seals the paracellular space, forcing molecules to cross via the transcellular route
  • Acts as a "fence" preventing lateral diffusion of membrane proteins between the apical and basolateral domains, maintaining cell polarity
  • Degree of "leakiness" varies with claudin composition (e.g., proximal renal tubule = leaky; urinary bladder = very tight)
• Clinical relevance: Clostridium perfringens enterotoxin binds claudins, disrupting tight junctions and causing secretory diarrhea. Helicobacter pylori targets ZO-1 and disrupts gastric epithelial tight junctions, contributing to ulcer formation.

2. Adherens Junction (Zonula Adherens)

• Location: Immediately below the tight junction; encircles the cell as a continuous band
• Structure: Contains cadherins (Ca²⁺-dependent transmembrane glycoproteins). Cadherins bind homophilically across the intercellular space; their cytoplasmic tails bind catenins, which link to actin filaments via actin-binding proteins. These actin filaments contribute to the "terminal web" at the apical pole.
• Function: Major site of attachment for intracellular microfilaments; stabilizes and reinforces the occluding tight junction above it; firmly anchors cells to neighbors

3. Desmosome (Macula Adherens)

• Location: Scattered as spot-welds on lateral cell surfaces (not a continuous belt); abundant in skin, cardiac muscle, cervical epithelium
• Structure: Disc-shaped thickenings of apposed plasma membranes. Transmembrane proteins are desmogleins and desmocollins (larger cadherin family members). Their cytoplasmic ends bind plakoglobins → desmoplakins in an electron-dense plaque → intermediate filaments (cytokeratins/tonofilaments in epithelia, desmin in cardiac muscle)
• Function: Provides very strong mechanical adhesion; distributes tensile forces across a tissue via the intermediate filament network
• Clinical relevance: Pemphigus vulgaris - autoantibodies against desmogleins (especially desmoglein-3) disrupt desmosomes, causing intraepidermal blistering of skin and oral mucosa

4. Hemidesmosome

• Location: Basal surface of epithelial cells, anchoring them to the underlying basal lamina
• Structure: Resembles half a desmosome but uses integrins (not cadherins) as the transmembrane link proteins. Connected intracellularly to intermediate filaments; extracellularly binds laminin in the basal lamina.
• Function: Attaches epithelium to the extracellular matrix
• Clinical relevance: Mutations in hemidesmosomal proteins (e.g., BP180/collagen XVII, BP230) cause inherited or autoimmune blistering diseases such as bullous pemphigoid and junctional epidermolysis bullosa

5. Gap Junction (Nexus)

• Location: Found in virtually all mammalian tissues; particularly important in cardiac muscle, smooth muscle, liver, lens of the eye
• Structure: The intercellular space is narrowed to ~4 nm. Each cell contributes a connexon (hemichannel) made of 6 connexin protein subunits (each with 4 membrane-spanning domains). Two connexons from adjacent cells align to form a complete dodecameric gap junction channel. Pore diameter ~0.8-1.4 nm; allows passage of molecules < 1000 Da. Humans have at least 20 different connexin-encoding genes.
• Function: Allows direct cell-to-cell passage of ions, sugars, amino acids, cAMP, IP₃, and other small signaling molecules. Enables electrical coupling (rapid propagation of action potentials in cardiac and smooth muscle) and chemical/metabolic coordination between cells.
• Regulation: Gap junction channels are gated; they close in response to increased intracellular Ca²⁺ or decreased pH (e.g., during cell injury).
• Clinical relevance: Connexin mutations cause:
  • Connexin 26 (GJB2) mutations → hereditary sensorineural hearing loss (most common form)
  • Connexin 32 mutations → Charcot-Marie-Tooth disease X (peripheral neuropathy)
  • Cardiac connexin defects → electrophysiological arrhythmias and sudden cardiac death

Summary Table