المحاضرة الثالثة فسيو (قبل التعديل)

Intercellular Connections

• Tight junctions (zonula occludens) are the key structural component of epithelial cell apical borders - Their core function is to tightly bind cells together, holding tissues in place and providing strength.
• Desmosomes (zonula adherens) act like spot welds for cells, providing structural support and stability to tissues. They primarily operate at the cell-cell interface, but also contribute to the cell's connection to its basal lamina.
• Gap junctions are crucial for intercellular communication - These junctions provide a pathway for the exchange of ions and molecules between neighboring cells. This ability is critical for the functioning of various tissues, including cardiac and smooth muscle.

Cell Communication

• Cells in multicellular organisms engage in communication through chemical messengers - They rely on a combination of local signaling (paracrine and synaptic signaling) and long-distance signaling (endocrine).
• Paracrine signalling: involves the release of chemical messengers that affect neighboring cells.
• Autocrine signalling: occurs when cells produce and release messengers that act on themselves.
• Juxtacrine signalling: requires direct contact between cells, with chemical messengers interacting with receptors on adjacent cells.

Hormone Action

• Earl Sutherland (1971 Nobel Prize Winner) identified the mechanism behind epinephrine's action on cells. - He proposed the three-step process of reception, transduction, and response.
• Reception: Cells use receptor proteins to detect specific ligands - These receptors can be either intracellular or cell-surface based.
• Transduction: is the process of converting the signal received by the receptor into a form that can trigger a specific response.
• Response: The signal, now transduced, elicits a specific cellular response.

Receptor Types

• Intracellular receptors: can bind to ligands that readily cross cell membranes. - Examples include steroid and thyroid hormones.
• Cell-surface receptors: are transmembrane proteins with three distinct domains:
  • External ligand-binding domain
  • Membrane-spanning region
  • Intracellular domain
• Types of cell-surface receptors:
  • Ligand-gated ion channel receptors: open a channel for ions to pass through upon ligand binding.
  • G-protein coupled receptors: activate G proteins, which in turn regulate downstream signaling pathways, leading to various responses.
  • Enzyme-linked receptors: have intracellular domains associated with enzymes, which become activated upon ligand binding.

Intercellular Connections

• Cells are connected by tight junctions, desmosomes, and gap junctions.
• Tight junctions are located at the apical borders of cells and hold cells together.
  • They can be tight (impermeable) or leaky (permeable).
  • Involved in the formation of epithelial tissues.
• Desmosomes provide strength and stability to epithelial tissues.
  • They act as cell-to-cell junctions.
• Gap junctions allow the transfer of small molecules between cells.
  • Consist of connexons (six subunits of connexins forming pathways for molecules).
  • Found in cardiac and smooth muscles, epithelial cells, and neurons.

Cellular Communication

• Cells communicate through local regulators (short distances, paracrine) and hormones (long distances, endocrine).
• Local regulators include paracrine and synaptic signals.
  • Paracrine are chemical signals released from a nearby cell and act on target cells in the vicinity.
  • Synaptic signals are released by neurons and act on target cells across synapses.
• Hormone action is categorized as paracrine, autocrine, and juxtacrine.
  • Paracrine: cells release hormones that act on neighboring cells.
  • Autocrine: cells release hormones that act on themselves.
  • Juxtacrine: cells release hormones that act on cells in direct contact.

Hormone Action

• Epinephrine's action on cells is defined by three key processes:
  • Reception: Binding of a signaling molecule to a specific receptor.
  • Transduction: Conversion of the signal to a form that can elicit a response.
  • Response: The cellular response to the signal.
• Receptors can be intracellular or cell-surface:
  • Intracellular receptors are located inside the cell and bind to hydrophobic molecules.
  • Cell-surface receptors are located on the cell membrane and bind to hydrophilic molecules.

Types of Receptors

• Intracellular receptors are found in the cytoplasm or nucleus.
  • They bind to steroid hormones (cytoplasmic) and thyroid hormones (nuclear).
• Cell-surface receptors have three main components:
  • External ligand-binding domain (extracellular domain)
  • Membrane-spanning region
  • Intracellular domain
• Types of cell-surface receptors:
  • Ligand-gated ion channel receptors: Ligand binding opens the channel, allowing ions to pass through.
  • G protein-coupled receptors: Ligand binding activates a G protein which then interacts with either an ion channel or an enzyme (e.g., adenyl cyclase).
  • Enzyme-linked receptors (tyrosine kinase receptors): Ligand binding stimulates phosphorylation of tyrosine residues on the receptor, activating downstream signaling pathways.

Second Messengers

• Second messengers are small molecules that relay signals from receptors to intracellular targets.
  • Examples include cyclic AMP (cAMP) and calcium ions (Ca2+).
• Key processes in cell signaling:
  • Activation of enzymes by second messengers.
  • Alteration of gene expression through the activation of transcription factors.

Intercellular Connections and Communications

• Tight junctions are attachments between cells at their apical borders, present in epithelial cells like renal proximal tubules, distal tubules, and the gall bladder.
• Desmosomes fasten cells to one another and surrounding tissues, providing strength and stability, present in epithelial cells.
• Gap junctions permit transfer of ions and other molecules from one cell to another, present in cardiac, smooth muscles, and epithelial cells
• Hemidesmosome & focal adhesion attach cells to their basal laminas.
• Tight junctions are impermeable to solutes and water in renal distal tubules and permeable to solutes and water in renal proximal tubules or gall bladder.
• Gap junctions provide low resistance pathways for the spread of ionic currents in cardiac and smooth muscles.
• Gap junctions facilitate the passage of metabolites and intercellular signals between cells.

Cell Communication

• Cells in a multicellular organism communicate by chemical messengers.
• Local signaling uses local regulators, messenger molecules that travel short distances.
• Long-distance signaling uses hormones, chemical messengers that travel long distances.
• Paracrine signaling utilizes chemical substances that diffuse through the interstitial space to affect neighboring cells.
• Autocrine signaling relies on a chemical substance acting on the same cells that produce them.
• Juxtacrine signaling involves interactions between chemical substances and specific receptors on juxtaposed cells.

Hormone Action

• Three processes are involved in cellular response to hormones:
  • Reception: Binding of a ligand to a protein on the cell surface or within the target cell.
  • Transduction: Conversion of the signal into a form that can trigger a specific cellular response.
  • Response: The specific cellular response to the signal.
• Receptors are protein molecules that bind ligands. There are two types:
  • Intracellular receptors found in the cytosol or nucleus of target cells.
  • Cell surface receptors located on the outer surface of the cell membrane.

Intracellular Receptors

• Intracellular receptors bind to steroid (cytoplasmic) and thyroid (nuclear) hormones.
• Steroid hormones readily cross the cell membrane and activate receptors inside the cytoplasm.
• Activated hormone-receptor complex (HRC) can act as a transcription factor, binding to specific regions of DNA called hormone response elements (HRE) to increase the transcription of specific genes into proteins.

Cell Surface Receptors

• They have three main components:
  • External ligand-binding domain: Binds ligands outside the cell.
  • Membrane-spanning region: Extends through the cell membrane.
  • Intracellular domain: Located inside the cell.
• Three main types of cell surface receptors:
  • Ligand-gated ion channel receptors: Open a channel through the membrane allowing specific ions to pass through upon binding to a ligand.
  • G protein-coupled receptors: Activate a membrane protein called a G protein upon ligand binding.
  • Enzyme-linked receptors: Have intracellular domains associated with enzymes, such as tyrosine kinase receptors, which activate specific downstream signaling pathways upon ligand binding.

Ligand-Gated Ion Channel Receptors

• Bind a ligand and open a channel through the membrane allowing specific ions to pass through.
• Lined with hydrophilic amino acids to facilitate the passage of ions.
• Conformational changes induced by ligand binding allow ions such as sodium, calcium, magnesium, and hydrogen to pass.

G Protein-Coupled Receptors

• Activate a membrane protein called a G protein (containing alpha, beta, and gamma subunits) upon ligand binding.
• The alpha subunit interacts with either an ion channel or an enzyme, such as adenyl cyclase or phospholipase C.
• Activation of these enzymes leads to increased production of second messengers, such as cAMP, inside the cell.

Enzyme-Linked Receptors

• Cell surface receptors with intracellular domains associated with enzymes, such as tyrosine kinase receptors.
• When a chemical messenger binds to the extracellular domain of two nearby tyrosine kinase receptors, they dimerize.
• Phosphorylation of tyrosine residues on the intracellular domains by the activated tyrosine kinases initiate downstream signaling pathways.

Intercellular Connections

• Tight junctions (Zonula Occludens) fasten cells together at their apical borders, providing strength and stability. They are present in epithelial cells of renal tubules, gall bladder, and other tissues. Tight junctions form a barrier that regulates the passage of ions and other molecules between cells.
• Desmosomes (Zonula Adherens) are also cell-to-cell attachments that provide strength and stability.
• Gap junctions allow direct communication between cells. They are found in cardiac and smooth muscle cells, epithelial cells, and other tissues. Gap junctions consist of channels that allow the movement of small molecules and ions between cells.
• Hemidesmosomes and focal adhesions connect cells to the extracellular matrix.

Intercellular Communication

• Cells communicate by chemical messengers, which can act over short or long distances.
• Local signaling involves short-range communication.
  • Paracrine signaling occurs between neighboring cells.
  • Autocrine signaling occurs when a cell releases a signal that binds to receptors on its own surface.
• Long-distance signaling involves hormones (endocrine signaling). Hormones are secreted by cells in endocrine glands and travel throughout the body to target cells.
• Synaptic signaling involves the release of neurotransmitters from nerve cells.

Mechanisms of Hormone Action

• The action of hormones can be classified as:
  • Paracrine: Hormones act on neighboring cells.
  • Autocrine: Hormones act on the same cells that produced them.
  • Juxtacrine: Hormones act on adjacent cells through direct contact.

Three Processes Involved in Hormone Signaling

• Reception: The hormone binds to a specific receptor protein on or within the target cell. Receptors can be intracellular or cell-surface.
• Transduction: The receptor binding triggers a series of intracellular events, often involving signal transduction pathways.
• Response: The signal transduction pathway leads to a specific cellular response, such as gene expression or enzyme activation.

Types of Receptors

• Intracellular receptors: Found within the cytoplasm or nucleus of the target cell. They bind to small, hydrophobic molecules, like steroid hormones and thyroid hormones.
• Cell-surface receptors: Found on the plasma membrane of the target cell. They bind to water-soluble signaling molecules.
• Ligand-gated ion channel receptors: These open or close ion channels in response to ligand binding.
• G protein-coupled receptors: Activate G proteins, which in turn activate signal transduction pathways.
• Enzyme-linked receptors: These have an intracellular domain that is associated with an enzyme, like tyrosine kinase.

Mechanism of Action of Intracellular Receptors

• Intracellular receptors bind to steroid and thyroid hormones that can diffuse across the cell membrane.
• The hormone-receptor complex binds to DNA, acting as a transcription factor that activates transcription of specific genes.

Structure of Cell-Surface Receptors

• Each cell-surface receptor has three main components:
  • Extracellular domain: Binds to the ligand.
  • Membrane-spanning region: Anchors the receptor in the membrane.
  • Intracellular domain: Mediates signaling within the cell.

Types of Cell Surface Receptors

• Ligand-gated ion channel receptors: Open or close ion channels in response to ligand binding.
• G protein-coupled receptors: Activate G proteins, which in turn activate signal transduction pathways.
• Enzyme-linked receptors: Have an intracellular domain that is associated with an enzyme, like tyrosine kinase.

Intercellular Connections

• Tight junctions are located at the apical borders of cells.
  • They hold cells together and provide strength and stability to tissues.
• Desmosomes act as a strong adhesive junction.
  • They fasten cells to one another.
  • They provide tissues with strength and stability.
• Gap junctions are direct connections between cells that permit intercellular communications.
  • They are present in cardiac, smooth muscle, and epithelial cells.
  • They allow the transfer of ions and other molecules between cells.

Intercellular Communications

• Local signaling uses chemical messengers called local regulators that travel short distances.
  • Paracrine signals affect neighboring cells.
  • Synaptic signals are released by nerve cells and act on target cells.
• Long-distance signaling uses hormones.
  • Hormones are produced in endocrine cells and travel throughout the body via the bloodstream.
  • Target cells must have specific receptors for hormones to elicit a response.

Mechanisms of Hormone Action

• Paracrine signaling involves a chemical substance diffusing through the interstitial space to affect neighboring cells.
• Autocrine signaling involves a chemical substance acting on the same cells that produce them.
• Juxtacrine signaling involves a chemical substance interacting with specific receptors on juxtaposed cells.

Three Processes of Cell Signaling

• Reception: a ligand binds to a specific receptor protein on the target cell.
  • Intracellular receptors are located in the cytosol or nucleus.
    • They bind to steroid hormones, which are small enough to cross the cell membrane, and thyroid hormones.
  • Cell surface receptors are located on the cell membrane.
    • They bind to larger, water-soluble ligand molecules that cannot penetrate the membrane.
• Transduction: the binding of a ligand to a receptor triggers a series of events within the cell, leading to a response.
• Response: the signal transduction pathway ultimately leads to a specific cellular response.

Cell Surface Receptors

• Ligand-gated ion channel receptors are membrane proteins containing a channel that opens when a ligand binds.
  • They allow specific ions to pass through.
• G-protein coupled receptors are membrane proteins linked to trimeric G-proteins (α, β, and γ subunits).
  • Binding of a ligand activates the G-protein, which can then interact with either an ion channel or an enzyme.
• Enzyme-linked receptors are cell-surface receptors with intracellular domains associated with specific enzymes.
  • For example, tyrosine kinase receptors are activated by the binding of a ligand, which triggers phosphorylation events within the cell.

Note

• Most water-soluble signal molecules bind to specific sites on receptor proteins that span the plasma membrane.

Key Facts

• Earl Sutherland won the Nobel Prize in 1971 for his discovery of cyclic AMP and hormone action.
• Sutherland proposed the three processes of cell signaling: reception, transduction, and response.
• Most hormones are water-soluble and cannot cross the cell membrane, requiring a cell surface receptor.
• The specific response to a signal depends on the type of receptor and the combination of signal transduction pathways activated.