Cell Junctions Lecture Notes

Cell Junctions

Learning Objectives

• Describe the structure and function of the main types of cell junctions.
• Recognize the importance of cell junctions.
• Understand transmembrane adhesion proteins and their roles in different cell junctions.

Introduction to Cell Junctions

• Membranes of adjacent cells can join to form cell junctions.
• Specialized cell junctions occur between cell-cell and cell-extracellular matrix in all tissues.
• They are particularly abundant in epithelia.
• Cell junctions are crucial for the construction of tissues and organs, influencing their shape, strength, and arrangement of cell types.
• Cell junctions and the extracellular matrix are critical for the organization, function, and dynamics of multicellular structures.

Types of Cell Junctions

1. Tight Junctions
   • Seal cells together into sheets, forming an impermeable barrier.
   • Prevent molecules from passing through the intercellular space.
   • Intercellular space is almost eliminated; outer surfaces of the two cell membranes appear in contact or even fused.
2. Anchoring Junctions
   • Attach cells (and their cytoskeleton) to other cells or the extracellular matrix.
   • Provide mechanical support.
3. Communicating Junctions
   • Allow the exchange of chemical/electrical information between cells.
   • Allow ions and small molecules to pass for intercellular communication.

Detailed Types of Cell Junctions

Anchoring Junctions

1. Adherens (cell-cell junctions)
2. Actin-linked cell–matrix (cell-matrix junctions)
3. Desmosomes (cell-cell junctions)
4. Hemidesmosomes (cell-matrix junctions)

Functions of Anchoring Junctions

• The lipid bilayer is delicate and cannot withstand large forces from cell-cell or from the cell-extracellular matrix.
• Anchoring junctions:
  1. Provide strength to the cell by acting like a mechanical attachment.
  2. Provide firm structural attachment between two cells or a cell and the extracellular matrix.
  3. Offer resistance against external forces that pull cells apart.
  4. Maintain structural integrity for the tissue.
• Most abundant in tissues subjected to severe mechanical stress (e.g., heart, muscle, and epidermis).
• Epithelial cells of the skin must remain tightly linked when stretched, pinched, or poked.
• Cell-cell anchoring junctions must be dynamic and adaptable for tissue remodeling, repair, or changes in forces.

Composition of Anchoring Junctions

Two main classes of proteins:

1. Intracellular Adaptor Proteins
   • Form a distinct plaque on the cytoplasmic face of the plasma membrane.
   • Connect the junction to either actin filaments or intermediate filaments.
2. Transmembrane Adhesion Proteins
   • Have a cytoplasmic tail that binds to one or more intracellular adaptor proteins.
   • Have an extracellular domain that interacts with either the extracellular matrix or the extracellular domains of specific transmembrane adhesion proteins on another cell.

Forms of Anchoring Junctions

1. Adherens junctions and desmosomes:
   • Hold cells together.
   • Formed by transmembrane adhesion proteins that belong to the cadherin family.
2. Hemidesmosomes and actin-linked junctions:
   • Bind cells to the extracellular matrix.
   • Formed by transmembrane adhesion proteins of the integrin family.

On the intracellular side of the membrane:

• Adherens junctions and actin-linked junctions serve as connection sites for actin filaments.
• Desmosomes and hemidesmosomes serve as connection sites for intermediate filaments.

Adherens Junctions

• Epithelial cells are held together by strong anchoring (adherens) junctions.
• The adherens junction lies below the tight junctions.
• In the gap between the two cells, there is a protein called cadherin:
  • The type of cadherin found in epithelial cells is E-cadherin.
  • The cadherins from adjacent cells interact to connect the two cells together.
• Inside the cell, actin filaments join up these junctions.
• The actin filament is attached to the membrane through a set of intracellular adaptor proteins (including catenins, vinculin, and α-actinin).
• Adherens junctions often occur in epithelia, where they often form a continuous adhesion belt (or zonula adherens) just below the tight junctions.
• The adhesion belts are directly next to each other in adjacent epithelial cells.

Desmosomes

• Desmosomes connect two cells together.
• A desmosome is also known as a spot desmosome because it is circular or spot-like in outline, not belt or band-shaped like adherens junctions.
• Desmosomes are structurally similar to adherens junctions but contain specialized cadherins that link to intermediate filaments.
• Desmosomes are particularly common in epithelia that need to withstand abrasion (e.g., skin).
• Provide mechanical strength in tissues such as heart muscle and the epidermis (the epithelium that forms the outer layer of the skin).
• Forms a structural framework (flexible and strong).
• The particular type of intermediate filaments attached to the desmosomes depends on the cell type:
  • Keratin filaments in most epithelial cells.
  • Desmin filaments in heart muscle cells.
• It has a dense cytoplasmic plaque composed of a complex of intracellular adaptor proteins (plakoglobin and desmoplakin) that are responsible for connecting the cytoskeleton to the transmembrane adhesion proteins.
• The adhesion proteins (desmoglein and desmocollin) belong to the cadherin family.

Hemidesmosomes

• These look similar to desmosomes but are different functionally and in their structure/proteins.
• They connect the basal surface of epithelial cells via intermediate filaments to the underlying basal lamina.
• The transmembrane proteins of hemidesmosomes are called integrins.

Anchoring Junction Summary

Tight Junctions

• The borders of two cells are fused together, often around the whole perimeter of each cell, forming a continuous belt-like junction known as a tight junction or zonula occludens.
• These regions of the cells are very tightly connected together such that the adjacent plasma membranes are sealed together.
• It prevents leaking from one side of the sheet to the other.
• Transmembrane adhesion proteins called occludin and claudin interact with each other in the membrane of adjacent cells.
• In the cytoplasm of the cell, occludin interacts with the actin cytoskeleton via proteins called zonula occludens.
• All epithelia have at least one function in common: they serve as selectively permeable barriers, separating the fluid that permeates the tissue on their basal side from fluid with a different chemical composition on their apical side.
• This barrier function requires that the adjacent cells be sealed together by tight junctions so that molecules cannot leak freely across the cell sheet.
• For example, these junctions are important in the gut, acting as a selective diffusion barrier, preventing diffusion of water-soluble molecules.
• The epithelial cells lining the small intestine form a barrier that keeps the gut contents in the gut cavity.

Functions of Tight Junctions

1. Strength and stability
2. Selectively permeable for ions
3. Fencing function
4. Maintenance of cell polarity
5. Blood-brain barrier

Communicating Junctions

Types of communicating junctions:

1. Gap junctions
2. Plasmodesmata (plants only)

• These junctions allow the intercellular exchange of substances (e.g., ions and molecules from one cell to another cell).
• Channel-forming junctions that create passageways linking the cytoplasm of adjacent cells.
• They are present in most animal tissues (connective tissues, epithelia, and heart muscle).

Function of Gap Junctions

• Gap junctions provide communication channels between adjacent cells.
• In tissues containing electrically excitable cells:
  • Some nerve cells, for example, are electrically coupled, allowing action potentials to spread rapidly from cell to cell without the delay that occurs at chemical synapses.
  • Electrical coupling through gap junctions synchronizes the contractions of both heart muscle cells and the smooth muscle cells responsible for the peristaltic movements of the intestine.
• Gap junctions also occur in many tissues that do not contain electrically excitable cells:
  • The sharing of small metabolites and ions provides a mechanism for coordinating the activities of individual cells in such tissues and for smoothing out random fluctuations in small molecule concentrations in different cells.
• A group of protein molecules called connexins form a structure called a connexon.
• When connexons from two adjacent cells align, they form a continuous channel between them.
• Gap junctions have a pore size of about $1.4 nm$, which allows the exchange of inorganic ions and other small water-soluble molecules, but not of macromolecules such as proteins or nucleic acids.
• Couples the cells both electrically and metabolically.
• Most cells in animal tissues are in communication with their neighbors via gap junctions.
• An electric current injected into one cell through a microelectrode causes an electrical disturbance in the neighboring cell due to the flow of ions carrying electric charge through gap junctions.

Plasmodesmata

• Plant cells have only one class of intercellular junction called plasmodesmata.
• Plasmodesmata perform many of the same functions as gap junctions.
• In plants, the cytoplasm is continuous from one cell to the next, allowing the passage of both small and large molecules (including some proteins and regulatory RNAs).
• The tissues of a plant are organized differently to those of an animal.
  • Plant cells are within rigid cell walls composed of an extracellular matrix rich in cellulose and other polysaccharides.
  • The cell walls of adjacent cells are firmly attached to those of their neighbors, which eliminates the need for anchoring junctions to hold the cells in place.
• The plasma membrane of one cell is continuous with that of its neighbor at each plasmodesma, and the cytoplasm of the two cells is connected by a roughly cylindrical channel.
• The cells of a plant can be viewed as forming a syncytium, in which many cell nuclei share a common cytoplasm.
• The cytoplasmic channels of plasmodesmata pierce the plant cell wall and connect all cells in a plant together.
• Running through the center of the channel in most plasmodesmata is a narrower cylindrical structure, the desmotubule, which is continuous with elements of the smooth endoplasmic reticulum (ER) in each of the connected cells.

Cell Junctions Summary

Transmembrane Adhesion Proteins

• Cell junctions are made up of transmembrane adhesion proteins
  • Important cell surface proteins molecules promoting cell-cell and cell-matrix interactions.
  • Important for many normal biological processes (immune system functions, wound healing).
  • Involved in intracellular signaling pathways (primarily for cell death/survival, secretion etc.).

Structure of Transmembrane Adhesion Proteins

• Also known as cell adhesion molecules (CAM)
• They express 3 major domains:
  • The extracellular domain allows one CAM to bind to another on an adjacent cell.
  • The cytoplasmic domain is directly connected to the cytoskeleton by linker proteins.

Cadherins

• Cadherins are present in all multicellular animals.
• Transmembrane glycoproteins.
• Form desmosomes and adherens junctions (cell-cell connection).
• Do not interact with extracellular matrix.
• They are dependent on $Ca^{2+}$ ions (removing $Ca^{2+}$ from the extracellular medium causes adhesions mediated by cadherins to come apart).
• E-cadherin is present on many types of epithelial cells.
• N-cadherin is present on nerve, muscle, and lens cells.
• P-cadherin is present on cells in the placenta and epidermis.

Integrins

• Integrins are transmembrane proteins.
• Integrins connect the extracellular matrix to the cytoskeleton in the cell through cytosolic proteins.
• Cell-matrix connection.