Cell Junctions

How junctions are organized in an epithelium

A polarized epithelial cell has an apical face (toward the lumen) and a basolateral face (toward neighbors and the basement membrane). Junctions stack along the lateral membrane in a conserved apical-to-basal order:

  apical (lumen side)
        │ TJ │  tight junction     ← seals paracellular space
        │ AJ │  adherens junction  ← actin belt, Ca²⁺-dependent
        │ DS │  desmosome          ← keratin spot-welds
        │ GJ │  gap junction       ← intercellular channels
  ════════════════════ basal lamina
        │ HD │  hemidesmosome      ← anchors cell to matrix

This stack is called the apical junctional complex. Histologists called the tight + adherens + desmosome triplet the "terminal bar" before electron microscopy resolved the parts in 1963 (Farquhar and Palade). Junctions are regulated complexes that assemble, mature, and dissolve through the cell cycle and during morphogenesis.

Tight junctions — the paracellular gatekeepers

Tight junctions are the most apical structure on the lateral membrane. Two transmembrane families do the sealing — claudins (24 paralogs in humans, each four-pass) and occludin. Junctional adhesion molecules (JAMs, immunoglobulin-superfamily single-pass) sit alongside. On the cytoplasmic face, scaffolds ZO-1/2/3 link claudins to actin and signaling proteins.

Selectivity is set by which claudins are expressed. Different tissues need different barriers — claudin-2 (kidney proximal tubule) is a leaky cation pore for Na⁺ paracellular flow; claudin-16 (loop of Henle) is Mg²⁺-permeable, with mutations causing familial hypomagnesemia; claudin-5 (brain endothelium) seals the blood-brain barrier so tightly that even sucrose cannot cross; claudin-14 (cochlea) is required for K⁺ recycling in hair cells, with mutations causing non-syndromic deafness. The number of strands visible in freeze-fracture EM correlates with leak-resistance — bladder has ten or more, proximal tubule only two or three.

Adherens junctions — the cadherin-catenin belt

Adherens junctions sit just basal to tight junctions. The transmembrane glue is E-cadherin in epithelia (N-cadherin in neurons and mesenchymal cells, VE-cadherin in vascular endothelium). E-cadherin extracellular domains zipper together with the E-cadherin on the neighboring cell — but only if Ca²⁺ is bound. Calcium chelators like EDTA dissolve adherens junctions in seconds.

The cytoplasmic tail of E-cadherin binds β-catenin, which binds α-catenin, which binds the actin cytoskeleton. β-catenin is dual-purpose — when not bound to E-cadherin at the membrane, it can translocate to the nucleus and activate TCF/LEF transcription factors in the Wnt pathway. APC mutations in colon cancer prevent β-catenin degradation, letting it pile up in the nucleus and drive proliferation. Loss of E-cadherin is itself a hallmark of the epithelial-mesenchymal transition — the tumor cell releases its neighbors, gains motility, and invades.

Desmosomes and hemidesmosomes — keratin spot-welds

Desmosomes are mechanical anchors — dense plaques on the cytoplasmic face of two opposing cells, spaced like rivets. The transmembrane proteins are desmogleins and desmocollins (calcium-dependent cadherins distinct from E-cadherin). Cytoplasmic plakoglobin and desmoplakin link these to keratin intermediate filaments — not actin. Hemidesmosomes look like half a desmosome under EM and anchor a basal cell to the basal lamina via α6β4 integrin binding laminin-332; plectin and BP230 link the integrin tail to keratin.

Gap junctions — direct cytoplasmic channels

Gap junctions are not adhesions — they are channels. Six connexin subunits assemble into a connexon (hemichannel). When a connexon on cell A docks with one on cell B, they form a continuous aqueous pore that bridges both cytoplasms. The pore is wide enough for ions and small metabolites under about 1 kDa (Ca²⁺, K⁺, cAMP, IP₃, glucose) but excludes proteins and nucleic acids.

Channels gate closed in response to high cytosolic Ca²⁺, low pH, or transjunctional voltage — protecting healthy neighbors from a dying cell. Connexin-43 (Cx43) is the workhorse of cardiac muscle, propagating action potentials across the ventricle through intercalated discs. Lens fibers use Cx46/Cx50 (loss causes congenital cataracts). Schwann cells use Cx32 across myelin layers; mutations cause X-linked Charcot-Marie-Tooth disease (CMTX1).

Tight vs adherens vs desmosome vs hemidesmosome vs gap junction

	Tight	Adherens	Desmosome	Hemidesmosome	Gap junction
Function	Seal paracellular space	Mechanical anchor + signaling	Spot-weld vs shear	Anchor to basal lamina	Intercellular channel
Transmembrane protein	Claudins, occludin, JAMs	E-cadherin (Ca²⁺-dependent)	Desmoglein, desmocollin	α6β4 integrin	Connexin (×6 = connexon)
Cytoskeletal partner	Actin (via ZO-1/2/3)	Actin (via β/α-catenin)	Keratin (via desmoplakin)	Keratin (via plectin)	None — channel
Cell-cell or cell-matrix	Cell-cell	Cell-cell	Cell-cell	Cell-matrix	Cell-cell
EM appearance	Strand ridges (freeze-fracture)	Continuous belt	Dense disc plaque	Half-disc on basal side	Hexagonal lattice (~1.5 nm pore)
Disease	FHHNC (claudin-16); BBB leaks in MS	Lost in carcinoma EMT	Pemphigus vulgaris; ARVD	Bullous pemphigoid; EB junctional	CMTX (Cx32); cataracts (Cx46/50)
Calcium-dependent	Indirect (through claudin pH)	Yes — Ca²⁺ holds zipper	Yes	No (integrin uses Mg²⁺)	Closed by high cytosolic Ca²⁺

Junctional diseases — when the glue fails

• Pemphigus vulgaris — IgG against desmoglein-3 dissolves desmosomes in the deeper epidermis; mucosa and skin blister; Nikolsky sign positive.
• Bullous pemphigoid — antibodies against BP180/BP230 in hemidesmosomes; tense subepidermal blisters in the elderly.
• Epidermolysis bullosa simplex — keratin-5/14 mutations; cytoskeleton tears under shear.
• Junctional epidermolysis bullosa — laminin-332 mutations; skin sloughs at the dermal-epidermal junction; often lethal in infancy.
• Charcot-Marie-Tooth X (CMTX1) — connexin-32 mutations disrupt Schwann cell gap junctions; demyelinating peripheral neuropathy.
• Arrhythmogenic right ventricular dysplasia (ARVD/C) — plakophilin-2 or desmoplakin mutations; cardiac desmosomes fail, fibrofatty replacement, sudden death in young athletes.
• Familial hypomagnesemia — claudin-16/19 mutations leak Mg²⁺ in the loop of Henle; nephrocalcinosis.
• Cancer EMT — loss of E-cadherin lets tumor cells dissociate; germline CDH1 mutations cause hereditary diffuse gastric cancer.

Common misconceptions

• Tight junctions are impermeable. They are selective, not impermeable; specific claudins create specific ion pores.
• Desmosomes connect to actin. They connect to keratin intermediate filaments — distinct cytoskeletal system.
• Gap junctions only carry electricity. They also carry second messengers like cAMP and IP₃ — metabolic coupling.
• Plant cells have gap junctions. They have plasmodesmata — a continuous ER strand passes through a sleeve in the cell wall.
• Cadherins always glue cells together. They also drive sorting; cells expressing different cadherins separate into distinct tissues.