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INTERCELLULAR JUNCTIONS

Presented By:Dr. Mamta SinghPGT - I

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INDEX• Introduction• Definitions• Classification• Tight junctions• Adherens junctions• Desmosomes• Gap junctions• Hemidesmosomes and focal contacts• Cellular adhesion• Summary

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INTERCELLULAR JUNCTIONS

• Specialized junctions at specific sites on the contacting cell membrane.

• Also called as membrane junctions.• Mediate 2 types of interactions:

1. Cell to cell

2. Cell to extracellular matrix• Abundant in epithelial tissues.

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• Maintain the mechanical integrity of animal tissues.

• Build up the paracellular barrier of epithelia.• Control the paracellular transport.• Provide contact between neighbouring cells or

between a cell and the extracellular matrix.

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• On the molecular level intercellular junctions consists of three components:

1. Transmembrane adhesive protein

2. Cytoplasmic adapter protein

3. Cytoskeletal filament

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CLASSIFICATION

INTERCELLULAR JUNCTIONS

OCCLUDING JUNCTIONS

COMMUNICATING JUNCTIONS

ANCHORING JUNCTIONS

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• The specialized junctions may be further classified as follows:

• OCCLUDING JUNCTIONS

Tight junctions (Zona Occludens)

• COMMUNICATING JUNCTIONS

Gap junctions

• ANCHORING JUNCTIONS

Adhesive junctions Cell-to-cell

1. Zonula adherens (adheren junctions)

2. Macula adherens (desmosome)

Cell-to-matrix

1. Focal adhesions

2. Hemidesmosomes

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Definitions

• Adherens junctions: A junction that links cell membranes and cytoskeletal elements within and between cells, connecting adjacent cells mechanically.

• Tight junctions: A junction at which adjacent plasma membranes are joined tightly together.

• Gap junctions: Narrowed portion of intercellular space containing channels.

• Desmosomes: Cell structure specialized for cell to cell adhesion

• Hemidesmosomes : Link the cell to the basal lamina and, through additional extracellular molecules, to ECM.

TIGHT JUNCTIONS

• Tight junctions, or zonula occludens: • Closely associated areas of two cells.• Form a tight belt like adhesive seal.• Selectively limits the diffusion of water, ions &

larger solutes as well as migration of cells.• Separating the interior of body from the external

world.

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In electron microscopic structureof thin sections of tight junctions the plasma membrane of adjacent cells appear to fuse together in a series of one or more contacts.

• Two structural proteins have been identified in the structure of tight junctions namely:

• Occludins• Claudin

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• A family of more than 20 proteins, called Claudins, constitutes the main structural proteins of tight junction strands.

• Claudins have four transmembrane sequences, but they are not related in sequence to occludin.

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A.Preliminary model of tight junction structure with claudin linking the two membranes together & peripheral protein ZO-1 linking the cytoplasmic tail of claudin to actin filaments.B-C. transmembrane topology of claudin & occludin.

Tight junctions

• Extracellular domains of claudins form rows of pores along tight

junction.

• Each claudin has a unique selectivity for cations or anions.

• At the zona occludens the membranes of adjoining cells

converge and are at a distance of 0.1- 0.3 µm.

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• Human gingival keratinocytes (HGKs) were studied by means of freeze-fracture technique for the investigation of intercellular contacts.

• In vivo the tight junctions, which were of low complexity were co-distributed with desmosomes; in one case, the strands ran directly through desmosomal plaques.

• Where tight junctions and desmosomes occurred together, no gap junctions were seen.

• In contrast, where no tight junctions were present, gap junctions and desmosomes were co-localized.

Meyle J,  Güttig K,  Rascher G and Wolburg H: Transepithelial electrical resistance and tight junctions of human gingival keratinocvtes. J Periodont Res 1999; 34: 214–222

• Adherens junctions and Desmosomes are two types of adhesive junctions using homophilic interactions of cadherins to bind epithelial cells to adjacent cells.

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ADHERENS JUNCTIONS

• The zonula adherens is a band like specialization of the membrane and cytoplasm that encircles the apex of adjoining cells and strongly bonds the cells together.

• In this junction the opposing membranes are 15 – 20 nm apart .

• It is a major site of epithelial cell cohesion.

Adherens Junction

• Cytoplasmic actin filaments bind adherens junctions.

• Homophilic interactions between densely clustered E-cadherens (the epithelial transmembranic adhesive protein) bind adjacent cells together at adherens junctions.

• β- catenin(cytoplasmic adapter protein) and Plakoglobin (desmosomal cytoplasmic adapter protein) bind the cytoplasmic domains of E-cadherin.

Adherens Junction

• An another cytoplasmic adapter protein, α-catenin, binds cadherins to actin filaments and β-catenin to actin filaments.

• Adherens junctions are first connections that are established between developing sheets of epithelial cells.

• The contact begins when cadherins on the tips of filopodia engage to the cadherins of another cell.

Adherens Junction

• Adherens junctions are a pre requisite for tight junctions that allow epithelial cells to establish polarity with proteins and lipids in plasma membranes.

• Zonula adherens is the major site for cell cohesion.

• It stabilizes the surface of epithelia.

• The junctions and polarity determine the orientation of mitotic spindle and the plane of division . This allows for asymmetrical division of stem cells (stratified epithelium).

Adherens junction

• In mature columnar epithelia a belt –like adherens junction called zonula adherens encircles the cell near the apical surface thus maintaining physical integrity of the epithelium.

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DESMOSOMES

• Desmos means ‘bound ‘ , Soma means ‘body’.

• It is also called Macula Adherens.

• Provide strong adhesion between the epithelial and muscle cells.

• These junctions are small disk shaped “spot welds” between adjacent cells.

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Desmosomes

• Ist observed in the spinous layer of epidermis by an

Italian pathologist Giulio Bizzazero.

• Helps to resist shearing force.

• Structure that forms the site of adhesion between

2 cells ,consisting of dense plate in each adjacent cells

seprated by a thin layer of extracellular material.

• Desmosomes link 2 cells together.

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Desmosomes

• Human Gingival Keratinocytes (HGK)s are interconnected on the cell periphery by Desmosomes.

• Consist of two dense attachment plaques into which tonofibrils insert and an intermediate, electron dense line in the extracellular compartment.

Desmosomes

• Cellular adhesions at desmosomes are mediated by transmembrane proteins:

• Desmogleins • Desmocollins.

• Plakoglobin also called gamma- catenin.

• Molecular composition of desmosomes vary in particular tissues

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Desmosomes

• Desmosomes are site for attachment, structural ability of epithelium linking cytoskeletal structures of two cells.

• Desmoglein -2 and desmocollin -2 are found in most of the desmosomes.

• The devlopment of animal tissues depends on desmosomes & their constituents proteins.

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GAP JUNCTIONS• Gap junctions are plaque that contain large intercellular

channels that connect the cytoplasm of a pair of cells.

• Half channels in each membrane are called connexons.

• Connexons consists of six protein subunits, called

connexins.

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Gap Junctions

• Connexin are named by their molecular weight.

• Found exclusively in chordates.

• Most connexons pair with identical connexons on the partner cell to form homotypic gap junctions.

• Gap junction communication is conditional• It depends on:• Number of channels• Fraction that are open or closed

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Gap Junctions

• Plants lacks gap junctions

• Cells in plant tissues maintain continuity through plasmodesmata.

• Molecules smaller than 1kd diffuse freely through plasmodesmata.

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Gap Junctions

• Oleamide- fatty acid amide produced by the brain , blocks gap junction and induce sleep in animals.

• Gap junctions allow osteocytes to maintain cellular supply line to acquire nutrients from distant blood vessels.

• White blood cells may also form transient gap junctions with endothelial cells.

• Cells in most metazoans communicate by gap junctions.

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Gap Junctions

• Mutations in connexins genes cause human disease.

• Recessive mutation in the connexin -26 gene are most common cause of human Deafness.

• Mutation in connexin-32 gene causes degeneration of myelin sheets around axons.

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HEMIDESMOSOMES

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Basal Cells

Tonofilaments

Lamina lucida

Lamina densa

Anchoring filaments

Anchoring fibrils

Type IV collagenProteoglycans

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Hemidesmosomes

HEMIDESMOSOMES

• Hemidesmosomes are adhesive

junction that link cytoplasmic

filaments to basal lamina. • Adhesion to extracellular

matrix is different from

intercellular adhesion

because integrins provide

transmembrane link between

cytoskeleton and extracellular

matrix.

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Contd…

• Two transmembrane proteins mainly found in hemidemosomes are α6β4 integrin and type XVII collagen.

• Outside the cell α6β4 integrin binds to laminin-5 in basal lamina.

• The extracellular collagen triple helix forms anchors filaments between membrane and basal lamina.

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Contd…

• STRUCTURE OF HEMIDESMOSOME:

– Adhesive protein – INTEGRIN– Cytoplasmic proteins – PECTIN, BP 180– Cytoskeletal element - INTERMEDIATE

FILAMENTS – Target molecule - LAMININ.

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CELLULAR ADHESION

PRINCIPLES OF CELLULAR ADHESION

1. First principle of adhesion

• Cells define their capacity for adhesive interactions by selectively expressing plasma membrane receptors with limited ligand binding activity.• For example: Endothelial cells produce E – selectin only when stimulated by inflammatory hormones

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Contd…

2. Second principle of adhesion• Many adhesion proteins bind one main ligand and many ligands bind a single type of receptor, for example Most cadherins bind to themselves, such homophilic interactions require Ca+2 ions.

3. Third principle of adhesion• It states that cell modulate adhesion by controlling the surface density, state of aggregation and state of activation of their adhesion receptors.

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CADHERIN FAMILY OF ADHESION RECEPTORS

• Cadherins name is derived from calcium dependent adhesion

protein.

• Homophilic interactions of cadherins link epithelial and muscle cells to adjacent cells at specialized junctions called adherens junctions and desmosomes.

• The cytoplasmic domains of cadherin junctions interact with actin filaments to maintain physical integrity of tissues.

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Contd…

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Structural Hallmark

of Cadherin family is

CAD domain

Cadherins are named according to their location or cells to which they are attached. for eg:

•Epithelial tissue -E-cadherin •Nervous tissue - N-cadherin •Placenta- P-cadherin • osteoblasts- O-cadherin•Kidney-K cadherin•muscle -M-cadherin

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• Integrins are the main cellular receptors for extra cellular matrix.

• Integrins tend to be more promiscous than most adhesion receptors as some bind to several protein ligands & many matrix molecule bind to 1 integrin.

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SUMMARY

• Intercellular junctions are fundamental to the interactions between cells.

• Mucosal barrier integrity is maintained by the physical

interactions of intercellular junctional molecules on opposing epithelial cells. 

• In the heart, cell junctions form the low-resistance pathways for rapid impulse conduction and propagation, enabling synchronous stimulation of myocyte contraction.

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SUMMARY

• In kidney, cell junctions help to maintain concentrations of fluid creating a balance between osmotic gradients.

• By means of these junctions, the activities of the individual cells that make up tissues are co-ordinated, enabling each tissue system to function as an integrated whole.

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