Cell Junctions

Cell junctions are proteinaceous structures that physically hold 2 surfaces (cell-to-cell or cell-to-matrix) together. Cell junctions aid in communication and structural support and act as a barrier. They are classified as occluding (tight junctions), anchoring (adherens, desmosomes and hemidesmosomes), and communicating (gap junctions). Type II hypersensitivity has been noticed with autoantibody production against the components of anchoring junctions, resulting in pathology such as pemphigus vulgaris and bullous pemphigoid.

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Tight Junctions

Defintion

Tight junctions (occluding junctions or zonula occludens) are intercellular adhesion complexes composed of proteins whose primary role is regulating the passage of water and solutes between epithelial cells (paracellular permeability). 

Location

  • Found on the apical and basolateral sides of epithelial cells
  • Mainly present in gastric mucosa, renal tubules, brain capillaries

Composition

Cell junctions are branching networks of sealing strands, each formed by multiple transmembrane proteins and associated intracellular proteins.

Transmembrane proteins:

  • Embedded in the plasma membrane of 2 adjacent cells: Extracellular domains of proteins in 1 cell are continuous with those of transmembrane proteins in the opposing cell.
  • Occludin proteins have extra- and intracellular loops that regulate paracellular permeability.
    • Influence intracellular activity such as gene expression and energy metabolism
    • Have 9 major domains, which are distributed intra- and extracellularly
    • Stabilize tight junctions
    • Support the barrier function of tight junctions
  • Claudin proteins are considered the backbone of tight junctions.
    • Seal paracellular space
    • 4 transmembrane domains, with both ends lying within the cytoplasm
    • Have the ability to bind to scaffolding proteins
  • Junctional adhesion molecules regulate the paracellular pathway. 
    • Have only 1 transmembrane domain
    • Help maintain cell polarity
Types of cell junctions

Illustration depicting strands of transmembrane proteins (claudins and occludins) tightly binding adjacent plasma membranes

Image: “Types of Cell Junctions” by OpenStax College. License: CC BY 3.0, edited by Lecturio.

Function

  • Diffusion barrier between adjacent cells
  • Prevent passage of ions and molecules between cells
    • Molecules are selectively allowed based upon size and charge.
    • Generally, cations are preferentially allowed in transit.
  • Separate tissue compartments into apical and basal sides and maintain the polarity of cells
    • Prevent lateral diffusion of proteins between the apical and basolateral surfaces
    • Preserve the functioning of specialized activities such as receptor-mediated endocytosis
  • Maintain osmotic balance
  • Generally, cells are classified as being tight or leaky. Tight junctions have an important role in determining whether cells have tight or leaky epithelial cells.
    • Tight epithelial cells include distal convoluted tubule cells in the kidney and bile ducts and the cells composing the blood–brain barrier (BBB).
    • Leaky epithelial cells include cells in the proximal tubule of the kidney. These cells contain fewer tight junctions, which contributes to their leakiness.

Anchoring Junctions

Adherens

Definition:

Adherens are junctions between cells that are linked to the actin cytoskeleton. These junctions are also known as zonula adherens, intermediate junctions, or belt desmosomes.

Location:

  • Between adjacent epithelial cells
  • Mainly seen in endothelial and epithelial cells
  • More basal than tight junctions

Composition:

  • Actin filaments
    • Intracellular 
    • Part of the cytoskeleton
  • E-cadherins
    • Transmembrane adhesion protein
    • Calcium dependent
    • Form homodimers
  • Actin filaments and E-cadherins are connected by vinculin and catenin. 
    • Catenins bind cadherin.
    • Catenins may also bind to the actin cytoskeleton.

Function:

  • Maintaining cells in a belt shape
  • Anchoring cells 
  • Providing strength
  • Maintaining cell shape (may serve a role in the actin contractile ring)
Adherens junctions interact with actin filaments through its proteins such as cadherin and catenin.

Adherens junctions interact with actin filaments through their proteins, such as cadherin and catenin.

Image: “Principal interactions of structural proteins at cadherin-based adherens junction” by Mariana Ruiz . License: Public Domain

Demosome

Definition:

Desmosomes are strong structures that assist in cellular adhesion, tethering intermediate filaments to the plasma membrane. These structures are also known as macula adherens or spot desmosomes.

Location:

  • Located between adjacent cells
  • Found in epithelial cells, cardiomyocytes (intercalated discs)
  • Generally, found in cells that are under large amounts of mechanical stress

Composition:

  • Desmosomal plaque:
    • Made of cadherin proteins
      • Desmoglein: a cellular adhesion protein
      • Desmocollin: a cellular adhesion protein
    • Located on the cytoplasmic side of the cell membrane
  • Keratin intermediate filaments
  • Desmin filaments

Function:

  • Structural support
  • Maintains cell structure against mechanical force

Disease:

Several diseases are associated with desmosomes. Cardiomyopathy and blistering conditions have been linked with mutations in the desmosome family of proteins. 

  • Arrhythmogenic cardiomyopathy (CM)
  • Pemphigus vulgaris
  • Pemphigus foliaceus
Desmosomes linking together adjacent cells

Desmosomes linking together adjacent cells

Image by Lecturio.

Hemidesmosome

Definition:

Hemidesmosomes are small specialized structures that function to connect a cell to the extracellular matrix. 

Location:

  • Found on the basal side of the epithelial cell
  • Located between the cell and the extracellular matrix, connecting basal epithelial cells to the lamina lucida
  • Mainly found in keratinocytes of the skin

Composition:

  • 2 classifications of hemidesmosomes:
    • Type 1
      • Located in stratified and pseudostratified epithelium
      • Contain 5 main proteins
    • Type 2: contain fewer proteins
  • Multiprotein complex:
    • Integrin (transmembrane linker)
    • Keratin filaments
    • Basement membrane (laminin, collagen)
  • Integrins integrate the intracellular cytoskeleton (keratin) to the basement membrane.

Function:

  • Forms the dermal–epidermal junction
  • Firm adhesion of cells to basement membrane

Disease:

Hemidesmosomes are important for keeping keratinocytes attached to the basal lamina. Disease of these structures leads to blistering conditions (epidermolysis bullosa)

Types of cell Junctions

Illustration of the 3 types of anchoring junctions that maintain cell shape

Image: “Types of Cell Junctions” by OpenStax College. License: CC BY 3.0, edited by Lecturio.

Gap Junctions

Definition

Gap junctions are protein channels that connect the cytoplasm of 2 cells to allow for molecular passage. This structure may also be called a nexus or macula communicans.

Gap cell junction

Gap junctions between 2 adjacent cells with multiple connexons

Image: “Gap cell junction” by Mariana Ruiz . License: Public Domain, edited by Lecturio.

Location

  • Located between adjacent epithelial cells
  • Found in any nonmotile cell in the body (not found in motile cells such as sperm)
  • Most often found in cardiac cells and retinal cells

Composition

  • Connexons make up the gap junction.
    • Made of 6 connexin proteins that span transmembranes
    • Form a tube with pores on either end
    • A pair of connexons connect within the intercellular space.
  • The intercellular space is between 2 and 4 nm.
  • Hemichannels consisting of the same proteins are called homomeric.
  • Hemichannels consisting of different proteins are called heteromeric.
Gap junction

Illustration of a gap junction

Image: “Types of Cell Junctions” by OpenStax College. License: CC BY 3.0, edited by Lecturio.

Function

  • Act as a way to communicate between cells
  • Form channels that permit exchange of:
    • Ions (electrical impulses)
    • Regulatory molecules (cytokines)
    • Metabolites
  • Allow for coupling of the electrical and metabolic functions between cells
  • Mediate activation of 2nd messengers and their impacts on cellular function
  • Adhesive capability between neighboring cells

Clinical Relevance

  • Metastasis: loss of E-cadherin function results in weakening in the anchoring of cells via the adherens junction. The loss of E-cadherin has been shown to increase cancer (CA) cell invasion. Cancer cells may migrate, causing metastasis without the functionality of the adherens junction.
  • Pemphigus vulgaris: a disease that is a type II hypersensitivity reaction whereby autoantibodies target the desmosome complex (desmogelin), which results in the loss of structural integrity, especially during shear forces on epidermis, causing the dermal layer to slide off, forming bullae. Despite being a rare condition, pemphigus vulgaris is the most common form of pemphigus. The condition is progressive without treatment. The primary treatment is a corticosteroid.
  • Bullous pemphigoid: a type II hypersensitivity reaction whereby autoantibodies target the hemidesmosome complex (desmogelin), which results in the loss of connection of the epidermis to the dermal basement membrane. Diagnosis requires a classic clinical presentation and confirmatory findings on biopsy. Patients present with tense bullae that rupture. Topical steroids are the main treatment modality.

References

  1. Alberts, B, Johnson, A, Lewis, J, et al. (2002). Cell junctions. Molecular Biology of the Cell, 4th Edition. New York: Garland Science. Available from: https://www.ncbi.nlm.nih.gov/books/NBK26857/.
  2. (2016). Guyton and Hall textbook of medical physiology (13th edition.). Philadelphia, PA: Elsevier.
  3. Goodenough, DA, & Paul, DL. Gap junctions. (2009). Cold Spring Harb Perspect Biol. 2009;1(1):a002576. doi:10.1101/cshperspect.a002576
  4. Meng, W, & Takeichi, M. (2009). Adherens junction: Molecular architecture and regulation. Cold Spring Harb Perspect Biol. 2009;1(6):a002899. doi:10.1101/cshperspect.a002899
  5. Muse, ME, & Crane, JS. Physiology, epithelialization. [Updated 2021 Apr 29]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK532977/.

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